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Background: Increased spatial and temporal dispersion of repolarization contributes to ventricular arrhythmogenesis. Beat-to-beat fluctuations in T-wave timing are thought to represent such dispersion and may predict clinical events.Objective: The purpose of this study was to assess whether a novel noninvasive measure of beat-to-beat instability in T-wave timing would provide additive prognostic information in post-myocardial infarction patients.Methods: We studied 678 patients from 12 hospitals with 32-lead 5-minute electrocardiogram recordings 6-8 weeks after myocardial infarction. Custom software identified R wave-to-T wave intervals (RTIs) and diastolic intervals (DIs). Repolarization scatter (RTI:DI(StdErr)) was then calculated as the standard error about the RTI:DI regression line. In addition, left ventricular ejection fraction (LVEF), short-term heart rate variability (HRV) parameters, and QT variability index were measured. Patients were followed for the composite endpoint of death or life-threatening ventricular arrhythmia.Results: After a mean follow-up of 63 months, 134 patients met the composite endpoint. An RTI:DI(StdErr) >5.50 ms was associated with a 210% increase in arrhythmias or deaths (P <.001). After adjusting for LVEF, RTI:DI(StdErr) remained an independent predictor (P <.001). RTI:DI(StdErr) was also independent of short-term HRV parameters and the QT variability index.Conclusions: Increased repolarization scatter, a measure of high-frequency, cycle-length-dependent repolarization instability, predicts poor outcomes in patients after myocardial infarction. [ABSTRACT FROM AUTHOR]

Background: Thoracic epidural anesthesia (TEA) has been shown to reduce the burden of ventricular tachycardia in small case series of patients with refractory ventricular tachyarrhythmias and cardiomyopathy. However, its electrophysiological and autonomic effects in diseased hearts remain unclear, and its use after myocardial infarction is limited by concerns for potential right ventricular dysfunction., Methods: Myocardial infarction was created in Yorkshire pigs (N=22) by left anterior descending coronary artery occlusion. Approximately, six weeks after myocardial infarction, an epidural catheter was placed at the C7-T1 vertebral level for injection of 2% lidocaine. Right and left ventricular hemodynamics were recorded using Millar pressure-conductance catheters, and ventricular activation recovery intervals (ARIs), a surrogate of action potential durations, by a 56-electrode sock and 64-electrode basket catheter. Hemodynamics and ARIs, baroreflex sensitivity and intrinsic cardiac neural activity, and ventricular effective refractory periods and slope of restitution (S max ) were assessed before and after TEA. Ventricular tachyarrhythmia inducibility was assessed by programmed electrical stimulation., Results: TEA reduced inducibility of ventricular tachyarrhythmias by 70%. TEA did not affect right ventricular-systolic pressure or contractility, although left ventricular-systolic pressure and contractility decreased modestly. Global and regional ventricular ARIs increased, including in scar and border zone regions post-TEA. TEA reduced ARI dispersion specifically in border zone regions. Ventricular effective refractory periods prolonged significantly at critical sites of arrhythmogenesis, and S max was reduced. Interestingly, TEA significantly improved cardiac vagal function, as measured by both baroreflex sensitivity and intrinsic cardiac neural activity., Conclusions: TEA does not compromise right ventricular function in infarcted hearts. Its antiarrhythmic mechanisms are mediated by increases in ventricular effective refractory period and ARIs, decreases in S max , and reductions in border zone electrophysiological heterogeneities. TEA improves parasympathetic function, which may independently underlie some of its observed antiarrhythmic mechanisms. This study provides novel insights into the antiarrhythmic mechanisms of TEA while highlighting its applicability to the clinical setting., Competing Interests: M. Vaseghi has patents related to neuromodulation at the University of California, Los Angeles, and has performed educational consulting for Biosense Webster, Medtronic, and Recor, Inc, and has shares in NeuCures and Anumana, Inc. The other authors report no conflicts.

Background: Mapping techniques to identify diseased myocardial substrate during ventricular tachycardia ablation procedures remain limited., Objective: We hypothesized that tissue derivative of the voltage with respect to time (dV/dt), the slope of the unipolar ventricular electrogram registered by local ventricular activation, represents a unique parameter for identifying potential arrhythmogenic tissue in the ischemic scar border zone., Methods: Using high-resolution electrical mapping, we examined dV/dt characteristics in the border zone of animals after chronic myocardial infarction (MI)., Results: Minimum dV/dt (dV/dt min ) in MI animals was less than that in control animals (-344.7 ± 68.7 in controls vs -174.2 ± 104.5 in MI; P < .001) and related to ventricular fibrosis. In MI animals, dV/dt min values were divided into high (≤-200 μV/ms) and low (>-200 μV/ms) dV/dt min . Low dV/dt min regions harbored arrhythmogenic substrates that were characterized by (1) high responsiveness to sympathetic stimulation, (2) presence of late potentials, and (3) lower unipolar and bipolar voltage amplitudes., Conclusion: Our data indicate that dV/dt min is a unique parameter for identifying arrhythmogenic myocardium and may add a useful metric to conventional mapping strategies., (Copyright © 2022. Published by Elsevier Inc.)

Objectives: The goal of this study was to evaluate whether intermittent VNS reduces electrical heterogeneities and arrhythmia inducibility during sympathoexcitation., Background: Sympathoexcitation increases the risk of ventricular tachyarrhythmias (VT). Vagal nerve stimulation (VNS) has been antiarrhythmic in the setting of ischemia-driven arrhythmias, but it is unclear if it can overcome the electrophysiological effects of sympathoexcitation in the setting of chronic myocardial infarction (MI)., Methods: In Yorkshire pigs after chronic MI, a sternotomy was performed, a 56-electrode sock was placed over the ventricles (n = 17), and a basket catheter was positioned in the left ventricle (n = 6). Continuous unipolar electrograms from sock and basket arrays were obtained to analyze activation recovery interval (ARI), a surrogate of action potential duration. Bipolar voltage mapping was performed to define scar, border zone, or viable myocardium. Hemodynamic and electrical parameters and VT inducibility were evaluated during sympathoexcitation with bilateral stellate ganglia stimulation (BSS) and during combined BSS with intermittent VNS., Results: During BSS, global epicardial ARIs shortened from 384 ± 59 milliseconds to 297 ± 63 milliseconds and endocardial ARIs from 359 ± 36 milliseconds to 318 ± 40 milliseconds. Dispersion in ARIs increased in all regions, with the greatest increase observed in scar and border zone regions. VNS mitigated the effects of BSS on border zone ARIs (from -18.3% ± 6.3% to -2.1% ± 14.7%) and ARI dispersion (from 104 ms 2 [1 to 1,108 ms 2 ] to -108 ms 2 [IQR: -588 to 30 ms 2 ]). VNS reduced VT inducibility during sympathoexcitation (from 75%-40%; P < 0.05)., Conclusions: After chronic MI, VNS overcomes the detrimental effects of sympathoexcitation by reducing electrophysiological heterogeneities exacerbated by sympathetic stimulation, decreasing VT inducibility., Competing Interests: Funding Support and Author Disclosures This study was funded by National Institutes of Health R01 HL148190 (to Dr Vaseghi). Dr Vaseghi has shares in NeuCures Inc; and has patents on neuromodulation at University of California, Los Angeles. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose., (Copyright © 2022 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

[Figure: see text].

