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The only known effective therapy for lethal disturbances in cardiac rhythm is defibrillation, the delivery of a strong electric shock to the heart. This technique constitutes the most important means for prevention of sudden cardiac death. The efficacy of defibrillation has led to an exponential growth in the number of patients receiving implantable devices. The objective of this book is to present contemporary views on the basic mechanisms by which the heart responds to an electric shock, as well as on the challenges and implications of clinical defibrillation. Basic science chapters elucidate questions such as lead configurations and the reasons by which a defibrillation shock fails. Chapters devoted to the challenges in the clinical procedure of defibrillation address issues related to inappropriate and unnecessary shocks, complications associated with the implantation of cardioverter/defibrillator devices, and the application of the therapy in pediatric patients and young adults. The book also examines the implications of defibrillation therapy, such as patient risk stratification, cardiac rehabilitation, and remote monitoring of patient with implantable devices.


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Edited by Natalia Trayanova

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Cardiac Defibrillation – Mechanisms, Challenges and Implications Edited by Natalia Trayanova Published by InTech Janeza Trdine 9, 51000 Rijeka, Croatia Copyright © 2011 InTech All chapters are Open Access articles distributed under the Creative Commons Non Commercial Share Alike Attribution 3.0 license, which permits to copy, distribute, transmit, and adapt the work in any medium, so long as the original work is properly cited. After this work has been published by InTech, authors have the right to republish it, in whole or part, in any publication of which they are the author, and to make other personal use of the work. Any republication, referencing or personal use of the work must explicitly identify the original source. Statements and opinions expressed in the chapters are these of the individual contributors and not necessarily those of the editors or publisher. No responsibility is accepted for the accuracy of information contained in the published articles. The publisher assumes no responsibility for any damage or injury to persons or property arising out of the use of any materials, instructions, methods or ideas contained in the book. Publishing Process Manager Romina Krebel Technical Editor Teodora Smiljanic Cover Designer Jan Hyrat Image Copyright jannoon028, 2011. Used under license from First published September, 2011 Printed in Croatia A free online edition of this book is available at Additional hard copies can be obtained from [email protected] Cardiac Defibrillation – Mechanisms, Challenges and Implications, Edited by Natalia Trayanova p. cm. ISBN 978-953-307-666-9

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free online editions of InTech Books and Journals can be found

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Preface IX

Part 1 Basic Mechanisms of Defibrillation 1

Chapter 1 Mechanisms of Defibrillation Failure 3 Takashi Ashihara, Jason Constantino and Natalia A. Trayanova

Chapter 2 The Role of the Purkinje System in Defibrillation 11 Edward J Vigmond, Patrick M. Boyle and Makarand Deo

Chapter 3 Analysis of the Lead Sensitivity Distribution in Implantable Cardioverter Defibrillator 27 Jesús Requena-Carrión, Juho Väisänen, Jari Hyttinen and Juan J. Vinagre-Díaz

Chapter 4 Modeling Defibrillation 39 Gernot Plank and Natalia Trayanova

Part 2 Challenges in Clinical Defibrillation 59

Chapter 5 What Can We Do Before Defibrillation? 61 Chunsheng Li, Shuo Wang and Junyuan Wu

Chapter 6 Pulmonary, Cardiovascular and Mechanical Complications of Implantable Cardioverter Defibrillators (ICDs) 71 Georgia Hardavella, Georgios Dionellis and Nikolaos Koulouris

Chapter 7 New Ways to Avoid Unnecessary and Inappropriate Shocks 81 Jorge Toquero, Victor Castro, Cristina Mitroi and Ignacio Fernández Lozano

Chapter 8 Cardiovascular Implantable Cardioverter Defibrillator-Related Complications: From Implant to Removal or Replacement: A Review 101 Mariana Parahuleva

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VI Contents

Chapter 9 Expanding Applications of Defibrillators and Cardiac Resynchronization Therapy to Include Adult Congenital Heart Disease 117 K Michael, B Mayosi, J Morgan and G Veldtman

Chapter 10 Role of Automated External Defibrillators (AED) in Sports 133 Saqib Ghani and Sanjay Sharma

Part 3 Pediatric Defibrillation 145

Chapter 11 Implantable-Cardioverter Defibrillator in Pediatric Population 147 María Algarra, Pablo Santiago, Luis Tercedor, Miguel Álvarez, Rocío Peñas, Francisca Valverde and Abdulreda Abdallah

Chapter 12 ICD Implantations in the Pediatric and Young Adult Population 167 Ten Harkel Arend DJ and Blom Nico A

Chapter 13 AED for Paediatric Use, Implications in the Design of Shock Advice Algorithms 183 Sofia Ruiz de Gauna, Jesus Ruiz, Unai Irusta and Elisabete Aramendi

Part 4 ICD Implications 205

Chapter 14 Role of Implantable Cardioverter Defibrillators for Dialysis Patients 207 Marlies Ostermann

Chapter 15 Cardiac Rehabilitation for Patients with an Implantable Cardioverter Defibrillator 213 Alan Robert Denniss and Robert Zecchin

Chapter 16 ICDs and Risk Stratification in Magnetic Field Imaging 221 Dania Di Pietro Paolo, Tobias Toennis and Sergio Nicola Erne

Chapter 17 Remote Monitoring of Implantable Cardioverter-Defibrillator Therapy 235 MJ Pekka Raatikainen and Ulla-Maija Koivisto

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According to the American Heart Association, an overwhelming number of sudden cardiac deaths, estimated at about 400,000 per year, are thought to result from ventricular fibrillation, the most lethal of all cardiac rhythm disorders. Ventricular fibrillation is the breakdown of the organized electrical activity driving the heart's periodic pumping into disorganized self-sustained electrical activation patterns. A fibrillation episode results in the loss of cardiac outpu and, unless timely intervention takes place, death quickly ensues. Cardiac defibrillation, as achieved by the delivery of high-intensity electric shocks, is currently the only reliable treatment for ventricular fibrillation. Indeed, external defibrillators have long been used as standard therapy for ventricular fibrillation, and implantable cardioverter/defibrillators (ICDs) have been demonstrated to be an effective, lifesaving technology, superior to pharmacological therapy. Large, well-controlled prospective ICD trials have revolutionized the concept of sudden cardiac death prophylaxis. These studies have resulted in rapid growth of the patient populations for whom ICDs are indicated, with over 200,000 devices implanted every year throughout the world. In addition, over 100,000 external transthoracic defibrillators are installed in cardiac clinics, and a growing number of automatic external defibrillators are being used in public places and in households.

The increasingly large and diverse populations of patients with ICDs have exposed some of the limitations of this clinical technology. Although mean defibrillation thresholds typically range from 7 to 11J, ICDs are designed to provide up to 40J shocks. This is to accommodate the nearly 25% of patients, which have higher defibrillation thresholds, requiring programming of the ICD at near maximum output. Clinical studies have recognized the desirability of reducing shock strength, and over 200 papers have been published in the last 10 years on the topic of defibrillation thresholds. Reducing shock strength remains a major challenge to clinical defibrillation.

Although ICD therapy has proved to be efficient and reliable in preventing sudden cardiac death, defibrillation is a traumatic experience. The therapy is painful and could be detrimental to cardiac function. Furthermore, clinical data from ICD trials have suggested that 6 out of 7 shocks delivered are classified as inadequate. Issues related to inappropriate and unnecessary shocks as well as patient risk stratification and post-

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X Preface

ICD cardiac rehabilitation are essential to the delivery of appropriate care to ICD recipients.

Additionally, certain special populations of patients are poorly served by current ICD technology. These include children and patients of small body size. Unique difficulties surround cardiac defibrillation in the pediatric population, including high rates of lead failure, frequent inappropriate therapy, and the mismatch of device and lead size to the body.

Many of the advances in defibrillation have been accomplished through the developments in hardware and software and by experimental trial and error. Further advances in the clinical procedure of defibrillation will require increased knowledge of the basic mechanisms by which the electric fields interact with heart tissue. Therefore, research on defibrillation mechanisms, particularly aimed at developing low-voltage defibrillation strategies, remains an important basic science topic.

The objective of this book is to present contemporary views on the challenges and implications of cardiac defibrillation, and specifically, on the subjects presented above. Basic science chapters elucidate questions such as lead configurations and the reasons by which a defibrillation shock fails. The chapters devoted to the challenges in the clinical procedure of defibrillation address issues related to inappropriate and unnecessary shocks, complications associated with the implantation of ICD devices, and the application of the therapy in pediatric patients and young adults. The book also examines the implications of defibrillation therapy, such as patient risk stratification, cardiac rehabilitation, and remote monitoring of patient with implantable devices.

Natalia Trayanova, PhD

Johns Hopkins University, MD, Baltimore USA

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Part 1

Basic Mechanisms of Defibrillation

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Mechanisms of Defibrillation Failure Takashi Ashihara1, Jason Constantino2 and Natalia A. Trayanova2

1Shiga University of Medical Science, 2Johns Hopkins University,

1Japan 2U.S.A.

