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IEEE 1188 TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 52, NO. 7, JULY 2005 Detection of Repolarization Alternans With an Implantable Cardioverter De brillator Lead in a Porcine Model Anil Maybhate*, Steven C. Hao, Sei Iwai, Jae Ung Lee, Amit B. Guttigoli, Kenneth M. Stein, Bruce B. Lerman, and David J. Christini, Member, IEEE Abstract Mechanistic links have been suggested between repolarization alternans (RPA) and the onset of ventricular tachycardia (VT) and/or brillation. Endocardial detection of RPA may, therefore, be an important step in future device-based treatments of arrhythmias. Here, we investigate if RPA could be detected during acute ischemia using an implantable cardioverter de brillator (ICD) lead (tip to distal coil) located in the right ventricular apex. In 18 pigs, the right coronary ( = 10) or left anterior descending coronary ( = 8) artery was occluded for 10 min using a balloon catheter, followed by reperfusion for 30 min, and re-occlusion for 30 min. RPA magnitude, computed using the modi ed moving average (MMA) method, showed a sharp increase in all 18 animals, from a mean baseline level of 1 9 1 3 mV to 3 0 1 3 mV during rst occlusion (p 0 001). RPA magnitude showed a prominent increase in 10 animals during re-occlusion, from a mean baseline level of 1 7 1 0 mV to 0 001). The protocol was terminated during 3 3 1 5 mV (p the rst two stages of occlusion and reperfusion for the remaining 8 animals due to the occurrence of ventricular brillation (VF). These results con rm that RPA increases under ischemic conditions and that it is possible to detect and track RPA dynamics with an ICD lead that is positioned in a clinically realistic location. Such an approach may be useful in formulating improved arrhythmia detection and control algorithms. Index Terms Alternans, repolarization, T-wave, ventricular tachycardia. I. INTRODUCTION T HE implantable cardioverter de brillator (ICD) is the most effective therapy for patients at high risk of sudden cardiac death due to ventricular tachyarrhythmias [1] [5]. This device continuously monitors the electrical activity of the heart and aims to detect and terminate arrhythmias. In response to a lethal arrhythmia, the device restores normal rhythm with a DC shock. Thus, by design the device acts only after the onset of arrhythmias. Although this approach is usually successful, the DC Manuscript received May 10, 2004; revised November 14, 2004. This work was supported by the Whitaker Foundation under Biomedical Engineering Research Grant RG-02-0369, in part by a Kenny Gordon Foundation Arrhythmia Research Grant, and inpart by the Medtronic CRM External Research Program.Asterisk indicates corresponding author. *A. Maybhate was with the Weill Medical College of Cornell University, 520 East 70th Street, Starr-463, New York, NY 10021 USA. He is now with Department of Kinesiology, Pennsylvania State University, University Park, PA 16802 USA (e-mail: axm55@psu.edu). S. C. Hao, S. Iwai, J. U. Lee, A. B. Guttigoli, K. M. Stein, B. B. Lerman, and D. J. Christini are with the Weill Medical College of Cornell University, New York, NY 10021 USA (e-mail: dchristi@med.cornell.edu). Digital Object Identi er 10.1109/TBME.2005.847537 shock can be painful, or it may occasionally fail to terminate the arrhythmia. A better approach might be to prevent ventricular tachyarrhythmias by recognizing and controlling the precursor events. One such precursor event may be repolarization alternans (RPA), which is a beat-to-beat alternation in magnitude of the transmembrane voltage of ventricular cells during repolarization. RPA manifests as T-wave alternans in the surface electrocardiogram (ECG). A close relationship has been established between T-wave alternans and vulnerability to ventricular brillation (VF) in animals [6] [8]. Clinically, T-wave alternans has been correlated with risk for recurrent ventricular arrhythmias and sudden cardiac death [9] [17]. Furthermore, recent experimental evidence supports the hypothesis that RPA may be a mechanistic precursor to ventricular tachyarrhythmias [18] [22]. These studies have suggested that increased heart rate can induce concordant alternans (i.e., all spatial regions of the ventricles alternate in phase), which can progress to discordant alternans (i.e., neighboring regions of the ventricles alternate