Background: The long QT syndrome (LQTS) is an arrhythmogenic disorder of QT interval prolongation that predisposes patients to life-threatening ventricular arrhythmias such as Torsades de pointes and sudden cardiac death. Clinical genetic testing has emerged as the standard of care to identify genetic variants in patients suspected of having LQTS. However, these results are often confounded by the discovery of variants of uncertain significance (VUS), for which there is insufficient evidence of pathogenicity., Objectives: The purpose of this study was to demonstrate that genome editing of patient-specific induced pluripotent stem cells (iPSCs) can be a valuable approach to delineate the pathogenicity of VUS in cardiac channelopathy., Methods: Peripheral blood mononuclear cells were isolated from a carrier with a novel missense variant (T983I) in the KCNH2 (LQT2) gene and an unrelated healthy control subject. iPSCs were generated using an integration-free Sendai virus and differentiated to iPSC-derived cardiomyocytes (CMs)., Results: Whole-cell patch clamp recordings revealed significant prolongation of the action potential duration (APD) and reduced rapidly activating delayed rectifier K + current (I Kr ) density in VUS iPSC-CMs compared with healthy control iPSC-CMs. ICA-105574, a potent I Kr activator, enhanced I Kr magnitude and restored normal action potential duration in VUS iPSC-CMs. Notably, VUS iPSC-CMs exhibited greater propensity to proarrhythmia than healthy control cells in response to high-risk torsadogenic drugs (dofetilide, ibutilide, and azimilide), suggesting a compromised repolarization reserve. Finally, the selective correction of the causal variant in iPSC-CMs using CRISPR/Cas9 gene editing (isogenic control) normalized the aberrant cellular phenotype, whereas the introduction of the homozygous variant in healthy control cells recapitulated hallmark features of the LQTS disorder., Conclusions: The results suggest that the KCNH2 T983I VUS may be classified as potentially pathogenic., (Copyright © 2018 American College of Cardiology Foundation. Published by Elsevier Inc. All rights reserved.)

Ventricular repolarization and its manifestation in the T wave of the electrocardiogram have long been a focus of clinical and experimental electrocardiology. In this short article, we shall review the basics of cellular and organ repolarization electrophysiology, the classical and emerging methods of measuring global repolarization, and methodology that relates directly measured cardiac indices of repolarization to the body surface electrocardiogram., (Copyright © 2017 Elsevier Inc. All rights reserved.)

Single high-intensity premature stimuli when applied to the ventricles during ventricular drive of an ectopic site, as in Winfree's "pinwheel experiment," usually induce reentry arrhythmias in the normal heart, while single low-intensity stimuli barely do. Yet ventricular arrhythmia vulnerability during normal sinus rhythm remains largely unexplored. With a view to define the role of anisotropy on ventricular vulnerability to unidirectional conduction block and reentry, we revisited the pinwheel experiment with reduced constraints in the in situ rat heart. New features included single premature stimulation during normal sinus rhythm, stimulation and unipolar potential mapping from the same high-resolution epicardial electrode array, and progressive increase in stimulation strength and prematurity from diastolic threshold until arrhythmia induction. Measurements were performed with 1-ms cathodal stimuli at multiple test sites ( n = 26) in seven rats. Stimulus-induced virtual electrode polarization during sinus beat recovery phase influenced premature ventricular responses. Specifically, gradual increase in stimulus strength and prematurity progressively induced make, break, and graded-response stimulation mechanisms. Hence unidirectional conduction block occurred as follows: 1 ) along fiber direction, on right and left ventricular free walls ( n = 23), initiating figure-eight reentry ( n = 17) and tachycardia ( n = 12), and 2 ) across fiber direction, on lower interventricular septum ( n = 3), initiating spiral wave reentry ( n = 2) and tachycardia ( n = 1). Critical time window (55.1 ± 4.7 ms, 68.2 ± 6.0 ms) and stimulus strength lower limit (4.9 ± 0.6 mA) defined vulnerability to reentry. A novel finding of this study was that ventricular tachycardia evolves and is maintained by episodes of scroll-like wave and focal activation couplets. We also found that single low-intensity premature stimuli can induce repetitive ventricular response ( n = 13) characterized by focal activations. NEW & NOTEWORTHY We performed ventricular cathodal point stimulation during sinus rhythm by progressively increasing stimulus strength and prematurity. Virtual electrode polarization and recovery gradient progressively induced make, break, and graded-response stimulation mechanisms. Unidirectional conduction block occurred along or across fiber direction, initiating figure-eight or spiral wave reentry, respectively, and tachycardia sustained by scroll wave and focal activations., (Copyright © 2017 the American Physiological Society.)

The influence of cardiac sympathetic innervation on electrical activation in normal and chronically infarcted ventricular myocardium is not understood. Yorkshire pigs with normal hearts (NL, n = 12) or anterior myocardial infarction (MI, n = 9) underwent high-resolution mapping of the anteroapical left ventricle at baseline and during left and right stellate ganglion stimulation (LSGS and RSGS, respectively). Conduction velocity (CV), activation times (ATs), and directionality of propagation were measured. Myocardial fiber orientation was determined using diffusion tensor imaging and histology. Longitudinal CV (CV L ) was increased by RSGS (0.98 ± 0.11 vs. 1.2 ± 0.14m/s, P < 0.001) but not transverse CV (CV T ). This increase was abrogated by β-adrenergic receptor and gap junction (GJ) blockade. Neither CV L nor CV T was increased by LSGS. In the peri-infarct region, both RSGS and LSGS shortened ARIs in sinus rhythm (423 ± 37 vs. 322 ± 30 ms, P < 0.001, and 423 ± 36 vs. 398 ± 36 ms, P = 0.035, respectively) and altered activation patterns in all animals. CV, as estimated by mean ATs, increased in a directionally dependent manner by RSGS (14.6 ± 1.2 vs. 17.3 ± 1.6 ms, P = 0.015), associated with GJ lateralization. RSGS and LSGS inhomogeneously modulated AT and induced relative or absolute functional activation delay in parts of the mapped regions in 75 and 67%, respectively, in MI animals, and in 0 and 15%, respectively, in control animals ( P < 0.001 for both). In conclusion, sympathoexcitation increases CV in normal myocardium and modulates activation propagation in peri-infarcted ventricular myocardium. These data demonstrate functional control of arrhythmogenic peri-infarct substrates by sympathetic nerves and in part explain the temporal nature of arrhythmogenesis. NEW & NOTEWORTHY This study demonstrates regional control of conduction velocity in normal hearts by sympathetic nerves. In infarcted hearts, however, not only is modulation of propagation heterogeneous, some regions showed paradoxical conduction slowing. Sympathoexcitation altered propagation in all infarcted hearts studied, and we describe the temporal arrhythmogenic potential of these findings.Listen to this article's corresponding podcast at http://ajpheart.podbean.com/e/sympathetic-nerves-and-cardiac-propagation/., (Copyright © 2017 the American Physiological Society.)