1. Introduction Since defibrillation by high-energy electric shocks is the only effective means for termination of ventricular fibrillation, defibrillation shocks are now widely used in clinical practice for prevention of sudden cardiac death. However, the high-energy shocks could result in myocardial dysfunction and damage (Runsio et al., 1997) and in psychological trauma (Maisel, 2006). Comprehensive understanding of the ventricular response to electric shocks as well as the mechanisms of defibrillation failure is the approach most likely to succeed in reducing shock energy. Recent experimental techniques, such as high-resolution mapping with multi-electrodes or optical recordings, have provided new characterizations of tissue responses to electric shocks. However, the mechanisms of the success and failure of defibrillation are not fully understood since the presently available experimental techniques, which provide detailed information about the myocardial surface (mostly epicardial) activity, are insufficient in resolving depth information during and after the electric shocks. Moreover, electrical or optical signal artifacts during the shock make it difficult for the researchers to get direct evidence regardig the mechanisms of electrical defibrillation. It has been demonstrated experimentally that after the delivery of shocks of strength near the defibrillation threshold (DFT) from an implantable cardioverter-defibrillator (ICD) device, the first global activation consistently arises focally on the left ventricle (LV) (Chattipakorn et al., 2001, 2003) following an isoelectric window (a quiescent period following the shock). Understanding the origins of the isoelectric window is thus of great importance for uncovering the mechanisms of defibrillation failure. Various hypothesis have been proposed for the existence of the isoelectric window, including virtual electrode-induced propagated graded response (Trayanova et al., 2003), calcium sinkholes (Hwang et al., 2006), and activations emanating from Purkinje fibers (Dosdall et al., 2007); however, the mechanisms responsible for it remain inconclusive. In this context, we hypothesized that submerged “tunnel propagation” of postshock activation (PA) through shock-induced intramural excitable areas underlies both fibrillation induction and failed defibrillation by shocks as well as the existence of an isoelectric window. To test this hypothesis, we analyzed the global three-dimensional activity in ventricles with the use of a recently-developed realistic computer model of stimulation/defibrillation in the rabbit heart (Trayanova et al., 2002). Simulations with this

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model, termed the rabbit bidomain model of defibrillation, have proven invaluable in understanding various aspects of the response of the heart to shocks (Rodriguez et al., 2005). The bidomain model is a continuum representation of the myocardium, which takes into account both intracellular and extracellular current distributions through the myocardium. The objectives of this book chapter are to demonstrate the use of the realistic three-dimensional bidomain rabbit ventricular model and failed defibrillation in uncovering the mechanisms of fibrillation induction and defibrillation failure.

2. Similarities between fibrillation induction and failed defibrillation An isoelectric window (Chen et al., 1986a), the quiescent period prior to the first global PA, has been experimentally documented following strong shocks. The presence of the isoelectric window following failed defibrillation attempts (Chen et al., 1986a; Shibata et al., 1988b; Wang et al., 2001) led to the understanding that an electric shock terminates ongoing fibrillation but then reinitiates it. Hence, the mechanisms of fibrillation induction and its reinitiation (failed defibrillation) are considered to be the same. Thus, elucidating the origin of PAs resulting in fibrillation induction provides invaluable insight into the mechanisms of defibrillation failure and could contribute significantly in finding novel ways to appreciably lower the shock energy. Indeed, striking similarities between these mechanisms have been found, particularly with regard to the propagation of the first global PA and the duration of the isoelectric window (Shibata et al., 1988a, 1988b; Wang et al., 2001). The similarity is supported by the significant correlation between the upper limit of vulnerability (ULV) and DFT (Chen et al., 1986b; Swerdlow et al., 1998). Based on these facts, we first focused on the mechanism responsible for the earliest-propagating PA in fibrillation induction by the electric shock, and then we extend the study to defibrillation failure.

3. Fibrillation induction following external shock First, we conducted simulations of fibrillation induction following uniform-field external shocks with the use of the rabbit bidomain ventricular model, extensively validated with experimental measurements (Rodriguez et al., 2005). Biphasic shocks were delivered via plate electrodes located in the vicinity of RV and LV free walls (Figure 1A). The ventricles were immersed in the perfusing bath. Figure 1B shows examples of arrhythmia non-induction and induction after 16- and 12-V/cm shocks, which are just above and near the ULV, respectively. Virtual electrodes (regions of positive and negative membrane polarization) induced by the shock (shock end, 0-ms panels) resulted in quick excitation of the ventricular surface (10-ms panels). Whereas no PA was induced by the 16-V/cm shock, for the 12-V/cm shock case, the earliest-propagated PA (arrows in 55-ms panel) led to the establishment of ventricular fibrillation (VF) (80-ms panel) following an isoelectric window. The origin of the initiating PA following the 12-V/cm shock is analyzed in Figure 1C. The initiating PA originated at the boundary between a recovered area unaffected by the shock and the shock-induced depolarized area as a virtual electrode-induced propagated graded response (zigzag arrow in 10-ms panel). This occurred deep within the LV wall, and the initiating PA proceeded transmurally toward the LV epicardium (20-ms panel), where tissue had already recovered, and became the earliest-propagated PA.

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Mechanisms of Defibrillation Failure


Fig. 1. Fibrillation induction following external biphasic shock.

4. Defibrillation failure following an ICD shock We then extended the simulation study to electrical defibrillation by nonuniform-field ICD shocks. Biphasic shocks were delivered via ICD electrodes, a catheter in RV and an active can in the bath near the posterior LV (Figure 2A). For near-DFT shock episodes, we examined PA origins, and we found that around half of the earliest-propagated PAs originated from shock-induced wavefronts and the other half from pre-existing wavefronts. This means that failed defibrillation for near-DFT shocks is not always associated with termination of pre-existing wavefronts and generation of new wavefronts by the shock. As shown in Figure 2B, the postshock excitable area in the RV after near-DFT shocks was directly depolarized by the shock and the one in the septum was immediately eradicated by break excitations elicited by the shock (black circles in 0- and 17-ms panels), whereas the main postshock excitable area was consistently located within the LV wall (red ellipsoid in 17-ms panel) since ICD electrodes generate weak virtual electrode polarization across the thick LV wall. Thus, the majority of postshock LV excitable area resulted from pre-existing excitable gaps during VF at the time of shock. This means that the larger excitable area in the LV wall allowed for postshock wavefronts of different origins to propagate unobstructed, increasing the likelihood of defibrillation failure. Thus, defibrillation shock outcome was affected by the preshock state. As shown in Figure 2C, whereas the earliest-propagated PA arose on the epicardium immediately after the 75-V shock end (white arrows in top panel), the increase in shock strength to 100 V changed the type of the earliest-propagated PA into a delayed breakthrough after an isoelectric window (middle panel). Further increase in the shock strength to 175 V caused the prolongation of the isoelectric window from 35 to 50 ms (compare middle and bottom panels). These simulation results suggest that high strength shocks caused the entire epicardium to become refractory and created midmyocardial

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excitable tunnel, through which a submerged initiating PA propagated during the isoelectric window, i.e., tunnel propagation occurred. After the isoelectric window, the initiating PA became the earliest-propagated PA, often reinitiating VF.

Fig. 2. Failed defibrillation following ICD shock.

Fig. 3. Examples of initiating PA following ICD shock.

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Mechanisms of Defibrillation Failure


We classified the events depending on the origin of the initiating PA, which was either pre-existing fibrillatory or shock-induced wavefront. Figure 3A shows an example of the tunnel propagation of pre-existing initiating PA after the near-DFT shock. A pre-existing fibrillatory epicardial wavefront (arrow in preshock panel) became submerged at shock end (arrow in 0-ms panel) and propagated within the midmyocardial tunnel following the 175-V shock (arrow in 20-ms panel). The tunnel formation and the submerging of the wavefront were due to the epicardium becoming refractory after this near-DFT shock (compare epicardial regions in 0- and 20-ms panels), resulting in an isoelectric window of LV epicardium. Tunnel propagation ended in a breakthrough (exit from the tunnel) on the near LV apex after the isoelectric window (32-ms panel), causing the shock to fail. In contrast, Figure 3B shows an example of the tunnel propagation of initiating PA induced by near-DFT shock. There was no pre-existing wavefront, resulting in initiating PA at shock end (0-ms panel). After the 125-V shock, a new shock-induced wavefront propagated intramurally through the LV tunnel (arrow in 16-ms panel), emerging focally on the LV epicardium after the isoelectric window (34-ms panel), and causing the shock to fail.