out of phase). Discordant alternans causes steep gradients of repolarization that can provide the substrate for unidirectional functional block and the initiation of reentrant propagation the mechanism by which alternans may initiate arrhythmias and cause brillation. Given that alternans may trigger arrhythmias, its control may be of therapeutic value. Earlier works have shown that closedloop control methods can, in principle, be used to suppress some types of alternans [23] [27]. Indeed, it was shown that dynamical control methods could be employed toterminate action potential duration alternans in small in vitro frog ventricle sections [28]. More recently, a theoretical study suggested that the ability to control alternans in large cardiac tissues may have signi cant rate and distance limitations [29]. However, because that study modeled a Purkinje ber, which has a conduction velocity (CV) approximately four times that of ventricular tissue and because the proposed theory suggests that control ef cacy increases as CV decreases [29], there is reason to believe that alternans control in the ventricles will be more feasible than predicted in [29]. To achieve such control clinically, it will be necessary to use an implantable device such as an ICD. As a rst step toward evaluating the feasibility of such an implementation, we sought to determine whether an ICD lead could be used to detect RPA and track its variation during ischemia. The ICD lead that we tested is used clinically and the placement of the lead in our experiments is similar to that used in clinical implantation pro- 0018-9294/$20.00 2005 IEEE MAYBHATE et al.: DETECTION OF REPOLARIZATION ALTERNANS 1189 cedures. Although RPA is inherently spatially extended, it has been recently shown that it is possible to detect RPA from an endocardial signal recorded from a single spatially-localized point in the heart [30]. However, that study focused on the ability to detect RPA endocardially during pacing. Here, we focus on detection of RPA occurring in a setting that is more relevant to sudden cardiac death, i.e., sinus rhythm prior to the onset of VF. Alternans has been detected in ICD signals prior to the onset of ventricular tachyarrhythmias in two studies: 1) using manual analysis of 4-beat patterns in dogs [31]; 2) using power spectral analysis (which cannot give beat-to-beat information as required for control) of clinical human ICD data [32]. We demonstrate here that with an appropriate quantifying scheme it is indeed possible to detect RPA and track its beat-to-beat variation using an ICD lead. II. METHODS 1) Experimental Procedure: We investigated the dynamics of repolarization alternans, as detected by an ICD lead, before, lb during and after coronary artery occlusion in eighteen Yorkshire pigs. All procedures were approved by the Institutional Animal Care and Use Committee of Weill Medical College of Cornell University. A tripolar ICD lead (Medtronic 6945; Minneapolis, MN) was advanced under uoroscopic guidance to the right-ventricular apex via the right internal jugular vein. Two quadripolar electrophysiology catheters (BARD EP, Billerica, MA) were advanced to the right ventricle (RV) apex or out ow tract and left ventricular (LV) apex regions via a femoral vein and artery, respectively. A balloon catheter (used for abrupt coronary-artery occlusion to induce ischemia; Guidant, ACS Rx Esprit 3.5 20 mm; Minneapolis, MN) was advanced via the right carotid artery to: 1) the left anterior descending artery (8 animals; for anterior/apical ischemia); or 2) the right coronary artery (10 animals; for right-ventricular, posterior-inferior ischemia). ICD lead signals (tip to distal-coil) were ampli ed and band-pass ltered (0.05 400 Hz) using an electrophysiology recording ampli er (BERS-400 A; Bloom Assoc. Ltd., Reading, PA). Using the quadripolar catheters, unipolar RV and LV signals (referenced to the algebraic sum of the surface electrocardiogram limb leads) were acquired, ampli ed, and ltered in the same bandwidth as that for the ICD lead signal. All signals were digitized at 1 kHz by a PCI-DAS1602-16 16-bit data acquisition board (Measurement Computing Inc., Middleboro, MA) and recorded on an AMD K6-II computer running our custom Real-Time Linux experiment interface system [33]. Prior to occlusion, the signals were acquired at baseline for 10 minutes. Following this stage, the balloon catheter was in ated (to pressure levels of 6 7 bar) to fully occlude the selected coronary artery and induce ischemia. Complete occlusion of a vessel was con rmed by injection of a contrast dye. If brillation occurred at any time during the protocol, the protocol was terminated at that time. The rst occlusion was maintained for 10 min, after which the balloon was released for a 30-min reperfusion/recovery stage. This timeline was similar to that which has been used in previous acute-ischemia experiments [9], [34], [35]. The balloon was then re-in ated and ischemia maintained for 30-min or until ventricular brillation occurred. 