Background: Existence of a relationship between the electrocardiographic QRS interval duration and the diurnally varying heart rate, of consistent sign and magnitude, is controversial and the relationship has not been fully characterized in normal populations., Methods and Results: We analyzed the QRS-RR interval relationship in 884 Holter recordings in 410 normal subjects participating in 5 clinical trials. The slope of the linear regression of QRS on RR was positive in 93% of subjects with an average slope of 0.0125, which indicates an increase in QRS duration of 1.25msec for an increase in RR interval of 100msec. The increase was 15% larger in women than in men. Age had no significant effect on the slope., Conclusions: In two populations of normal subjects we observed a robust, direct relationship between the spontaneously changing RR interval and intraventricular conduction time represented by the duration of the QRS interval. As heart rate increases, QRS duration decreases. The change is larger in women. These observations have important physiological and clinical implications., (Copyright © 2016 Elsevier Inc. All rights reserved.)

At the April, 2015 International Society for Computerized Electrocardiology (ISCE) Annual Conference in San Jose, CA, a special session entitled Remembering Ron & Rory was held to pay tribute to the extraordinary work and lives of two experts in electrocardiology. The session was well attended by conference attendees, Childers' family members and friends, and additional colleagues who traveled to San Jose solely to participate in this session. The purpose of the present paper is to document the spirit of this special session as faithfully as possible using the words of the session speakers., (Copyright © 2015 Elsevier Inc. All rights reserved.)

Human induced pluripotent stem cell-derived cardiomyocyte (iPSC-CM)-based assays are emerging as a promising tool for the in vitro preclinical screening of QT interval-prolonging side effects of drugs in development. A major impediment to the widespread use of human iPSC-CM assays is the low throughput of the currently available electrophysiological tools. To test the precision and applicability of the near-infrared fluorescent voltage-sensitive dye 1-(4-sulfanatobutyl)-4-{β[2-(di-n-butylamino)-6-naphthyl]butadienyl}quinolinium betaine (di-4-ANBDQBS) for moderate-throughput electrophysiological analyses, we compared simultaneous transmembrane voltage and optical action potential (AP) recordings in human iPSC-CM loaded with di-4-ANBDQBS. Optical AP recordings tracked transmembrane voltage with high precision, generating nearly identical values for AP duration (AP durations at 10%, 50%, and 90% repolarization). Human iPSC-CMs tolerated repeated laser exposure, with stable optical AP parameters recorded over a 30-min study period. Optical AP recordings appropriately tracked changes in repolarization induced by pharmacological manipulation. Finally, di-4-ANBDQBS allowed for moderate-throughput analyses, increasing throughput >10-fold over the traditional patch-clamp technique. We conclude that the voltage-sensitive dye di-4-ANBDQBS allows for high-precision optical AP measurements that markedly increase the throughput for electrophysiological characterization of human iPSC-CMs., (Copyright © 2014 the American Physiological Society.)

The heartbeat arises rhythmically in the sino-atrial node (SAN) and then spreads regularly throughout the heart. The molecular mechanism underlying SAN rhythm has been attributed by recent studies to the interplay between two clocks, one involving the hyperpolarization activated cation current If (the membrane clock), and the second attributable to activation of the electrogenic NaCa exchanger by spontaneous sarcoplasmic releases of calcium (the calcium clock). Both mechanisms contain, in principle, sources of beat-to-beat cycle length variability, which can determine the intrinsic variability of SAN firing and, in turn, contribute to the heart rate variability. In this work we have recorded long sequences of action potentials from patch clamped guinea pig SAN cells (SANCs) perfused, in turn, with normal Tyrode solution, with the If inhibitor ivabradine (3 µM), then back to normal Tyrode, and again with the ryanodine channels inhibitor ryanodine (3 µM). We have found that, together with the expected increase in beating cycle length (+25%), the application of ivabradine brought about a significant and dramatic increase in beat-to-beat cycle length variability (+50%). Despite the similar effect on firing rate, ryanodine did not modify significantly beat-to-beat cycle length variability. Acetylcholine was also applied and led to a 131% increase of beating cycle length, with only a 70% increase in beat-to-beat cycle length variability. We conclude that the main source of inter-beat variability of SANCs firing rate is related to the mechanism of the calcium clock, whereas the membrane clock seems to act in stabilizing rate. Accordingly, when the membrane clock is silenced by application of ivabradine, stochastic variations of the calcium clock are free to make SANCs beating rhythm more variable.

Advances in induced pluripotent stem cell (iPSC) technology have set the stage for routine derivation of patient- and disease-specific human iPSC-cardiomyocyte (CM) models for preclinical drug screening and personalized medicine approaches. Peripheral blood mononuclear cells (PBMCs) are an advantageous source of somatic cells because they are easily obtained and readily amenable to transduction. Here, we report that the electrophysiological properties and pharmacological responses of PBMC-derived iPSC CM are generally similar to those of iPSC CM derived from other somatic cells, using patch-clamp, calcium transient, and multielectrode array (MEA) analyses. Distinct iPSC lines derived from a single patient display similar electrophysiological features and pharmacological responses. Finally, we demonstrate that human iPSC CMs undergo acute changes in calcium-handling properties and gene expression in response to rapid electrical stimulation, laying the foundation for an in-vitro-tachypacing model system for the study of human tachyarrhythmias.

Background: Precise measurement of the QT interval is often hampered by difficulty determining the end of the low amplitude T wave. Root mean square electrocardiography (RMS ECG) provides a novel alternative measure of ventricular repolarization. Experimental data have shown that the interval between the RMS ECG QRS and T wave peaks (RTPK) closely reflects the mean ventricular action potential duration while the RMS T wave width (TW) tracks the dispersion of repolarization timing. Here, we tested the precision of RMS ECG to assess ventricular repolarization in humans in the setting of drug-induced and congenital Long QT Syndrome (LQTS)., Methods: RMS ECG signals were derived from high-resolution 24 hour Holter monitor recordings from 68 subjects after receiving placebo and moxifloxacin and from standard 12 lead ECGs obtained in 97 subjects with LQTS and 97 age- and sex-matched controls. RTPK, QTRMS and RMS TW intervals were automatically measured using custom software and compared to traditional QT measures using lead II., Results: All measures of repolarization were prolonged during moxifloxacin administration and in LQTS subjects, but the variance of RMS intervals was significantly smaller than traditional lead II measurements. TW was prolonged during moxifloxacin and in subjects with LQT-2, but not LQT-1 or LQT-3., Conclusion: These data validate the application of RMS ECG for the detection of drug-induced and congenital LQTS. RMS ECG measurements are more precise than the current standard of care lead II measurements.

Myocardial infarction (MI) induces neural and electrical remodeling at scar border zones. The impact of focal MI on global functional neural remodeling is not well understood. Sympathetic stimulation was performed in swine with anteroapical infarcts (MI; n = 9) and control swine (n = 9). A 56-electrode sock was placed over both ventricles to record electrograms at baseline and during left, right, and bilateral stellate ganglion stimulation. Activation recovery intervals (ARIs) were measured from electrograms. Global and regional ARI shortening, dispersion of repolarization, and activation propagation were assessed before and during sympathetic stimulation. At baseline, mean ARI was shorter in MI hearts than control hearts (365 ± 8 vs. 436 ± 9 ms, P < 0.0001), dispersion of repolarization was greater in MI versus control hearts (734 ± 123 vs. 362 ± 32 ms(2), P = 0.02), and the infarcted region in MI hearts showed longer ARIs than noninfarcted regions (406 ± 14 vs. 365 ± 8 ms, P = 0.027). In control animals, percent ARI shortening was greater on anterior than posterior walls during right stellate ganglion stimulation (P = 0.0001), whereas left stellate ganglion stimulation showed the reverse (P = 0.0003). In infarcted animals, this pattern was completely lost. In 50% of the animals studied, sympathetic stimulation, compared with baseline, significantly altered the direction of activation propagation emanating from the intramyocardial scar during pacing. In conclusion, focal distal anterior MI alters regional and global pattern of sympathetic innervation, resulting in shorter ARIs in infarcted hearts, greater repolarization dispersion, and altered activation propagation. These conditions may underlie the mechanisms by which arrhythmias are initiated when sympathetic tone is enhanced.