5. Implications of the tunnel propagation hypothesis The external monophasic shock study from our group (Rodriguez et al., 2005) demonstrated that shock outcome and the type of postshock arrhythmia depend on the distribution of the intramural excitable area (tunnel) formed by shock-induced deexcitation of previously refractory myocardium. We extended these findings and proposed the “tunnel propagation” hypothesis (Ashihara et al., 2008) for shock-induced arrhythmiogenesis that unifies all known aspects and findings regarding the postshock electric behavior of the heart, e.g., mechanisms of PA origin and isoelectric window after electric shocks, and the increase in isoelectric window duration for high strength shocks. Furthermore, we found that the tunnel propagation hypothesis is applicable to not only arrhythmia induction with external uniform-field shocks (Ashihara et al., 2008) but also defibrillation failure following nonuniform-field ICD shocks (Constantino et al., 2010). As previously suggested by the ULV hypothesis (Chen et al., 1986a; Shibata et al., 1988b; Wang et al., 2001), failed defibrillation by near-DFT shock may result from the reinitiation of VF following the isoelectric window since the pre-existing VF is entirely terminated by the shock (Figure 4A). If this is the case, the shock outcome must not be affected by the preshock state of ventricles. However, both defibrillation shock outcome and the DFT have probabilistic nature (Davy et al., 1987; Yashima et al., 2003). The tunnel propagation hypothesis (Figure 4B) explains surmises that for successful defibrillation, pre-existing wavefronts may not be terminated by the strong shock but instead remain hidden in the intramural tunnel, in contrast to what was previously believed. Moreover, the tunnel propagation hypothesis can link defibrillation shock outcome to the preshock state of the ventricles. Based on the tunnel propagation hypothesis, both pre-existing and new shock-induced wavefronts propagate through the intramural excitable tunnel during the isoelectric window before the reinitiation of VF (defibrillation failure), and therefore the probability of defibrillation failure varies depending on the timing of shock delivery during VF. In fact, here we observed in the simulations that postshock propagation within the LV mid-myocardium was strongly dependent on preshock state.

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Fig. 4. Comparison between the previous hypothesis for VF reinitiation and the tunnel propagation hypothesis.

However, the concepts proposed here do not limit the origin of the initiating PAs; these might have alternative origins, such as Purkinje fibers (Dosdall et al., 2007). The tunnel hypothesis is independent of the origin of wavefronts that propagate through it. The increase in isoelectric window after high strength shock can also be explained by the prolongation of the epicardial refractoriness (surface polarization), resulting in the longer tunnel propagation. This is because intramural virtual electrode polarization is lower magnitude than surface polarization (Entcheva et al., 1999) and thus the LV mid-myocardium, less affected by the shock, still contributes to the excitable tunnel even for higher strength shocks. Considering the high probability of the existence of the postshock excitable tunnel even for above-DFT shocks, defibrillation success may be explained by the fact that initiating PAs, originating within the wall, cannot find an excitable exit onto the epicardium and die out in the mid-myocardium. Obtaining such insight into the mechanisms of defibrillation would have been impossible with the use of experimentation alone.

6. Conclusion The tunnel propagation hypothesis, as part of the set of mechanisms operating during defibrillation, is expected to shed light on possible strategies for lowering DFT as well as for developing new defibrillation devices.

7. Funding sources This work was supported by Grant-in-Aid 21790717, 22136011, and 21500420 for Scientific Research from the Ministry of Education, Culture, Sports, Science, and Technology of Japan (to T.A.), and by NIH grants R01 HL082729 and R01 HL103428 and NSF grant CBET-0933029 (to N.T.).

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Mechanisms of Defibrillation Failure


8. References Ashihara, T.; Constantino, J. & Trayanova, N. A. (2008). Tunnel propagation of postshock

activations as a unified hypothesis for fibrillation induction and isoelectric window. Circ Res, Vol. 102, pp. 737-745

Chattipakorn, N.; Banville, I.; Gray, R. A. & Ideker, R. E. (2001). Mechanism of ventricular defibrillation for near-defibrillation threshold shocks: a whole-heart optical mapping study in swine. Circulation, Vol. 104, pp. 1313-1319

Chattipakorn, N.; Fotuhi, P. C.; Chattipakorn, S. C. & Ideker, R. E. (2003). Three-dimensional mapping of earliest activation after near-threshold ventricular defibrillation shocks. J Cardiovasc Electrophysiol, Vol. 14, pp. 65-69

Chen, P-S.; Shibata, N.; Dixon, E. G.; Wolf, P. D.; Danieley, N. D.; Sweeney, M. B.; Smith, W. M. & Ideker, R. E. (1986). Activation during ventricular defibrillation in open-chest dogs: evidence of complete cessation and regeneration of ventricular fibrillation after successful shocks. J Clin Invest, Vol. 77, pp. 810-823

Chen, P-S.; Shibata, N.; Dixon, E. G.; Martin, R. O. & Ideker, R. E. (1986). Comparison of the defibrillation threshold and the upper limit of vulnerability. Circulation, Vol. 73, pp. 1022-1028

Constantino, J.; Long, Y.; Ashihara, T. & Trayanova, N. A. (2010). Tunnel propagation following defibrillation with ICD shocks: hidden postshock activations in the left ventricular wall underlie isoelectric window. Heart Rhythm, Vol. 7, pp. 953-961

Davy, J. M.; Fain, E. S.; Dorian, P. & Winkle, R. A. (1987). The relationship between successful defibrillation and delivered energy in open-chest dogs: reappraisal of the defibrillation threshold concept. Am Heart J, Vol. 113, pp. 77-84

Dosdall, D. J.; Cheng, K. A.; Huang, J.; Allison, J. S.; Allred, J. D.; Smith, W. M. & Ideker, R. E. (2007). Transmural and endocardial Purkinje activation in pigs before local myocardial activation after defibrillation shocks. Heart Rhythm, Vol. 4, pp. 758-765

Entcheva, E.; Trayanova, N. & Claydon, F. J. (1999). Patterns of and mechanisms for shock-induced polarization in the heart: a bidomain analysis. IEEE Trans Biomed Eng, Vol. 46, pp. 260-270

Hwang, G-S.; Hayashi, H.; Tang, L.; Ogawa, M.; Hernandez, H.; Tan, A-Y.; Li, H.; Karagueuzian, H. S.; Weiss, J. N.; Lin, S-F. & Chen, P-S. (2006). Intracellular calcium and vulnerability to fibrillation and defibrillation in Langendorff-perfused rabbit ventricles. Circulation, Vol. 114, pp. 2595-2603

Maisel, W. H. (2006). Pacemaker and ICD generator reliability; meta-analysis of device registries. JAMA, Vol. 295, pp. 1929-1934

Rodriguez, B.; Li, L.; Eason, J. C.; Efimov, I. R. & Trayanova N. A. (2005). Differences between left and right ventricular chamber geometry affect cardiac vulnerability to electric shocks. Circ Res, Vol. 97, pp.168-175

Runsio, M.; Kallner, A.; Kallner, G.; Rosenqvist, M. & Bergfeldt, L. (1997). Myocardial injury after electrical therapy for cardiac arrhythmias assessed by troponin-T release. Am J Cardiol, Vol. 79, pp. 1241-1245

Shibata, N.; Chen, P-S.; Dixon, E. G.; Wolf, P. D.; Danieley, N. D.; Smith, W. M. & Ideker, R. E. (1988). Influence of shock strength and timing on induction of ventricular arrhythmias in dogs. Am J Physiol, Vol. 255, pp. H891-H901

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Shibata, N.; Chen, P-S.; Dixon, E. G.; Wolf, P. D.; Danieley, N. D.; Smith, W. M. & Ideker, R. E. (1988). Epicardial activation after unsuccessful defibrillation shocks in dogs. Am J Physiol, Vol. 255, pp. H902-H909

Swerdlow, C. D.; Kass, R. M.; O’Connor, M. E. & Chen, P-S. (1998). Effect of shock waveform on relationship between upper limit of vulnerability and defibrillation threshold. J Cardiovasc Electrophysiol, Vol. 9, pp. 339-349

Trayanova, N.; Eason, J. & Aguel, F. (2002). Computer simulations of cardiac defibrillation: a look inside the heart. Comput Visual Sci, Vol. 4, pp. 259-270

Trayanova, N.; Gray, R. A.; Bourn, D. W. & Eason, J. C. (2003). Virtual electrode-induced positive and negative graded responses: new insights into fibrillation induction and defibrillation. J Cardiovasc Electrophysiol, Vol. 14, pp. 756-763

Wang, N-C.; Lee, M-H.; Ohara, T.; Okuyama, Y.; Fishbein, G. A.; Lin, S-F.; Karagueuzian, H. S. & Chen, P-S. (2001). Optical mapping of ventricular defibrillation in isolated swine right ventricles: demonstration of a postshock isoelectric window after near-threshold defibrillation shocks. Circulation, Vol. 104, pp. 227-233

Yashima, M.; Kim, Y-H.; Armin, S.; Wu, T-J.; Miyauchi, Y.; Mandel, W. J., Chen, P-S. & Karagueuzian, H. S. (2003). On the mechanism of the probabilistic nature of ventricular defibrillation threshold. Am J Physiol Heart Circ Physiol, Vol. 284, pp. H249-H255

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1. Introduction

Only relatively recently have we begun to understand how defibrillation shocks work onthe mechanistic level (Cheng et al., 1999; Trayanova & Skouibine, 1998). Virtual electrodepolarization has offered a plausible mechanism for explaining far field effects of defibrillationshocks. However, this body of work has not considered the role of the specialized cardiacconduction system, the Purkinje System (PS), in the defibrillation process.Despite its crucial role in activation, relatively little is known about the role of the PS indefibrillation. This is due to several factors which make recording from it challenging: ThePS is a fine structure lying on the endocardium which makes it difficult to see and impalewith microelectrodes. While Langendorf preparations allow easy access to the epicardium foroptical recordings, the PS lies on the endocardium and is, therefore, much harder to accesswhile maintaining the integrity of the ventricles. Depending on species, the PS penetratesvarious depths into the myocardium, masking midmyocardial activation. Plunge electrodesare one option for recording from the midmyocardium, but amplifier saturation immediatelyfollowing large shocks would lose important information. Since the PS fibres are fine,the signals produced by them are very small and get easily swamped by signals from themyocardium. This is true for both electrical and optical recordings. Computer modelling,therefore, offers an attractive platform for studying the role of the PS in defibrillation, sincethe electrical activity everywhere in the system is known and can be visualized.