2) Post-Experimental Data Analysis and Computational Method: In the post-experimental procedure, depolarizations were automatically annotated via a peak-detection algorithm (with manual correction as needed) using custom C++ software. For characterization of RPA, we used the Modi ed Moving Average (MMA) method [36] recently proposed for TWA detection. The method is advantageous over other alternative methods such as the complex demodulation method [9], [37] or power spectral analysis [30] because unlike these methods, the MMA method does not require a large set of stationary data before it reliably and robustly computes the alternans magnitude. This characteristic makes MMA more suitable for continuous tracking of RPA magnitude on a beat-to-beat basis. As a starting point of the analysis, the beats were numbered and classi ed as odd and even beats for further computation. The sets of odd and even beats were then labeled as (1) (2) where the index beat and the index The ordered sets and scheme given by counts the data sample within a counts the beat number. are then used to set up an iterative (3) (4) (5) (6) where the bar denotes the so called modi ed moving average beat and the function is the weightage function as de ned . in [36]. The scaling factor was Finally as in [36], RPA magnitude for the th pair of odd and even beats was de ned by (7) denotes the maximum value within . is the repolarization region, de ned to start a xed percentage (5% in our study) of the RR interval after the previous R-wave and end a xed percentage (15% 20% in our study) of the RR interval before the next R-wave. The RPA magnitude can, thus, be computed on a beat-to-beat basis, and the variation can be plotted as a function of time. We studied the temporal variation of RPA magnitude in all three recorded signals (ICD lead, RV-unipolar, and LV-unipolar). For each signal, time-averages of RPA magnitude were computed during all phases of the experiment. Repeated measures analysis of variance was performed for statistical comparisons. All averages are presented here as mean standard deviation. where III. RESULTS Fig. 1 shows RPA magnitude (7) as measured by the ICD lead, as a function of time for two representative animals. RPA magnitude shows a prominent increase during the occlusion phase i.e., occlusion induced repolarization alternans. The 1190 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 52, NO. 7, JULY 2005 Fig. 2. Variation of raw as a function of time. The plot shows the for the ICD signal voltage at 180 ms after the ducial points for difference successive recorded beats. Alternans corresponds in this plot to an alternating oscillation of between a high and a low value. Soon after the right coronary artery was occluded (O1), the oscillations of became progressively larger. These oscillations decreased in amplitude as the reperfusion phase started (R), but grew just before the animal went into VF. Inset (a) shows that variations prior to occlusion were small and aperiodic. Inset (b) shows that after occlusion,1V alternated on a beat-to-beat basis. These alternations are clearer in inset (c), just before the onset of VF. 1V 1V 1V 1V 1V Fig. 1. RPA magnitude computed from a right-ventricular apex ICD-lead signal in two pigs. A coronary artery [right coronary artery for the trial shown in (a); left anterior descending for the trial shown in (b)] was occluded in two phases (O1 and O2) separated by a 30 min reperfusion period (R). The starting points of these phases are marked by arrows in the plots. Each animal showed a sharp increase in RPA magnitude during the occlusion phases. (a) Example that showed a sharp increase in RPA prior to the occurrence of VF during the second occlusion phase. In the second animal (b) RPA increased