Left stellate or right stellate ganglion stimulation (LGSG or RSGS, respectively) is associated with ventricular tachyarrhythmias; however, the electrophysiological mechanisms remain unclear. We assessed 1) regional dispersion of myocardial repolarization during RSGS and LSGS and 2) regional electrophysiological mechanisms underlying T-wave changes, including T-peak to T-end (Tp-e) interval, which are associated with ventricular tachyarrhythmia/ventricular fibrillation. In 10 pigs, a 56-electrode sock was placed around the heart, and both stellate ganglia were exposed. Unipolar electrograms, to asses activation recovery interval (ARI) and repolarization time (RT), and 12-lead ECG were recorded before and during RSGS and LSGS. Both LSGS and RSGS increased dispersion of repolarization; with LSGS, the greatest regional dispersion occurred on the left ventricular (LV) anterior wall and LV apex, whereas with RSGS, the greatest regional dispersion occurred on the right ventricular posterior wall. Baseline, LSGS, and RSGS dispersion correlated with Tp-e. The increase in RT dispersion, which was due to an increase in ARI dispersion, correlated with the increase in Tp-e intervals (R(2) = 0.92 LSGS; and R(2) = 0.96 RSGS). During LSGS, the ARIs and RTs on the lateral and posterior walls were shorter than the anterior LV wall (P < 0.01) and on the apex versus base (P < 0.05), explaining the T-wave vector shift posteriorly/inferiorly. RSGS caused greater ARI and RT shortening on anterior versus lateral or posterior walls (P < 0.01) and on base versus apex (P < 0.05), explaining the T-wave vector shift anteriorly/superiorly. LSGS and RSGS cause differential effects on regional myocardial repolarization, explaining the ECG T-wave morphology. Sympathetic stimulation, in line with its proarrhythmic effects, increases Tp-e interval, which correlates with increases in myocardial dispersion of repolarization.

Increased cardiac sympathetic activation worsens dispersion of repolarization and is proarrhythmic. The functional differences between intrinsic nerve stimulation and adrenergic receptor activation remain incompletely understood. This study was undertaken to determine the functional differences between efferent cardiac sympathetic nerve stimulation and direct adrenergic receptor activation in porcine ventricles. Female Yorkshire pigs (n = 13) underwent surgical exposure of the heart and stellate ganglia. A 56-electrode sock was placed over the ventricles to record epicardial electrograms. Animals underwent bilateral sympathetic stimulation (BSS) (n = 8) or norepinephrine (NE) administration (n = 5). Activation recovery intervals (ARIs) were measured at each electrode before and during BSS or NE. The degree of ARI shortening during BSS or NE administration was used as a measure of functional nerve or adrenergic receptor density. During BSS, ARI shortening was nonuniform across the epicardium (F value 9.62, P = 0.003), with ARI shortening greatest in the mid-basal lateral right ventricle and least in the midposterior left ventricle (LV) (mean normalized values: 0.9 ± 0.08 vs. 0.56 ± 0.08; P = 0.03). NE administration resulted in greater ARI shortening in the LV apex than basal segments [0.91 ± 0.04 vs. 0.63 ± 0.05 (averaged basal segments); P = 0.003]. Dispersion of ARIs increased in 50% and 60% of the subjects undergoing BSS and NE, respectively, but decreased in the others. There is nonuniform response to cardiac sympathetic activation of both porcine ventricles, which is not fully explained by adrenergic receptor density. Different pools of adrenergic receptors may mediate the cardiac electrophysiological effects of efferent sympathetic nerve activity and circulating catecholamines.

The sympathetic nervous system is thought to play a key role in genesis and maintenance of ventricular arrhythmias. The myocardial effect of sympathetic stimulation on myocardial repolarization in humans is poorly understood. The purpose of this study was to evaluate the effects of direct and reflex sympathetic stimulation on ventricular repolarization in patients with postinfarct cardiomyopathy (ICM). The effects of direct sympathetic stimulation were assessed using isoproterenol, while those of reflex sympathetic stimulation were assessed with nitroprusside infusion in ICM patients (n = 5). Five patients without cardiomyopathy were also studied. Local repolarization was measured from intracardiac electrograms that were used to calculate the activation recovery interval (ARI), a surrogate of action potential duration. Isoproterenol significantly increased heterogeneity in repolarization in patients with ICM; the decrease in ARI from baseline was 72.9 ± 9.1 ms in more viable regions, 64.5 ± 8.9 ms in the scar, and 54.9 ± 9.1 ms in border zones (P = 0.0002 and 0.014 comparing normal and scar to border zones, respectively). In response to nitroprusside, the ARI at the border zones decreased significantly more than either scar or surrounding viable myocardium, which showed an increase in ARI (P = 0.014 and 0.08 comparing normal tissue and scar to border zones, respectively). Furthermore, isoproterenol increased ARI dispersion by 70%, while nitroprusside increased ARI dispersion by 230% when ICM patients were compared to those with structurally normal hearts (P = 0.0015 and P < 0.001, respectively). In humans, both direct and reflex sympathetic stimulations increase regional differences in repolarization. The normal tissue surrounding the scar appears denervated. Dispersion of ARI in response to sympathetic stimulation is significantly increased in patients with ICM.

Background: Repolarization heterogeneity and rate dependency have long been established as factors contributing to arrhythmogenic risk. However, there are conflicting observations regarding the nature and extent of ventricular repolarization heterogeneity that complicate understanding of arrhythmogenic mechanisms. To explore these disparate findings, we studied ventricular repolarization heterogeneity and rate dependency in a canine, rapid pacing model of heart failure., Methods and Results: We studied ventricular repolarization heterogeneity and rate dependency in 10 canine hearts (5 normal and 5 after 1 month of rapid pacing at 240 beats per minute) by analyzing 64 body surface electrocardiograms, 64 epicardial, and 190 intramural plunge electrograms. We estimated mean ventricular depolarization and repolarization times from R- and T-wave peaks of the root-mean-square electrocardiogram (body surface) and local depolarization and repolarization times using activation-recovery interval (ARI) methods from recordings obtained during a range of fixed rate pacing. In addition, we estimated local epicardial and transmural gradients of ARIs to assess cardiac locations of greatest spatial repolarization heterogeneity. We compared changes in repolarization at different rates between normal and heart failure hearts. Findings documented prolongation of repolarization, repolarization rate dependency, and increased repolarization gradients in the heart failure hearts compared with control as observed from body surface, epicardial, and transmural measurements. Maximum local epicardial and intramural ARI gradients were comparable both in heart failure and control hearts. Intramural ARI distributions tended to be more irregular in the heart failure hearts compared with the systematic epicardium to endocardium ARI increase observed in control animals., Conclusions: This study documented prolongation of repolarization, increase in both epicardial and transmural repolarization gradients, and irregularity of transmural distribution in a rapid pacing canine model of heart failure compared with control animals. The findings support previously published results of increased repolarization heterogeneity and repolarization prolongation observed in rapid pacing models of heart failure. New findings are the irregularity of transmural heterogeneity and the ability of noninvasive root-mean-square electrocardiogram R-T intervals to estimate mean ventricular repolarization duration in the setting of rapid pacing models of heart failure. These findings suggest increased arrhythmogenic risk in this model and potentially in patients with heart failure., (Copyright © 2011 Elsevier Inc. All rights reserved.)