2. Description of the Purkinje System

The specialized conduction system begins at the atrioventricular node with the bundle of His.The His bundle runs through the ventricular septum, and bifurcates into the left and rightTawara branches, which further subdivide into major fascicles and later form a network onthe endocardial surface. There are three major fascicles in the left ventricle, and two in theright.A large portion of the conduction system is located within the ventricular cavities and istermed free running. Fibres that run within the ventricular walls are very difficult to visualize,requiring histological examination. Referring to the PS network as a tree is incorrect since,unlike true tree structures, fibres follow paths which join back together and at the final level,

The Role of the Purkinje System in Defibrillation Edward J Vigmond1, Patrick M. Boyle1 and Makarand Deo2

1University of Calgary 2University of Michigan

1Canada 2U.S.A.


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2 Will-be-set-by-IN-TECH

forming more of a mesh-like topology. This may give redundancy to the network so that apart of the PS may fail without comprising sinus activation.Segments of the PS run as bundles wrapped in collagen sheaths. This is easily seen in thebundle of His, which is a large trunk of many fibres. At branch points of thicker fibre bundles,individual fibres do not bifurcate. However, in the distal PS, where a network segment may beformed from a few fibres, individual fibres may branch. Longitudinal coupling is very strong,while lateral connections are sparser.The PS is electrically isolated from the myocardium except for the termini of the network,where Purkinje-Myocyte Junctions (PMJs) are formed. While the PS can be selectivelystained and visualized on the endocardium, determining PMJ locations is difficult. PMJsmay be located well within the ventricular wall, which means that histological examination isnecessary. Currently, the number of functional PMJs is not well characterized. Although thedensity of the PS on the endocardium appears high, the number of penetrating segments isunknown, as is the number of PMJs that successfully transmit pulses (Morley et al., 2005).There are significant species differences in the degree of transmural penetration of terminalPS fibres. Species can roughly be grouped into three categories (Canale et al., 1986): Group1 comprises the ungulates which have deeply penetrating fibres, reaching almost to theepicardium. Group 2 includes primates and carnivores which have PS termini that penetrateabout 1/3 of the way through the wall. Group 3 contains rodents with very little penetrationof the PS into the myocardial wall. This factor may be especially important for interpretingexperimental results between species.

3. Modeling methods

Modelling the reaction of the of the ventricles and PS to defibrillation shocks is acomputationally demanding task since the timestep during the defibrillation pulse must bevery small. This is because high field strengths induce rapid changes in model parameters,and numerical instabilities may develop Vigmond et al. (2008). Lastly, ionic models aredeveloped under normal physiological conditions. Defibrillation shocks are outside thebounds of the models developed so additional measures need be taken such as adding anionic current to properly account for high voltage responses Ashihara & Trayanova (2004).The bidomain equations are the most complete macroscopic description of cardiac tissue,even being predictive of polarization patterns(Sepulveda et al., 1989) induced by extracellularstimulation. They can be cast into a elliptical and parabolic equation:

∇ · (σi + σe)∇φe = −∇ · σi∇Vm − Ie (1)

∇ · σi∇Vm = −∇ · σi∇φe + βIm (2)

where subscripts i and e denote intra- or extracellular quantities respectively, φ is potential,σ̄ is the conductivity tensor, Ie is an applied extracellular stimulus current, β is the surfaceto volume ratio, and Im is the transmembrane current. Another set of ordinary differentialequations is required to model the flow of the ions across the cell membrane and isembedded in Im. These equations can be solved using an operator splitting method whereextracellular potential (Eqn. 1), ionic currents, and the transmembrane voltage (Eq. 2 aresolved sequentially (Vigmond et al., 2008).

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The system is solved by using the finite element method. In our simulations, rabbit ventriculargeometry (Vetter & McCulloch, 1998) was discretized at approximately 350 μm resolutionresulting in about 550,000 nodes comprising the myocardium and another 300,000 nodescomprising the cavities and a surrounding bath. The PS was modelled as a network of onedimensional cubic Hermite finite elements added within the myocardial mesh (Vigmond &Clements, 2007). Two methods have been used to generate PSs for computer modellingstudies: One approach is more generic and does not rely on mapping a particular PS.The endocardia of the two ventricles are unrolled and the PS drawn on according to basicphysiological principles outlined in the preceding section (Vigmond & Clements, 2007). Afractal method could be used to further increase the endocardial mesh density (Ijiri et al.,2008). The second approach uses high resolution imaging to reconstruct the free running PS(see Fig. 1). This may further be augmented by staining the PS to reveal the endocardialmesh. With either method, the insertion of the PS into the myocardium must follow arule-based method since the PS cannot be imaged within the myocardium, but requirescareful histological examination, electron microscopy or genetic tagging (Miquerol et al.,2004). to reveal its transmural course (Ono et al., 2009). Furthermore, while the endocardialnetwork appears dense, the number of functional PMJs is far less (Morley et al., 2005).The one-dimensional cubic Hermite finite elements are only electrically connected to themyocardium at end points through gap junctions. Due to their higher polynomial order, cubicHermite elements possess the property that they can enforce current continuity at junctions,as well as at PMJs. Discretization of the PS was at the cellular length level with discrete gapjunctions.Since the discretization of the finite element model is much coarser than the actual physicalPMJ structure, a phenomenological approach is followed whereby a single PS terminusstimulates a volume of myocardium. The current flowing from the PS into a myocardial nodeis given by

iPMJ =1


m − Vmyom ) (3)

and iPMJ is treated as an intracellular stimulus by the myocardium.From the PS perspective, the currents are handled as explicit boundary conditions:

iL =1



m − Vmyom,j )iL = (4)

where j is the set of myocardial nodes coupled to a PS terminus, and K is a scaling factorwhich accounts for the current amplification by transitional cells which occurs at scales finerthan that discretized. By setting RPMJ and K, it is possible to recreate asymmetric propagationacross the PMJ with an anterograde transmission delay on the order of 5 ms and retrogradetransmission delay on the order of 1 ms as observed experimentally Huelsing et al. (1998);Wiedmann et al. (1996).

4. Role in fibrillation

It is important to first understand the role of the PS in fibrillation. It has been implicatedas a major player in the initiation and maintenance of fibrillation. First, the PS can be a

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source of focal firing. Chemical ablation of the PS by Lugol’s solution, to selectively removethe endocardial layer and the PS embedded within it, has been shown to greatly diminishrepetitive endocardial focal discharges and eliminate sustained VF (Wu et al., 2009). Partof this comes from the intrinsic nature of the Purkinje cells, which are resistant to ischemiabecause of large glycogen stores (Streit, 1987). This is especially important in long durationVF, at which point much of the myocardium has been compromised.Second, the PS can provide alternative pathways for reentrant pathways. This is supportedby experiments wherein chemical ablation of the PS has also been shown to reduce theinducibility of ventricles to VF(Armiger & Knell, 1988; Dosdall et al., 2008) In agreement,computer simulations have also shown an increase in VF vulnerability to large shocks whena PS is present (Deo et al., 2009). Several factors were identified which were responsible forthe arrhythmogenic influence of the PS: 1) The presence of a PS produces more activations,which directly lead to reentrant activity. 2) The frequency of scroll waves is increased sincethe PS accelerates conduction. This acceleration may be visible as a breakthrough occurringahead of the wavefront, or it may not be visible since the breakthroughs become coincidentwith the wavefront. This latter synchronization of activity starts to occur after several cycles.3) Refractory tissue forms small islands around the PMJs, which induce more wavebreakswhen a wavefront tries to propagate through the region. Finally, 4) the PS can provide escapepathways for wavefronts which would otherwise die by running into refractory tissue.The PS affects fibrillation in many ways. Exposure to a large shock may disrupt pathwaysthrough the PS to terminate reentry, or ectopically firing PS cells may be reset. Disruptionby an external shock may, therefore, influence reentrant activity but exactly how these factorsrelate remains to be elucidated.