sharply and remained high during the second occlusion (30 min); spontaneous VF did not occur in this animal. rst animal [Fig. 1(a); right coronary occlusion] showed a sharp initial increase in RPA magnitude during occlusion; RPA magnitude returned to baseline during reperfusion. During the second occlusion phase, this animal went into VF after a brief and sharp increase in RPA magnitude. In the second case [Fig. 1(b); LAD occlusion], the animal brie y recovered from the initial high alternans phase following the rst occlusion period. During reperfusion, the RPA magnitude was reduced except for a transient increase, likely indicating recovery from ischemia. RPA magnitude increased sharply and remained high in the second occlusion phase. Spontaneous VF did not occur in this animal. Note that during baseline, the RPA magnitude computed using the MMA method is not zero. This results from probabilistic occurrences of alternans resulting from signal noise. Fig. 2 shows a representative case of the raw RPA magnitude variations during the rst occlusion phase. This animal developed VF during reperfusion after the rst occlusion. Fig. 2(a) shows the difference between the voltages of successive recorded beats at a xed time (180 ms) after the ducial point (chosen to coincide with the R-wave in the surface ECG) of each beat, as a function of time. Alternans corresponds in this graph to an alternating oscillation of between a positive variations and a negative value. During the baseline phase, were small and apparently random. As the right main coronary artery was occluded, the oscillations of became progressively larger. As the reperfusion phase started, the oscillations decreased in amplitude before increasing sharply just before the animal went into VF. Fig. 3 shows the variation of the RPA magnitude time averages for 2 groups of animals, those in which the right coronary artery was occluded and those in which the LAD was occluded. For each group, the graphs show the RPA magnitude computed from the ICD signal, the RV signal, and the LV signal. A statistically signi cant increase in RPA magnitude occurred during the mV rst occlusion phase from a mean baseline level of mV during rst occlusion . All of the 13 to animals that reached the reperfusion period showed a recovery from the occlusion with a decrease in the RPA magnitude. Three animals developed VF during reperfusion and the remaining 10 underwent a second phase of occlusion after the 30-min reperfusion. RPA magnitude in these animals increased sharply as the selected coronary artery was reoccluded from a mean baseline mV to mV . Spontaneous level of VF did not occur in 7 of 18 animals. There were no statistically signi cant differences in alternans occurrence between animals that had VF (solid red lines) and those that did not (dashed black lines). Fig. 4(a) shows three sets of mean values of RPA magnitude time averages for the rst two phases of the protocol, baseline (left columns) and the 10-min phase of the rst occlusion (right columns). The three sets correspond to the ICD, RV, and LV signals. Fig. 4(a) shows that, in all three signals, there was a signi cant ( for ICD, for RV, and MAYBHATE et al.: DETECTION OF REPOLARIZATION ALTERNANS 1191 Fig. 3. RPA magnitude time averages in 2 groups, right coronary artery occluded animals [(a) (c)] and LAD occluded animals [(d) (f)]. For a given animal, symbols are consistent for (a) (c) and for (d) (f). In all panels, data points for animals that went into VF are joined by solid red lines and those for animals that did not go into VF are joined by dashed black lines. For both groups the graphs show the RPA magnitude computed from the ICD signal [(a), (d)], the RV signal [b), (e)], and the LV signal [(c), (f)]. A prominent increase in RPA magnitude in the ICD signal, relative to baseline level, occurred in 17 of 18 animals during the rst occlusion phase. During reperfusion, all 13 animals that reached that stage showed a recovery from high RPA magnitude. The RPA again showed a sharp increase in 9 of 10 animals that were re-occluded. for LV) increase in the alternans magnitude during the rst occlusion phase as a result of ischemia. Fig. 4(b) shows three sets of mean values of RPA magnitude time averages for the last two phases of the protocol, reperfusion (left columns) and the 30-min phase of the second occlusion (right columns). As in Fig. 4(a), the