Background: Atrial fibrillation (AF) has been shown to be associated with reduced survival and increased ventricular arrhythmogenesis. The purpose of this study was to assess the effects of AF with adequate rate control on the electrophysiologic properties of the ventricles. We hypothesized that AF results in increased ventricular arrhythmogenic risk and that reverse remodeling occurs post-successful cardioversion., Methods: In nine patients with persistent AF, we recorded 12-lead electrocardiograms (ECGs) and 1-hour high-resolution Holter ECGs (H12+, Mortara Instrument, Inc. Milwaukee, WI, USA; recorders [1000 sps] immediately following cardioversion (Day 1) and after 30 days of maintaining sinus rhythm (Day 30). We measured QTc, QT dispersion, and calculated estimates of mean ventricular action potential duration (RT), diastolic interval (DI), T-wave width (TW), T-wave peak-to-end, and their respective scatter on Day 1 and Day 30. Maintenance of normal sinus rhythm was confirmed with a weekly trans-telephonic ECG transmission., Results: The average QTc interval decreased from 449 ± 28 ms on Day 1 to 422 ± 36 ms on Day 30 (P = 0.04). There was no significant difference in the average QT dispersion. A significant decrease was also noted in DI and TW scatter at Day 30 when compared with Day 1 (P = 0.03 and 0.04, respectively). A decrease in RT scatter was also noted albeit not statistically significant (P = 0.07)., Conclusion: Our results suggest a greater propensity to ventricular arrhythmogenesis in the immediate period following restoration of sinus rhythm and reverse electrical remodeling of the ventricles during the first month after successful maintenance of sinus rhythm. (PACE 2010; 33:1198-1202)., (©2010, The Authors. Journal compilation ©2010 Wiley Periodicals, Inc.)

There is currently much interest in exploring new ways to optimize ECG acquisition. In the current study, we have investigated optimal configurations of ECG leads with respect to: 1) best signal magnitude (maximal signal variance) and 2) best reconstruction of the total body surface potential distribution and the 12-lead ECG. Principal component analysis was applied to a set of 117-lead body surface potential maps (BSPMs) recorded from 559 subjects. Three bipolar leads, referred to as "eigenleads," were identified from the extrema on the resulting eigenvectors. Recording sites for the three leads were largely located in the precordial region. The magnitude of the signals recorded from the eigenleads was calculated on a set of 185 unseen subjects. The accuracy of the eigenleads in the reconstruction of BSPMs and the 12-lead ECG was also assessed for each subject. These results were compared to existing limited lead systems. It was found that, when compared to conventional leads, eigenleads could be used to increase signal strength (rms voltage) by 27.9%, 39.0%, and 20.3% for P-waves, QRS segments, and STT segments, respectively. Although the eigenleads were not able to reconstruct total body surface information as well as the 12-lead ECG (24.4 mu V versus 20.2 mu V), the eigenleads did perform comparably with other limited lead systems in the estimation of the 12-lead ECG. In particular, the eigenleads performed well in the reconstruction of precordial leads in comparison to the EASI lead system and a limited lead system made up of a subset of precordial leads. The proposed leads are a suitable alternative limited leads system, and can be used to improve SNR. More work is needed to test the practicality of such leads.

Patients increasingly require longer durations of left ventricular assist device (LVAD) therapy. Despite a recent trend toward continuous flow VADs, the HeartMate XVE is still commonly used, but its longevity remains a significant limitation. Existing surveillance methods of pump failure often give inconclusive results. XVE electrical current waveforms were collected regularly (2001-2008) and sorted into quartiles according to number of days until pump failure (Q1, 0-34; Q2, 34-160; Q3, 160-300; and Q4, 300-390 days). Thoratec waveform files were converted into text files. The 10-second electrical current, voltage waveform was identified and isolated for analysis. Waveforms were analyzed by principal component analysis (PCA) and with a fast Fourier transform. Quartiles were compared with analysis of variance (ANOVA). Waveforms (n = 454) were collected for 21 patients with failed pumps. An artificial neural network was used to predict pump failure within 30 days from the waveform characteristics identified though signal processing.

We conducted a retrospective study of a set of previously published electrocardiographic data to investigate the possible direct association between levels of particulate air pollution and changes in ventricular repolarization -- the cardiac electrophysiologic process that manifests itself as the T wave* of the electrocardiogram (ECG) and that is definitively linked to and responsible for increased arrhythmogenesis. The published findings from this data set demonstrated a clear cardiac effect, namely, a reduction in heart rate variability (HRV) parameter values with increased levels of particulate air pollution (Pope et al. 2004), suggesting possible arrhythmogenic effects. Given this positive finding and the well-established sensitivity of cardiac repolarization to physiologic, pharmacologic, and neurologic interventions, and in light of emerging novel tools for assessing repolarization, we hypothesized that high levels of particulate air pollution would alter repolarization independent of changes in heart rate and, consequently, would increase arrhythmogenic risk. The likely mechanism of any deleterious effects on repolarization would be alteration of sodium, calcium, and potassium channels. The channel's structure, function, and kinetics are responsible for generating the cellular action potentials, which, when summed over the entire heart, result in the waves recorded by the ECG. A positive finding would provide evidence that increased levels of air pollution may be directly linked to increases in arrhythmogenic risk and, potentially, sudden cardiac death. The study population consisted of 88 nonsmoking, elderly subjects in whom multiple, continuous, 24-hour, 2-channel ECG recordings were collected, along with blood samples to evaluate inflammatory mechanisms (not pursued in the current study). The concentration of fine particulate matter (PM2.5, particulate matter with an aerodynamic diameter < or = 2.5 microm) in daily samples was measured or estimated and used to trigger recording sessions for days considered to have "low" or "high" PM2.5 concentrations. Each subject participated in one to five recordings over the study period, and all subjects lived within the greater Salt Lake Valley in Utah. We reanalyzed these recordings using custom software that incorporated a magnitude function of the ECG -- the root mean square of all recorded leads (RMS ECG) -- to determine the following for each beat in the 24-hour recording: cycle length (RR); RR dispersion; the interval between the RMS R- and T-wave peaks (RT), a robust estimate of mean duration of ventricular action potential; the width of the RMS T wave (TW), a robust estimate of the range of repolarization times that relates to repolarization dispersion and arrhythmogenesis; the RMS QT interval (QT) measured from the QRS onset to T-wave offset of the RMS ECG; and the regression slopes of RT versus RR, QT versus RR, and TW versus RR, which provide estimates of so-called repolarization restitution, or rate dependency of repolarization, which also is associated with arrhythmogenesis. The study findings did not support the original hypothesis and demonstrated a lack of sensitivity of repolarization to changes in PM2.5 concentrations. None of the repolarization variables showed a statistically significant change between days of low and high PM2.5 concentrations, although we observed statistically significant differences for some variables using fixed-effects modeling. However, we did find a significant decrease in the standard deviation of cycle length, in concert with findings in the original study that showed a decrease in HRV parameter values. There was a slight but statistically insignificant increase in the width of the TW between recordings from days of low and days of high PM2.5, suggesting that, in a setting of prolonged exposure to high levels of PM, the original hypothesis might be supported. We conclude that in this study the short-term (day-today) differences in air pollution, specifically PM2.5 concentration, did not affect ventricular repolarization. A likely explanation for the negative result is that the day-today variability of repolarization (arising from autonomic influences, activity, and heart rate) far outweighs the changes that might be induced by air pollution, if any. In addition, the study may have been underpowered. The findings do not refute the possibility of the deleterious repolarization effects of PM, particularly over prolonged periods of exposure, but suggest the need for exposure studies that provide better controls. In light of recent studies, it is also likely that in an at-risk population -- for example, patients compromised with heart disease -- repolarization changes may be more apparent.