5. Response to electric fields

The response of myocardial tissue to a strong electric shock depends on the orientation ofthe cells with respect to the electric field and how conductivity changes with respect to thedirection of the electric field. This is seen in the expression for the generalized activatingfunction, S (Sobie et al., 1997):

S = Gi : ∇(∇φe) + (∇ · Gi) · ∇φ (5)

where the colon signifies the matrix inner product. Looking at the two terms, activation canresult from a gradient in the electric field, or from the irrotational portion of the conductivityfield. Conductivity must be defined as a spatially-dependent tensor since its directionalproperties are determined by cellular orientation, which varies throughout the heart. Thisdirectional dependence arises from gap junction connectivity, which allows current to mosteasily flow longitudinally and experiences the highest resistance flowing across laminar sheets(Legrice et al., 1997).The PS is essentially a network of one dimensional cables which repeatedly bifurcate andunify. In addition to the complex topology, the PS fibres undergo sudden changes indirection, as well as have termini which abruptly end. These properties all get reflectedin the conductivity tensor. The complicated path of the fibres ensures that at least partof the PS is aligned in such a way as to be excited by the applied electric field. The endof the fibre is an abrupt discontinuity to zero conductivity outside of the fibre. Terminal

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fibre segments which are aligned with the electric field will, therefore, have transmembranepotentials induced. Ends which face the cathode will be depolarized while ends facing theanode will be hyperpolarized.The effect of field stimulation is shown in Fig. 1, where an MRI-derived isolated rabbit PSis exposed to shocks. The normal activation pattern is shown for reference, where it can beseen that it takes more than 30 ms for the entire network to be excited. When a shock isapplied, many regions are excited simultaneously, not just one. This greatly abbreviates theexcitation time of the tree and consequently, will result in near synchronous activation of themyocardium.

Fig. 1. Response of MRI-derived rabbit Purkinje System to electric fields. A: Normalactivation starting at the proximal His bundle. B: 2.5 ms 125 mA point current source in theright ventricle C: 3 ms uniform 5 V/cm field oriented along the major axis of the heart. Colorindicates transmembrane voltage. Times are given relative to stimulus onset.

Even on the cellular level, the PS reacts differently to high voltage shocks compared toventricular myocytes. Using a papillary muscle preparation, Li et al. (1993) found that abovea field strength of 20 V/cm, shocks induced a baseline shift and high frequency bursting in PScells. In contrast, the ventricular myocytes entered a refractory state immediately after largeshocks.Thus, the PS is easily excited by electric field. Due to its one-dimensional nature and complexfibre trajectories, some part of it is always in a position to be excited by the field. This leads torapid activation of the PS and, hence, of the myocardium connected through the PMJs. This

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Fig. 2. Response of the quiescent ventricles and PS to a 2.5 V/cm shock. Field orientation isalong the long axis, as shown in A. When the PS is present, additional far-field activationscan be seen on the endocardial surface.

will tend to be antiarrhythmic since the excitable gaps, which allow activity to keep excitingrecovered tissue, will be more quickly consumed.

6. Quiescent ventricle studies

Simulations of the application of defibrillation-strength shocks to the quiescent ventricles withand without PS allow for the contribution of the PS to be identified. When stimulation isapplied, large polarization gradients form in segments of the PS that are parallel to the electricfield. The myocardium is also subject to excitation by direct and virtual electrode stimuli,but activation patterns in the two tissues do not necessarily coincide since PS fibres do notalways run in the same direction as underlying ventricles cells. Furthermore, current flowin PS fibres is physically constrained and excitation spreads rapidly through the network, soeven very weak shocks produce rapid excitation of the entire network. Thus, under the rightcircumstances, the contribution of the PS to the response of the quiescent ventricles can beremarkable.Consider Fig. 2, where a 2.5 V/cm field is applied along the long axis of the heart (from apexto base). Far-field excitations on the endocardial surface due to anterograde transmissionof shock-induced activity in the PS is clearly visible (A); the presence of these effects is dueto rapid propagation in the PS (B) and the relative lack of myocardial excitation from thefield, which can be seen explicitly in the ventricles-only response (C). Consequently, the totalventricular activation time (tact) is dramatically abbreviated.

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X Y ZPS+ PS− % ↓ PS+ PS− % ↓ PS+ PS− % ↓

–2.5 V/cm 55.7 100.1 44.3 29.3 29.8 1.6 28.4 29.1 2.2+2.5 V/cm 41.1 63.1 34.8 26.1 26.9 3.2 28.2 29.4 4.1

–5 V/cm 43.1 67.0 35.6 28.3 28.4 0.1 28.2 28.3 0.3+5 V/cm 33.6 57.3 41.4 24.6 24.8 1.0 27.5 27.7 0.7

–7.5 V/cm 37.3 42.4 12.1 28.2 28.2 0.2 28.5 28.3 0.5+7.5 V/cm 30.7 38.3 19.9 22.6 23.2 2.2 27.6 27.7 0.3–10 V/cm 30.0 36.1 17.0 28.4 28.3 0.3 28.1 28.0 0.5+10 V/cm 30.1 34.5 12.6 22.4 22.4 0.0 27.8 27.9 0.2

Table 1. Total activation time (tact) with and without PS. tact was measured between thebeginning of the shock and complete ventricular activation for four shock strengths in sixdirections, as described in the text.

In terms of tact, the contribution of the PS to the response of the quiescent ventricles is onlysignificant in cases where myocardial tissue in the vicinity of Purkinje-myocardial junctions(PMJs) is not excited by the shock. For the simulations discussed here, three orthogonalorientations were tested–along the long axis (X), across the septum (Y), and along the septum.As shown in the tabulated results for all simulations (Tab. 1), significant tact abbreviation wasonly observed for shocks in the X direction.

Fig. 3. Local activation times for different field orientations, 2.5V/cm shock. Earlyactivations due to PS activation make the biggest difference for shocks in the X direction,where myocardium near the PS is not significantly activated by the field. For shocks in the Yand Z differences, the PS causes some regions to activate much earlier (i.e. LV endocardialfree-wall for Y), but overall activation time is not significantly abbreviated.

Interestingly, while the PS did not have a significant effect on tact for shocks in the Y andZ directions, it did sometimes alter the pattern of local activation. For example, as shown in

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Fig. 3, a weak shock in the Y direction resulted in much earlier activation of the LV endocardialfree-wall due to PS excitations. Although tact did not differ between simulations with andwithout the PS in this case, the modified order of activation could have consequences onsubsequent beats due to gradients in refractoriness that might arise from local heterogeneity.

Fig. 4. Local activation times for different field strengths along the long axis. As shockstrength increases, the role of the PS in the response of the quiescent ventricles is diminished,since the field causes excitation in a larger amount of myocardium. For the strongest shock(10 V/cm) only a few regions near PMJs, particularly in the septal region, contribute to tactabbreviation. Stronger shocks abbreviate the activation delay between coupled PS andventricular cells.

Increasing shock strength resulted in larger regions of myocardial polarization from the field,which effectively reduced the importance of the PS contribution in the response; this accountsfor the diminishing returns in tact abbreviation for shocks in the X direction, which is obviousin Tab. 1. As shown in Fig. 4, for the strongest shocks along the long axis simulated in thisstudy, the primary source of tact abbreviation was early activation of the septum, which is noteasily excited by such shocks.Interestingly, increased shock strength seemed to hasten the local effects of PS onendocardium. For example, in Fig. 4A, consider the dark regions on the endocardial surfaces,which are associated with early activation due to PS excitation. As the strength of stimulationincreases (left to right), these regions become darker and larger, suggesting an abbreviation ofanterograde transmission delay, perhaps due to the larger gradients in polarization. Theseobservations were confirmed by inspecting voltages at the junctional voltage level (notshown), where the delay between coupled PS and ventricular cell upstroke was found to bealmost uniformly shorter for larger shocks.

7. Isoelectric window

In general, shocks above a certain minimal strength result in sustained reentry; however,there is also a threshold for a maximum strength above which reentry is not induced. ThisUpper Limit of Vulnerability (ULV) is an important measure since it tends to correspond to

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the Defibrillation Threshold (DFT)–the minimum shock strength necessary to halt ventricularfibrillation(Chen, Shibata, Dixon, Martin & Ideker, 1986). The ULV is particularly valuableas an easier to find surrogate measurement for DFT. Thus, insights on the ULV will provideinsight on the DFT, which is of direct clinical importance.Following failed defibrillation shocks near the ULV, there is a period of time during which newactivity is not seen on the epicardium.(Chen, Shibata, Dixon, Wolf, Danieley, Sweeney, Smith& Ideker, 1986) This Isoelectric Window (IW) can be considerable, on the order of tens ofmilliseconds. It ends when activations break through on the epicardium and reentry resumes.Many long-standing questions surround this phenomenon: What is the nature of concealedactivity during the IW? What is the mechanism that allows it to remain hidden for such a longtime? Some researchers have argued that the PS plays an important role;(Dosdall et al., 2010)others have proposed the tunnel propagation theory, which suggests that cardiac surfaces aredriven into refractory states and post-shock activity is confined to a thin transmural spacewith no excitable path to the epicardium.(Ashihara et al., 2008; Constantino et al., 2010) Sometime later, the surface tissue recovers from refractoriness and activations break through. Whilethe computer simulations carried out to construct this hypothesis were carefully constructed,it must be noted that they did not include a model of the PS.For the purpose of comparison, we performed a set of simulations with the PS. A cross-shockprotocol was applied with the second shock near the ULV to identify possible contributions ofthe PS during the IW. First, the ventricles were excited, either by transmembrane stimulationat the apex or by His bundle current injection. The former emulates experimental preparationswhile the latter results in a more physiological excitation pattern. During ventricularrepolarization, a shock with appropriate strength and timing to induce arrhythmia wasdelivered by parallel plates, with the extracellular electric field oriented along the short axisof the heart.