three sets correspond to the ICD, RV, and LV signals. Fig. 4(b) shows that, in two of the three recorded signals there was a signi cant ( for ICD, and for LV) increase in the alternans magnitude during the rst occlusion phase as a result of ischemia. Interestingly, both Fig. 4(a) and (b) show that mean increase in the RPA magnitude time averages was most prominent in the ICD lead signal. No statistically signi difference cant was found in the two groups of animals divided on the basis of site of occlusion. IV. DISCUSSION In this study we experimentally investigated the temporal variation of repolarization alternans during and after occlusion-induced ischemia, as measured by a commercially available ICD lead and as quanti ed using the MMA method. Our results show that alternans magnitude can be effectively measured endocardially using such an ICD lead. It is important to note that the ICD lead signal was better suited for detection of RPA than the RV or LV unipolar signals (Fig. 4). We believe that this is because the ICD signal used a reference (distal coil) that was inside the heart. Because of this location, the noise level was lower relative to the RV or LV signals, for which the reference was to the surface signals, leading to higher noise levels. Speci cally, the peak-to-peak signal-to-noise ratio for the 18 animals for the ICD signal was , while those for RV and LV signals were and , respectively. Although our results con rm that alternans magnitude increases during ischemia [9], [11], [38], there were no statistically signi cant differences in alternans occurrence between animals that had VF and those that did not. The lack of discrimination may have resulted from the use of full occlusion of a major coronary artery in fact, we chose this aggressive occlusion protocol to ensure alternans occurrence so that we could test ICD-lead detection. Future studies which utilize partial occlusion should help illuminate whether or not alternans level, as detected by an ICD lead, is predictive of arrhythmia onset. The reasons for selection of the particular method used in this study for quantifying RPA variation are as follows. As compared to some of the earlier methods suggested for characterization of alternans magnitude, such as power spectral analysis [30] or the complex demodulation method [9], [37], the modi ed moving average method has been shown to be robust to noise and phase reversals. Unlike power spectral analysis or complex demodulation, the MMA method does not require a large set of stationary data; instead, it utilizes a beat-to-beat analysis. As depicted by Fig. 2, the RPA magnitude, as measured by the ICD lead and quanti ed by the MMA method, tracks the beat-to-beat voltage differences in repolarization phase. Such beat-to-beat tracking would be crucial for alternans control methods. 1192 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 52, NO. 7, JULY 2005 V. CONCLUSION Our study suggests that, with an appropriate quanti cation scheme, it is indeed possible to detect RPA and track its variation using an ICD lead. Quanti cation with the ICD lead (using a tip to distal-coil electrode combination) is superior to quanti cation with standard unipolar electrophysiological signals, likely due to reduced noise resulting from the use of an internal signal reference. As expected, the results here also show that RPA magnitude increases sharply during acute ischemia. In the future, this approach may be useful in the formulation of improved arrhythmia therapy techniques for ICD devices. REFERENCES [1] A. E. Buxton et al., Prevention of sudden death in patients with coronary artery disease: The multicenter unsustained tachycardia trial (MUSTT), Prog. Cardiovasc. Dis., vol. 36, pp. 215 226, 1993. 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(b) Shows the RPA magnitude time-averages (mean SD) for last two phases of the protocol, reperfusion (left columns) and the 30-min phase of the second occlusion (right columns) for all animals that reached the reocclusion phase. The three sets correspond to the ICD(n = 10); RV(n = 9), and LV(n = 10) signals. For ICD and LV signals, there was a signi cant increase above reperfusion level (R) in the alternans magnitude during the second occlusion (O2) phase as a result of ischemia. 