Background: A widened QRS complex as a primary indication for cardiac resynchronization therapy (CRT) for heart failure patients has been reported to be an inconsistent indicator for dyssynchronous ventricular activation. The purpose of this study was to conduct a detailed experimental investigation of total ventricular activation time (TVAT), determine how to measure it accurately, and compare it to the commonly used measure of QRS width. In addition, we investigated a measure of electrical synchrony and determined its relationship to the duration of ventricular activation., Methods: Unipolar electrograms (EGs) were recorded from the myocardial volume using plunge needle electrodes, from the epicardial surface using "sock" electrode arrays, and from the surface of an electrolytic torso-shaped tank. EGs were analyzed to determine a root mean square (RMS)-based measure of ventricular activation and electrical ventricular synchrony., Results: The RMS-based technique provided an accurate means of measuring TVAT from unipolar EGs recorded from the heart, the entire tank surface, or the precordial leads. In normal canine hearts, a quantification of ventricular electrical synchrony (VES) for normal ventricular activation showed that the ventricles activate, on average, within 3 ms of each other with the left typically activating first., Conclusion: Conclusions from this study are: (1) ventricular activation was reflected accurately by the RMS width obtained from direct cardiac measurements and from precordial leads on the tank surface and (2) VES was not strongly correlated with TVAT.

Introduction: Several noninvasive measures of cardiac risk such as heart rate variability (HRV) cannot be used in patients with atrial fibrillation (AF). One promising exception is the measure of ventricular cycle length entropy (VCLE) where initial data suggest that a reduction in VCLE portends an increased risk of cardiac death in patients with chronic AF. In this study, we hypothesized that measures of short-term HRV during sinus rhythm would correlate with measures of cycle length entropy during paroxysms of AF., Methods: We tested 25 Holter recordings of paroxysmal AF from the Physionet AF Prediction Database. We calculated HRV parameters including standard deviation of all NN intervals (SDNN), the root mean square root of the differences between adjacent NN intervals (RMSSD), standard deviation of 5-minute averages of NN intervals (SDANN), percentage of adjacent NN interval differences >50 ms (pNN50), and interbeat correlation coefficient (ICC) from 30 minutes of normal sinus rhythm, and entropy measures (the Shannon Informational Entropy [ShEn] and Average of Approximate Entropy [ApEn]) from 5 minutes of AF that occurred during the same 24-hour monitor. Pairwise correlations were used to assess associations, as regression residuals were normally distributed., Results: The mean entropy measures during AF were: ShEn: 4.78 +/- 0.82, ApEn: 0.198 +/- 0.21. When assessed during the 30 minutes immediately preceding AF onset, ICC showed a significant negative correlation with both ShEn (r =-0.65, P < 0.001) and ApEn (r =-0.60, P < 0.01). RMSSD also correlated with both ShEn (r = 0.41, P = 0.04) and ApEn (r = 0.39, P = 0.05), but other HRV measures showed no correlation with VCLE during AF., Conclusion: Reductions in RMSSD or increases in ICC, two short-term HRV measures that are known to reflect parasympathetic function in sinus rhythm, are correlated with reductions in the entropy of ventricular response intervals during AF. Our findings suggest that entropy during AF may be modulated, in part, by vagal innervation.

In this study, based on 120-lead body surface potential maps (BSPMs), we explored the improvement in electrocardiogram (ECG) diagnosis obtained by adding additional leads and using estimation of unmeasured leads. We found that adding a few leads observed to be optimal for diagnosis or signal capture combined with the existing 12-lead ECG improves diagnostic performance. Separately, using reconstruction (estimation) of BSPMs and using diagnostic criteria derived for maps also improve diagnostic performance over that provided by the recorded 12-lead ECG alone. Combining these 2 ideas, namely, addition of optimal leads and estimation of BSPMs improves performance even more.

Background: The mechanisms for the antiarrhythmogenic effects of preconditioning in ischemic hearts, although well demonstrated, are not clear. We measured indices of activation and repolarization using data from a high-resolution epicardial sock electrode array in preconditioned (PC) and non-PC hearts in an attempt to gain further insight into protective mechanisms., Methods and Results: Five canine hearts were subjected to a coronary artery occlusion lasting at least 1 hour, and 5 were subjected to a similar occlusion preceded by a preconditioning protocol. Epicardial electrograms were recorded using a 490-electrode sock. Representative beats were selected at intervals of 1 minute for analysis. The mean ST elevation for the PC group both rose slowly after occlusion and also resolved more slowly than the non-PC group. Electrocardiographic markers for propagation such as Total Activation Time, the QRSRMS width, and magnitude of steepest downstroke of the QRS complex all showed that the PC group maintained conduction velocity initially and also varied less dramatically than the control group. The regression line slope computed on a scatter plot of QT width vs cycle length was 0.23 for the PC group and 0.58 for non-PC. During occlusion, the incidence of premature ventricular contractions (PVCs) peaked at approximately 17 minutes followed by a second peak at approximately 27 minutes in the non-PC group, the PC group showed similar peaks at approximately 24 and approximately 53 minutes respectively., Conclusion: The slower rate of resolution of ST elevation in PC hearts suggests a delay in gap junction closure, thus maintaining intracellular resistivity and reducing the likelihood of arrhythmia. The speed of conduction is adequately maintained during the early stages of ischemia in PC hearts. The mQTi-mRR regression line, a surrogate measure of rate dependency of repolarization (restitution), has a lower slope in the PC case, thus suggesting a mechanism of reduced arrhythmogenesis. The conclusions are supported by a delay of peak PVCs in PC hearts.