7.1 Effects of varying coupling intervals and shock strengths on IWFig. 5 shows IW duration within the window of vulnerability for various combinationsof shock timing–i.e. the coupling interval (CI)–and strength. For the AP+PS pre-shockconfiguration (A), the average IW decreased from 36 to 21 ms as CI increased from 145 to155 ms. Similar IW gradients were seen for decreasing CI within the AP-PS (B) and His (C)configurations, from 49 to 34 ms and from 37 to 19 ms, respectively.A similar trend was observed for increasing shock strength. In the AP+PS and Hiscases, where IW duration was determined by the time between the shock and the firstPS-to-myocardial activation, the average IW decreased with increasing shock strength. ForAP+PS, shocks ranging from 3.3 to 9 V/cm produced average IWs between 33 and 23 ms; forincreasing shock strengths within the His configuration, IWs decreased from 31 to 20 ms. Inthe AP-PS configuration, where IW duration was determined by the spread of shock-inducedactivations in the apical region, average IW was reduced from 47 to 34 ms as shock strengthincreased from weakest to strongest. In the AP+PS and His cases, the PS was actively involvedin the generation of first post-shock activity, so it was unsurprising that the IW was shorterthan in AP-PS, where the PS was absent. This observation supports the hypothesis that the PSplays an important role in the immediate response to defibrillation shocks.

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(a) (b) (c)

Fig. 5. IW duration for various combinations of shock strength and timing for three reentryinduction protocols: (A) apical pacing with the PS (AP+PS), (B) apical pacing without the PS(AP-PS), and (C) His pacing. In general, longer CIs lead to shorter IWs.

7.2 First post-shock activation and the IW periodActivations were always observed in the PS immediately following the shock. During AP+PSruns, the first post-shock myocardial activation emanated from the PS 11 ms after the shock.After 15 ms, significant endocardial activation had occurred, as shown in Fig. 6(a). Thisis shorter than clinically-observed IWs due to the significant delay during which excitationpropagates from the site of transmission to the epicardium. Fig. 6(b) shows the appearanceof PS activations on the epicardium 23 ms after the shock; in most shocks applied to modelswith the PS during the vulnerable period, this pattern of excitation led to the first epicardialbreakthrough. Note that the epicardial activation site is immediately opposite the endocardialPS insertion point. Mechanistically, the first PS activation initiated an endocardial rotor, whichled to an epicardial activation (black arrow in Fig. 6); the underlying pattern of transmuralactivation is clearly shown.As discussed earlier in this chapter, the distinct physiology and geometry of the PS leadto different polarization patterns than in the myocardium; in these simulations, the earliestpost-shock activation was always observed within the PS. Excitation spread rapidly throughthe network and coupled myocardial tissue was activated by anterograde transmission. Thus,the first post-shock ventricular activation always emanated from the PS. In simulationswithout the PS, large gradients were induced near the apical region, leading to post-shockwavefronts.Most experimental studies that reported an IW after defibrillation-level shocks mapped onlyepicardial or endocardial surfaces. Recently, Dosdall et al. (Dosdall et al., 2007) observedepicardial and subepicardial activations in pigs soon after shocks. Since the PS in pigsexhibits full transmural insertion (Chattipakorn et al., 2003), it is plausible that these mappedactivations were first post-shock excitations provided by the PS. Furthermore, the earliestmyocardial activations recorded were preceded by Purkinje potentials, which is in agreementwith our findings. To the best of our knowledge, this is the first attempt to map PS activationsfollowing defibrillation. While limited spatial resolution prevented the authors from stating aclear conclusion, the results suggest that our simulation results are a step in the right direction.Other studies have observed endocardial or intramural activations that broke through to theepicardium 42 ms post-shock in sheep hearts (Evans & Gray, 2004). Given the fact that thePS terminates in the subendocardium in sheep,(Ansari et al., 1999) these observations are also

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Fig. 6. Earliest postshock activation. (a) The first activation emanating from the PS 15 msafter the shock is clearly seen in the endocardial cross-section. (b) After 23 ms, the PSactivation provides a focal breakthrough on the epicardium. Note the breakthrough site(arrow) is situated opposite the PS insertion point. Transmural depolarization due to theearliest postshock activation is evident. The right panel of (a) shows the LV endocardial freewall while the right panel of (b) shows a cross-section perpendicular to the septum with theposterior surface hidden.

consistent with our findings. Our study involves a smaller heart size, which explains thereduced IW durations compared to experimental values discussed here.In our simulations, the PS was always strongly excited by the shock. In somecases, we observed midwall excitations similar to those observed in tunnel propagationstudies.(Ashihara et al., 2008; Constantino et al., 2010) These were isolated by surfacerefractoriness, with excitable tissue confined to intramural paths. However, activations thatoriginated in the PS broke through more quickly than purely myocardial midwall excitations,as shown in Fig. 7. Rapid conduction in the PS ensured that this happened consistently.To further test our hypothesis that the PS was the source of epicardial breakthroughs followingthe IW, we changed the transmural insertion depth of PS endpoints. Figure 8 shows that theIW duration is dramatically reduced when the PS penetrates to the subepicardial layer. Thisis consistent with the PS being the primary source of post-shock epicardial activations due torapid field-induced activations: deeper penetration brings PS fibres closer to the epicardium,so it makes sense that the IW is shorter. We observed that IW duration varied from 12 ms(full insertion) to 30 ms (no insertion). Epicardial breakthrough sites remained the same inall simulations for a given insertion depth; these sites were consistently situated opposite PS

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(a) (b) (c) (d) (e)

Fig. 7. Transmural postshock activations in the septum (top) and LV free wall (bottom).White arrows indicate the propagation pathways of transmural wavefronts; black arrowsindicate epicardial breakthrough sites (a)-(d) or PS-induced propagating activity (e). In (a)and (b), the response to a 10 ms shock is shown in the absence of the PS. Activations originatein the septum and propagate through the free wall. In (c) and (d), similar activations are seenfollowing a 5 ms shock using the AP+PS configuration. Wavefronts originating from PStransmission arrive at the epicardium before shock-induced myocardial wavefronts. (e)shows the response to an even shorter shock (3 ms) for the same configuration. Dashed linesrepresent cross-section planes relative to the top and bottom views. Vm is shown with thesame color scheme used in Fig. 1.

insertion points. While IW abbreviation was indisputable for the fully-penetrating PS, it wasless clear for cases where the PS terminated in the midwall. Notably, these cases were subjectto a higher degree of variability from sample to sample, which could be the result of surfacepolarization blocking PS activity.In our model, rapid conduction through the PS was the source of the epicardial breakthroughterminating the IW. However, there are several limitations and differences with Trayanova’swork. We only considered monophasic defibrillation shocks while her group consideredbiphasic shocks which would lead to different postshock surface states. Our modelling of thePS cell response to large shocks may not be accurate. This is true for all ionic models wherebehavior outside of the physiological voltage range is not well characterized. If PS conductionbecame compromised due to a field induced conduction block, or refractory myocardiumprevented anterograde transmission across the PMJs, then the tunnel propagation mechanismcould account for the IW. In reality, it is likely that both mechanisms play a role, dependingon circumstances.

8. Defibrillation

A limited set of computer simulations has been performed with ventricles including a modelof the PS(Deo et al., 2009). With an 8 V/cm defibrillation shock, ventricles with a PS weresuccessfully defibrillated while those without a PS were not. The most obvious difference

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Fig. 8. Effect of PS insertion depth on IW duration. The IW was longest for surface-bound PSand shortest in the case of fibre endpoints that penetrated to the sub-epicardial layer. Errorbars correspond to maximum deviation from mean values (n = 6).

between the two situations was the more rapid and widespread activation of the epicardiumwhich eliminated excitable gaps. Without the PS, an excitable gap persisted under the anode,allowing reentry to be reinduced. Thus, the PS aided in defibrillation. Experimentally,application of Lugol’s solution to the endocardium results in a doubling of DFT(Damianoet al., 1986), suggesting that the PS facilitates defibrillation at lower field strengths.

9. Summary

Based on experimental findings, which are supported by our modelling studies, we concludethat the PS plays a major role in defibrillation. Due to its cable-like nature and complicatedgeometry, it is excited in many places by an applied electric field, which leads to rapidactivation of the entire network. Any excitable gaps are quickly consumed and reentry cannotbe reestablishing. This effect is less prominent as shock strength is increased since moremyocardium is directly excited by the shock. The complex postshock propagation patternpresent with a PS may also play a role in rapid ventricular activation to stop fibrillation.

10. References

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Armiger, L. C. & Knell, C. M. (1988). Fine structural alteration in the atrioventricular junctionalconduction tissues of the dog heart during severe ischaemia., J Submicrosc Cytol Pathol20(4): 645–656.

Ashihara, T., Constantino, J. & Trayanova, N. A. (2008). Tunnel propagation of postshockactivations as a hypothesis for fibrillation induction and isoelectric window., Circ Res102(6): 737–745.URL:

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Ashihara, T. & Trayanova, N. A. (2004). Asymmetry in membrane responses to electric shocks:insights from bidomain simulations., Biophys J 87(4): 2271–2282.URL:

Canale, E., Campbell, G., Smolich, J. & Campbell, J. (1986). Cardiac muscle:, Vol. II,Springer-Verlag, Berlin-Heidelberg-New York-Tokyo, chapter 7, pp. 60–103.