6 6 There are, however, some limitations to this approach. The MMA method was originally developed for TWA detection in surface ECG signals [36]. Accordingly the parameters ( and in (5) and (6)) were designed for a surface ECG signal. Nevertheless, we were able to effectively detect RPA using identical parameters. It is possible that parameter values that are tailored to endocardial signals may improve alternans detection. 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Anil Maybhate received the Ph.D. degree in nonlinear dynamics from University of Pune, Pune, India, in 2002. He did his postdoctoral research in cardiac electrodynamics laboratory at Weill Medical College of Cornell University, NY. He has recently moved to Department of Kinesiology of the Pennsylvania State University, University Park. His research interests mainly include dynamical systems theory and its applications to complex biological systems. He is currently involved in nonlinear dynamical investigation of human movement control. Steven C. Hao received the B.S. degree from the Massachusetts Institute of Technology, Cambridge, in 1992 and an M.D. from the University of Pennsylvania, Philadelphia, in 1996. He completed postgraduate training in internal medicine at The New York Hospital and a cardiology fellowship at Cornell University Medical Center, New York. He is currently completing a cardiac electrophysiology fellowship at Cornell University Medical Center and his research interests include cardiac action-potential alternans as a predictor of ventricular arrhythmias and modulation of cardiac action-potential restitution with adrenergic tone and beta blockade. Sei Iwai is currently an Assistant Professor of Medicine at the Weill Medical College of Cornell University, and works in the Cardiac Electrophysiology Laboratory at the New York Weill Cornell Medical Center, New York. His research interests include mechanisms of atrial tachycardia, molecular genetic basis of atrial brillation and idiopathic ventricular tachycardia, and action potential duration restitution and alternans as predictors of ventricular arrhythmias. Jae Ung Lee, photograph and biography not available at the time of publication. Amit B. Guttigoli graduated from Jawaharlal Nehru Medical College, Belgaum, India. His postgraduate training included residency in Internal Medicine at Coney Island Hospital, Brooklyn, NY, and a fellowship in cardiovascular disease and Cardiac Electrophysiology at Weill Medical College of Cornell University, New York. He is currently an attending electrophysiologist at the Methodist Dallas Medical Center, Dallas, TX. His research interests include syncope and de brillation threshold in patients with cardiomyopathy. 1194 IEEE TRANSACTIONS ON BIOMEDICAL ENGINEERING, VOL. 52, NO. 7, JULY 2005 Kenneth M. Stein received the A.B. degree in economics from Harvard University, Cambridge, MA, in 1983 and the M.D. from New York University, New York, in 1987. He is an Associate Professor of Medicine and Associate Director of the Cardiac Electrophysiology Laboratory at the New York Weill Cornell Medical Center. His research interests include the interactions between the autonomic nervous system and arrhythmogenesis and the application of nonlinear dynamics to the analysis and control of cardiac arrhythmias. Bruce B. Lerman is the H. Altschul Professor of Medicine, Chief of the Division of Cradiology, and Director of the Cardiac Electrophysiology Laboratory at the New York Weill Cornell Medical Center, New York. His research interests include biophysical mechanisms of de brillation, myocardial signal transduction and molecular and cellular mechanisms of idiopathic ventricular tachycardia. David J. Christini (S 89 M 97) received the B.S. degree in electrical engineering from the Pennsylvania State University, University Park, in 1991 and the M.S. and Ph.D. degrees in biomedical engineering from Boston University, Boston, MA, in 1993 and 1997, respectively. He did postdoctoral training in cardiac electrophysiology at Cornell University Medical College. He is currently an Assistant Professor of Medicine at the Weill Medical College of Cornell University and Assistant Professor of Physiology and Biophysics at the Weill Graduate School of Medical Sciences of Cornell University. His primary research interests are in cardiac electrophysiology, with an emphasis on adaptive pacing control and nonlinear-dynamical analysis of cardiac arrhythmias.

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