Background: We report on 5 patients who presented to the emergency department (ED) with chest pain, had negative serum troponin levels, and were discharged with a presumed noncardiac diagnosis. Thereafter, retrospective analysis of Holter monitoring data recorded for a clinical trial revealed ST events indicative of transient myocardial ischemia that was unrecognized clinically., Study Aim: The purpose of this analysis was to determine whether initial body surface potential maps estimated from optimal ischemia electrode sites estimated body surface potential map (EBSPM) showed signs of ischemia in the missed ischemia group that could have prevented misdiagnosis., Methods: This is a secondary analysis of data from a prospective clinical trial in which patients were attached to 2 Holter monitor devices for simultaneous recordings. One Holter device recorded a standard Mason-Likar 12-lead electrocardiogram (ECG) and the other recorded a 10-electrode lead set considered optimal for ischemia detection. A body surface potential map was then estimated from the optimal lead set., Results: At 1 year, 2 of the 5 patients with missed ischemia died and a third had an acute myocardial infarction (MI) (40% mortality, 60% death/nonfatal MI). In comparison, 1-year mortality was 5.7% in 159 similar patients treated for unstable angina at the same institution over the same period (P = .037). The initial standard ECG showed no abnormalities in 3 patients and showed left ventricular hypertrophy in 1. The fifth patient with a history of recent MI had slight ST elevation in leads III and aVF and Q waves that were considered indicative of recent (not acute) MI. EBSPM data recorded at the time of ED presentation matched the standard ECG (normal in 3, left ventricular hypertrophy or inconclusive in 2). During transient ischemia, all 5 EBSPMs showed areas of ischemia overlapping with standard electrode sites., Conclusion: Patients evaluated in the ED for chest pain are at high risk for death or nonfatal MI if they have ischemic events with continuous ST-segment monitoring that are unrecognized clinically. In this small cohort with unrecognized ischemia, the initial body surface potential maps estimated from optimal ischemia electrode sites did not improve on 12-lead ST-segment monitoring to identify this high-risk group.

Unlabelled: Patients presenting to the emergency department with chest pain are triaged to early reperfusion therapies based on their initial 12-lead electrocardiogram (ECG). The standard 12-lead ECG lacks sensitivity to detect acute myocardial infarction (AMI). Electrocardiographic diagnosis of non-ST-elevation myocardial infarction (non-STEMI) is especially difficult and is delayed until cardiac biomarkers turn positive, indicating onset of myocardial necrosis., Study Aims: The purpose of this analysis was to extract global ST-T waveform features from patients with chest pain, compare these features in patients with and without AMI, and then identify features that distinguish diagnostic categories., Methods: This is a secondary analysis of data from the Ischemia Monitoring and Mapping in the Emergency Department in Appropriate Triage and Evaluation of Acute Ischemic Myocardium study, a prospective clinical trial in which patients were attached to Holter monitor devices to obtain 24 hours of continuous ECG data. Digital recordings from 176 patients were analyzed: 88 with AMI (STEMI and non-STEMI) and 88 without AMI or unstable angina. The non-acute coronary syndrome (ACS) group was further subdivided into those with non-ACS cardiac conditions such as heart failure and those without cardiac disease who had noncardiac chest pain. For each patient, 10 consecutive waveforms were obtained within the first 120 minutes of emergency department presentation. The waveforms were time-aligned to the QRS, signal-averaged, baseline-adjusted. ST-T waveforms were complied according to diagnostic category and pooled for further analysis. Eigenvector-lead feature coefficients (Karhunen-Loève [K-L] coefficients) were obtained for each patient by taking the dot product of the ST-T wave (ST segment or entire waveform) and the first 3 common eigenvectors, producing 24 K-L coefficients. Cumulative probability distribution function curves were plotted for each diagnostic category. Statistical significance of category coefficient distribution differences was determined. Multinomial regression was used to assess accuracy of feature coefficients to predict diagnostic category., Results: Non-STEMI and non-ACS cardiac category K-L coefficient curves were statistically different in 11 of 24 feature curves (P < .001-.047). ST-segment (50 samples) coefficients predicted non-ACS cardiac patients 11.5% more often (P = .02) than those derived from the entire ST-T wave., Conclusion: Patients diagnosed with non-STEMI have distinct distribution of K-L coefficients compared with non-ACS cardiac patients. Coefficients from the first 50 samples of the ST-T wave (ST segment) better predict diagnostic category than do coefficients derived from the entire ST-T wave. Karhunen-Loève coefficient feature analysis may provide early diagnostic information to distinguish patients with non-STEMI vs non-ACS cardiac patients.

Background: Accurate detection of the earliest signs of ischemia on the surface electrocardiogram (ECG) is essential for timely diagnosis and management of potentially life-threatening ischemic events. Yet, accuracy of ischemia analysis in ECG monitors remains suboptimal because of a number of confounding factors, including changes in body position and other artifacts. Hence, the goals of this study were (1) to examine the duration and time course of ischemic events and (2) to compare ECG changes caused by "true" ischemic events with those caused by changes in body position. Continuous, 12-lead Holter ECGs obtained from patients who presented to the emergency department with chest pain and enrolled in the Ischemia Monitoring and Mapping in the Emergency Department in Appropriate Triage and Evaluation of Acute Ischemic Myocardium study were analyzed. Holter recordings were initiated within the first 40 minutes after patients' arrival to the emergency department. Here we present preliminary results., Methods: Twelve patients (age, 59 +/- 16 years; 5 women, 2 with a final diagnosis of non-ST-segment elevation myocardial infarction, 4 with unstable angina, and 6 with other cardiovascular diseases), in whom ischemic ST deviations were identified on Holter data, underwent 4 consecutive, 2-minute recordings in the following body positions: (1) supine, (2) on the left side, (3) on the right side, and (4) sitting (or standing) upright. After baseline correction, beat-to-beat changes in QRS and ST-T segments were examined in all 8 channels and the root-mean-square curve by using an adaptive algorithm that computes the slope, amplitude, duration, area, and the Karhunen-Loève-derived representation of the corresponding segment. To prevent possible biases toward patients with more frequent ischemic events, a single index event was chosen for analysis in each patient. There were 3 ST-elevation events and 9 ST-depression events; these events reached the maximum ST deviation 11 +/- 8 hours (mean +/- SD) after the beginning of the recording., Results and Conclusions: In most patients with transient myocardial ischemia, the microvolt-level, subthreshold deviation of the ST segment developed gradually, over 15 to 20 minutes, until it reached the maximum, superthreshold level. Despite the different ischemia localizations, the root-mean-square curve allowed accurate detection of significant changes in the ST segment in the studied group (Friedman analysis of variance for repeated measurements over a 1-hour interval). Changes in body position could be identified by tracking dynamics of the QRS pattern/axis. Adaptive algorithms for tracking of the ST dynamics with simultaneous tracking of the patterns of QRS complexes to discriminate the true and "false"-positive events are presented and discussed.

Background: In this study we propose the development of a new algorithm for selecting optimal recording sites for limited lead body surface potential mapping. The proposed algorithm differs from previously reported methods in that it is based upon a simple and intuitive data driven technique that does not make any presumptions about deterministic characteristics of the data. It uses a forward selection based search technique to find the best combination of electrocardiographic leads., Methods: The study was conducted using a dataset consisting of body surface potential maps (BSPM) recorded from 116 subjects which included 59 normals and 57 subjects exhibiting evidence of old Myocardial Infarction (MI). The performance of the algorithm was evaluated using spatial RMS voltage error and correlation coefficient to compare original and reconstructed map frames., Results: In all, three configurations of the algorithm were evaluated and it was concluded that there was little difference in the performance of the various configurations. In addition to observing the performance of the selection algorithm, several lead subsets of 32 electrodes as chosen by the various configurations of the algorithm were evaluated. The rationale for choosing this number of recording sites was to allow comparison with a previous study that used a different algorithm, where 32 leads were deemed to provide an acceptable level of reconstruction performance., Conclusion: It was observed that although the lead configurations suggested in this study were not identical to that suggested in the previous work, the systems did bear similar characteristics in that recording sites were chosen with greatest density in the precordial region.