Chattipakorn, N., Fotuhi, P. C., Chattipakorn, S. C. & Ideker, R. E. (2003). Three-dimensionalmapping of earliest activation after near-threshold ventricular defibrillation shocks.,J Cardiovasc. Electrophysiol. 14: 65–69.

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Chen, P. S., Shibata, N., Dixon, E. G., Wolf, P. D., Danieley, N. D., Sweeney, M. B., Smith, W. M.& Ideker, R. E. (1986). Activation during ventricular defibrillation in open-chestdogs. evidence of complete cessation and regeneration of ventricular fibrillation afterunsuccessful shocks., J Clin Invest 77(3): 810–823.URL:

Cheng, Y., Mowrey, K. A., Wagoner, D. R. V., Tchou, P. J. & Efimov, I. R. (1999).Virtual electrode-induced reexcitation: A mechanism of defibrillation., Circ Res85(11): 1056–1066.

Constantino, J., Long, Y., Ashihara, T. & Trayanova, N. A. (2010). Tunnel propagationfollowing defibrillation with icd shocks: hidden postshock activations in the leftventricular wall underlie isoelectric window., Heart Rhythm 7(7): 953–961.URL:

Damiano, R. J., Smith, P. K., Tripp, H. F., Asano, T., Small, K. W., Lowe, J. E., Ideker, R. E. &Cox, J. L. (1986). The effect of chemical ablation of the endocardium on ventricularfibrillation threshold., Circulation 74(3): 645–652.

Deo, M., Boyle, P., Plank, G. & Vigmond, E. (2009). Arrhythmogenic mechanisms ofthe purkinje system during electric shocks: a modeling study., Heart Rhythm6(12): 1782–1789.URL:

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Dosdall, D. J., Osorio, J., Robichaux, R. P., Huang, J., Li, L. & Ideker, R. E. (2010).Purkinje activation precedes myocardial activation following defibrillation afterlong-duration ventricular fibrillation., Heart Rhythm 7(3): 405–412.URL:

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Evans, F. G. & Gray, R. (2004). Shock-induced epicardial and endocardial virtual electrodesleading to ventricular fibrillation via reentry, graded responses and transmuralactivation, J Cardiovasc. Electrophysiol. 15: 79–87.

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1. Introduction

Most current Implantable Cardioverter Defibrillators (ICD) use intracardiac leads forelectrogram (EGM) sensing and defibrillation (Belott & Reynolds, 2007). Intracardiac leadsconsist of several electrodes that for the basic functionality of ventricular tachyarrhythmiadetection and termination, are inserted transvenously into the right ventricle (Gradaus et al.,2003; Swerdlow et al., 2007). In addition to intracardiac electrodes, ICD also use the casing ofthe implant as an indifferent, distant electrode.In ICD technology, three main intracardiac lead configurations are distinguished based on thecombination of electrodes that they use, namely unipolar, dedicated bipolar and integratedbipolar. Unipolar leads, so-called because they use the casing of the implant as an indifferentelectrode, consist of a single electrode located in the right ventricle, whereas bipolar leads,both dedicated and integrated, consist of two closely spaced electrodes located in the rightventricle. In general, unipolar lead configurations are used for cardiac defibrillation, whilebipolar lead configurations are used for EGM sensing, i.e. they provide with the EGM signalsfrom which heart rhythm can be extracted.Previous studies indicate that lead configuration can affect EGM sensing and ICDperformance. For instance, it is well known that fundamental EGM features such aswave duration, wave amplitude and power spectrum, depend on the configuration of therecording leads (DeCaprio et al., 1977; Jenkins, 1992; Langberg et al., 1988; Parsonnet et al.,1980). Also, differences in ventricular fibrillation detection and redetection times have beenreported when comparing ICD dedicated and integrated bipolar leads (Cooklin et al., 1999;Frain et al., 2007; Goldberger et al., 1998; Natale et al., 1996). Other studies have addressedthe effects on EGM sensing, of artifacts originating from non-ventricular bioelectric sources.For example, inappropriate ICD discharges have been ascribed to myopotentials oversensing(Deshmukh & Anderson, 1998; Kowalski et al., 2008; Sandler & Kutalek, 1994; Schulte et al.,2001). Pacing stimulus artifacts, which are often associated to ICD undersensing, have beenfound to be greater in integrated than in dedicated bipolar leads (Menz et al., 1998). Finally,an optimized lead design for atrial sensing has been proposed, in order to facilitate rejectionof artifacts such as R-waves and myopotentials (Nash et al., 2005). Therefore, the existing

Analysis of the Lead Sensitivity Distribution in Implantable Cardioverter Defibrillator

Jesús Requena-Carrión1, Juho Väisänen2, Jari Hyttinen2 and Juan J. Vinagre-Díaz1

1University Rey Juan Carlos 2Tampere University of Technology

1Spain 2Finland


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evidence indicates that by carefully designing ICD intracardiac leads, EGM sensing and henceICD overall performance can be further improved.The effects of lead configuration on ICD sensing performance can be explored throughthe notion of lead sensitivity distribution, also known as lead field. The lead sensitivitydistribution describes the ability of leads to measure the electrical activity generated bybioelectric organs and tissues in the body and hence, it can help to identify the sourcesof bioelectric artifacts and to quantify their effects. In addition to this, the analysis ofthe lead sensitivity distribution can contribute to widen the range of functionality of ICDsystems by providing with an estimation of lead spatial resolution. The quantification ofthe lead spatial resolution could be of great interest, especially in those scenarios wherethe underlying cardiac pathology is caused by local physiological abnormalities such asmyocardial ischemia (Asbach et al., 2006; Bunch & Day, 2008; Williams et al., 2008), or whenthe underlying pathology can be related to tissue spatial heterogeneities (Zaitsev et al., 2000).The sensitivity distributions of two unipolar and two bipolar ICD intracardiac leadconfigurations have been investigated in a previous study (Requena-Carrión et al., 2009). Bycombining a detailed numerical model of the human thorax and finite difference methods(FDM), the sensitivity distribution at the ventricles of each lead configuration was obtained.The sensitivity distribution also allowed to quantify the spatial resolution of each leadconfiguration, and significant differences in sensing between different lead configurationswere found. However, a more complete picture of EGM sensing in ICD should account forthe measurement of the activity of other bioelectric sources that could affect ICD performance,such as myopotentials. The analysis of the sensitivity of intracardiac leads at other bioelectricsources in the human body would improve our understanding on how electrophysiologicalartifacts affect EGM sensing and therefore, it would help to devise new strategies to rejectsuch artifacts by means of designing new lead configurations.In this study, the sensitivity distribution of four ICD intracardiac lead configurations iscalculated at the ventricles, the atria and near skeletal muscles. For that purpose, adetailed computational model of the human thorax is used in combination with numericalmethods. Additionally, a discrimination index which is based on the sensitivity distributionis used for quantifying differences in sensing at the ventricles, atria and near muscles. Thisdiscrimination index takes the accumulated sensitivity of ICD leads at the ventricles, wherethe signals of interest are originated, and compares it with the accumulated sensitivity at theother bioelectric sources.

2. Principles of bioelectric signals measurement

Bioelectric measurement models consist of two basic elements, namely a bioelectric sourceand a volume conductor (Malmivuo & Plonsey, 1995). The bioelectric source is the biologicaltissue or organ that generates electric currents for regulating a physiological function, whereasthe volume conductor is the conducting medium in which the bioelectric source resides.Well-known examples of bioelectric sources are the heart, the brain and the skeletal muscle;the human body as a whole, on the other hand, behaves electrically as a volume conductor.As a consequence of the activity of bioelectric sources, a time-varying voltage gradient isinduced across the volume conductor. This voltage gradient can be measured by means ofmeasurement leads, which consist of at least one pair of electrodes in contact with the volumeconductor. From the point of view of the measurement leads, the time-varying measuredvoltage u(t) can be modeled mathematically as a weighted linear combination of the currents

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Analysis of the Lead Sensitivity Distribution in Implantable Cardioverter Defibrillator 3

J(t, v) generated by the bioelectric source V:

u(t) =∫

VL(v) · J(t, v)dv. (1)