The purpose of this study was to demonstrate errors in activation time maps created using the time derivative method on fractionated unipolar electrograms, to characterize the epicardial distribution of those fractionated electrograms, and to investigate spatial methods of activation time determination. Electrograms (EGs) were recorded using uniform grids of electrodes (1 or 2 mm spacing) on the epicardial surface of six normal canine hearts. Activation times were estimated using the time of the minimum time derivative, maximum spatial gradient, and zero Laplacian and compared with the time of arrival of the activation wave front as assessed from a time series of potential maps as the standard. When comparing activation times from the time derivative for the case of epicardial pacing, spatial gradient and Laplacian methods with the standard for EGs without fractionation, correlations were high (R2 = 0.98, 0.98, 0.97, respectively). Similar comparisons using results from only fractionated EGs (R2 = 0.85,0.97,0.95) showed a lower correlation between times from the time derivative method and the standard. The results suggest an advantage of spatial methods over the time derivative method only for the case of epicardial pacing where large numbers of fractionated electrograms are found.

Cardiac repolarization, particularly its heterogeneity, is known to play a significant role in arrhythmogenesis. Steepness of cardiac restitution, or the cycle length dependency of repolarization, has also been implicated as a condition that favors occurrence of reentrant arrhythmias. However, most assessments of heterogeneity and restitution are based on static observations and do not directly account for the extent or heterogeneity of dynamic changes. The uncertainty and unpredictability of arrhythmias and the difficulty of identifying patients most at risk may possibly be explained by the lack of consideration of dynamic changes of repolarization, its heterogeneity and time varying restitution. In this brief article, we show the global changes in repolarization that occur in normal canine hearts in response to programmed cycle length sequences. Specifically, we show the beat-to-beat tracking of repolarization during rapid (step) changes in cycle length as well as linear up and down (sawtooth) changes, and random cycle length sequences. The measurement and robust characterization of the dynamic repolarization response to specific cycle length sequences may offer an opportunity to characterize the substrate for arrhythmias to a greater extent than has been possible to date. Although there is no guarantee that characterization of repolarization dynamics will provide definitive means to identify patients at risk, such assessment will, at a minimum, put into perspective the role that repolarization dynamics may play in detecting states of increased arrhythmia risk. Another potential use of these techniques is in the assessment of repolarization in patients undergoing EP testing, pharmacological therapies or during other provocative testing.

Einthoven gave to us the electrocardiogram. Electrocardiographic mapping demonstrated that localized electrophysiological events and phenomena have localized body surface electrocardiographic manifestations. Clinical electrocardiography has given us "reasonably good" means (criteria) with which to detect and characterize medically significant cardiac conditions, events, and diseases. However, clinical electrocardiography is imperfect, largely as a consequence of inadequate or redundant spatial sampling. This compromises the sensitivity and specificity of diagnosing cardiac diseases for which electrocardiographic manifestations are present but undetected due to imperfect sampling that results in a low signal-to-noise ratio for the specific abnormality. Correlation structure of body-surface potential distributions between and across populations or individuals provides important insight into and justification for the selection and use of "limited", "reduced", or "derived" lead systems aimed at improving the capture and use of electrocardiographic information. In this paper, we show the electrocardiographic voltage correlation relationships that occur on the body surface, across groups of subjects, either with or without cardiac disease. In addition, we demonstrate the correlation relationships between torso-surface and epicardial-surface potential distributions in experiments incorporating isolated canine hearts in a human-shaped torso tank. Analysis of these correlation relationships provides an explanation for the long-standing success of clinical electrocardiography but also suggests the means to improve its performance by incorporating new leads and/or their estimation from appropriately selected leads.

T-wave alternans (TWA) is a harbinger of ventricular vulnerability and an important prognostic indicator for torsade de pointes and likely sudden death in patients with LQTS. We analyzed the occurrence of TWA in 18 patients with LQTS (7 males, 11 females, ages ranging from 6 months to 32 years--median 8.4 years). Analysis was performed with software to investigate dynamics of cycle length mediated repolarization changes. Digital Holter ECG analysis revealed macroscopic, true TWA in 3 of 18 patients. TWA showed a variable morphological expression. One patient had continuous changes of T wave polarity, but not on a periodic beat-to-beat basis. Onsets of macroscopic TWA were preceded by long/short cycle length sequences and tachycardic rates above 130 to 140 bpm. Impact of ventricular premature beats on TWA onset was insignificant. Two of the identified patients with TWA had sudden cardiac death during follow-up (one refused PM therapy). At present, TWA cannot be detected automatically from Holter ECGs and therefore may be missed, despite the potential danger for the individuals. The observation that predominantly high beat rates and not beat rate changes, per se, triggered episodes of TWA renders difficult general therapeutic recommendations for the identified patients at risk.

Ventricular repolarization continues to be an enigma to clinical cardiologists and cardiac electrophysiologists. On the one hand, a century of experience has documented an association between abnormal T-wave morphology, QT prolongation and dispersion, T-wave alternans, and nonspecific ST-T waves with arrhythmia risk or negative prognostic outcome. On the other hand, recent advances in molecular electrophysiology have definitively implicated abnormal function and structure of cardiac ion channels associated with repolarization as primary arrhythmogenic mechanisms in long QT syndrome, Brugada's Syndrome, and idiopathic ventricular fibrillation and ventricular tachycardia. In spite of this extensive clinical experience and newly established mechanistic knowledge, robust measurements of repolarization and sensitive algorithms for reliable assessment of risk and prediction of arrhythmia occurrence have remained elusive. New insights into electrocardiographic waveform that reflect and capture the underlying spatial and dynamic characteristics of repolarization offer opportunity to devise clinical indices of repolarization that might be more predictive of risk or outcome than those currently used. Experimental and model data show evidence that the location and size of repolarization lesions may be deduced from T waveform. The changes of repolarization induced by altered activation sequence, and cycle length mediated alterations to repolarization offer additional means to assess the magnitude and significance of such lesions that are linked to increased arrhythmogenic risk. This article explores indices of repolarization that are sensitive to repolarization and its change and that provide opportunity to better characterize and assess repolarization for risk stratification.

It is recognized that 2:1 intraventricular (IV) block can result in T-wave alternans but is usually assumed that it would also affect QRS waveform. Block in a local region is not, however, varied activation sequence of the same muscle mass because the blocked region is not activated and is not part of the mass that is activated in cycles without block. Also, the block region may have electrocardiogram (ECG) effects when its state differs from other regions. In view of those considerations, the ECG effects of IV block were evaluated by using a computer model of excitation and recovery. ECGs were calculated from differences between the excited state and various degrees of recovery. Results provided evidence that boundaries associated with regions of block rather than regions having varied activation sequence were the major factors in T-wave alternans caused by IV block. Effects of the boundaries included cancellation of the effects of IV block on QRS complexes. Findings suggest that IV block cannot be excluded as a mechanism of T-wave alternans in the absence of QRS alternans.