In this equation L(v) denotes the lead sensitivity distribution and it describes the ability of thelead to measure the bioelectric currents J(t, v) generated by the source at v ∈ V. In general,since the lead sensitivity distribution will be larger in some regions of the bioelectric sourcethan in others, the contribution to the total measured voltage will vary from one region withinthe bioelectric source to another. As a consequence, it can be said that the lead sensitivitydistribution focus the measurement on selected regions within the bioelectric source andtherefore, the lead sensitivity distribution will define a characteristic lead spatial resolution.Whenever more than one bioelectric source reside within the volume conductor, by virtue ofthe superposition principle the total voltage measured by the leads can be expressed as thesum of the voltages induced by each source independently. For example, if two sources V1and V2 exist, the total voltage u(t) will be expressed as:

u(t) = u1(t) + u2(t) =∫


L(v) · J(t, v)dv +∫


L(v) · J(t, v)dv, (2)

where u1(t) and u2(t) are the voltages generated by sources V1 and V2, respectively. In thisscenario, the lead sensitivity distribution will determine the contribution of each region V1and V2 to the total measured voltage. If, for instance, L(v) is much larger in V1 than in V2,the contribution of V1 to the total measured voltage u(t) will be expected to be higher thanthe contribution of V2. Consequently, the lead sensitivity distribution, in addition to definethe lead spatial resolution, will also allow to investigate the ability of a measurement lead todiscriminate between different bioelectric sources.Since the lead sensitivity distribution depends on both the volume conductor and the designand arrangement of the measurement leads, different leads will be characterized by differentmeasurement properties. Based on the analysis of the lead sensitivity distribution, severaltechniques have been devised in the literature for investigating how current lead systemsmeasure bioelectric phenomena. One of the earliest and most popular methods is the analysisof iso-sensitivity surfaces, which consists of depicting the surfaces in the bioelectric sourcewhere the magnitude of the lead sensitivity distribution remains constant. This analysismethod was used by Rush and Driscoll for describing electroencephalographic (EEG) leads(Rush & Driscoll, 1969) and by Arzbaecher et al. for investigating the sensitivity of precordialand esophageal electrocardiographic (ECG) leads (Arzbaecher et al., 1979).The sensitivity distribution has also been the basis for quantifying the lead spatial resolution.Based on the estimation of iso-sensitivity surfaces, Malmivuo et al. proposed the halfsensitivity volume (HSV), which was defined as the bioelectric region enclosed by the surfacewhere the sensitivity magnitude drops to half of the maximum sensitivity (Malmivuo et al.,1997). By using the HSV, the spatial resolutions of EEG and magnetoencephalographysystems were compared. Also, by combining sensitivity distribution models and numericalsimulations of cardiac dynamics, Requena-Carrión et al. proposed the resolution volume(ResV) for quantifying lead spatial resolution (Requena-Carrión et al., 2007). The ResVwas defined as the bioelectric region that contributes to a given fraction of the measuredsignal power, and it was used for quantifying the spatial resolution of surface ECG leads(Requena-Carrión et al., 2007) and intracardiac leads in ICD (Requena-Carrión et al., 2009).Finally, Väisänen et al. further explored the notion of lead spatial resolution by proposing

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ICD CasingHeight (mm) 64Width (mm) 51Depth (mm) 15

HelixLength (mm) 2Diameter (mm) 3

RingLength (mm) 3Diameter (mm) 3

Right ventricular coil Length (mm) 57Diameter (mm) 3

Interelectrode spacingHelix-Ring (mm) 8Helix-Coil (mm) 12

Table 1. Electrode specifications.

the region of interest sensitivity ratio (ROISR), defined as the ratio between the averagesensitivities of any two regions within the bioelectric source (Väisänen et al., 2008). TheROISR allowed to quantify the specificity of EEG (Väisänen et al., 2008) and surface ECGmeasurements (Väisänen & Hyttinen, 2009).In summary, the lead sensitivity distribution constitutes both a useful theoretical tool forunderstanding the nature of bioelectric signals, and a useful practical tool for describingquantitatively the sensing properties of measurement leads. In this study, the sensitivitydistribution will be used to quantify and compare the ability of four ICD intracardiac leadsto measure ventricular bioelectrical events and reject bioelectrical artifacts from the atria andnear muscles. For that purpose, the sensitivity distribution of each lead configuration underinvestigation will be analyzed and in addition to this, a measure of discrimination based onthe sensitivity distribution will be proposed.

3. Methods

3.1 Intracardiac ICD leadsThe measurement properties of four ICD intracardiac lead configurations (two unipolar, onededicated bipolar and one integrated bipolar) were investigated. In order to define thegeometry and the anatomical location of the electrodes that formed each intracardiac lead,a commercial ICD system was used as a reference model. This system consisted of twoelements, namely the Medtronic Secura ICD (Medtronic, 2008) and the Medtronic SprintQuattro Secure ventricular lead (Medtronic, 2010). The Medtronic Secura ICD is a singlechamber ICD which is used in combination with a right ventricular lead for analyzing heartrhythm and providing defibrillation, cardioversion and both bradycardia and antitachycardiapacing therapies. As for the Medtronic Sprint Quattro Secure, it is a quadripolar ventricularlead designed for pacing, sensing, cardioversion and defibrillation therapies.The Secura ICD is intended to be located in the pectoral region. Its casing, which can be usedas an indifferent, distant electrode, has the physical dimensions shown in Table 1. As for theSprint Quattro Secure ventricular lead, it consists of a helix electrode located at the tip of thelead, followed consecutively by a ring electrode, a right ventricular coil and a superior venacava coil. The helix and the ring electrode are used for EGM sensing and pacing, while bothcoils in combination with the ICD casing are used for defibrillation. Since this study focuses

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Analysis of the Lead Sensitivity Distribution in Implantable Cardioverter Defibrillator 5

Unipolar A helix to casing

Unipolar B coil to casing

Dedicated bipolar helix to ring

Integrated bipolar helix to coil

Table 2. Intracardiac leads definition.

on bioelectric measurement of ventricular events, the electrodes that were considered were thehelix, the ring and the right ventricular coil. The physical dimensions and relative distancesof the electrodes that were considered for this study are shown in Table 1.Based on the aforementioned electrode specifications, the four intracardiac ICD leads weredefined as follows (Table 2): the unipolar A lead used the casing of the implant and the helixelectrode; the unipolar B lead used the casing of the implant and the right ventricular coil;the dedicated bipolar lead used the helix and the ring electrodes and finally, the integratedbipolar lead used the helix electrode and the right ventricular coil.

3.2 Computational model of the human thoraxA realistic 3D computational model of the bioelectric properties of the human thorax wasimplemented for calculating the lead sensitivity distributions. This computational modelwas defined based on the widely used Visible Human Man dataset, and consisted of a341×594×394 cubic grid with a 1 mm×1 mm×1 mm resolution (Sachse et al., 1998). Thehuman thorax model was segmented into 20 different organ and tissue types, including theatria, the ventricles and near muscles, and they were assigned resistivity values previouslyreported in the literature (Gabriel et al., 1996).Lead sensitivity distributions were calculated in the realistic human thorax by applyingthe principle of reciprocity (Malmivuo & Plonsey, 1995), which states that when a lead isreciprocally energized, the current field that is induced in the volume conductor correspondsto the lead sensitivity distribution. An FDM approach was developed for calculating thecurrent field induced in the realistic human thorax when each electrode pair was reciprocallyenergized. The FDM solver was based on the Incomplete Cholesky Preconditioner andConjugate Gradient (Takano, 2002) and was executed on an AMD 3000+ 64Bit, 2 GB RAM,200GB SATA RAID computer.

3.3 Discrimination powerLead sensitivities at the ventricles were compared to lead sensitivities at the atria andnear muscles. For that purpose, two discrimination indices based on the notion of ROISR(Väisänen et al., 2008) were defined as follows:

diAV =

∫atria |L(v)|dv∫

ventricles |L(v)|dv(3)

diMV =

∫muscle |L(v)|dv∫

ventricles |L(v)|dv

The discrimination index diAV allowed to compare the accumulated sensitivities at the atriawith the accumulated sensitivities at the ventricles, whereas the diMV allowed to compare the

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accumulated sensitivities at near skeletal muscles with the accumulated sensitivities at theventricles. A logarithmic transformation was subsequently applied to both indices:

DIAV = 20 log10 (diAV) (4)

DIMV = 20 log10 (diMV)

Consequently, the lower the value of a discrimination index for a given lead, the lower thesensitivity of that lead to the corresponding non-ventricular source (atria or skeletal muscle)and therefore, the lower the effects of bioelectric artifacts from that source.

4. Results

The analysis of the sensitivity distribution of each intracardiac lead reveals that, irrespectiveof the lead configuration and design, sensitivity is always higher at the close proximity ofthe electrodes and decreases with the distance. Specifically, as shown in Figures 1 and 2, thesensitivity of configurations using the signal provided by the helix electrode, i.e. unipolarA, dedicated bipolar and integrated bipolar, is highest near the ventricular apex, into whichthe helix electrode is usually inserted; similarly, the sensitivity across the ventricular septumis significantly higher in configurations using the right ventricular coil, i.e. unipolar B andintegrated bipolar configurations. Figures 1 and 2 also show that the sensitivity of unipolarconfigurations decreases more slowly with the distance to the electrodes than the sensitivityof bipolar configurations and therefore, unipolar measurements are more uniform throughoutthe heart than bipolar measurements. In other words, bipolar configurations concentrate theirmeasurements more than unipolar configurations.As a consequence of the previous observation, since intracardiac ICD leads are insertedinto the right ventricle, their sensitivity at the ventricular myocardium is higher than atthe atrial myocardium. However, it is worth noting that the sensitivity distribution at theatria depends on the configuration of the lead. As seen in Figures 1 and 2, in the case ofunipolar configurations the sensitivity distribution at the atria is of roughly the same orderof magnitude as the sensitivity distribution at the ventricles, whereas in the case of bipolarconfigurations, the sensitivity distribution drops several orders of magnitude. In addition tothis, by comparing bipolar configurations it can be concluded that the sensitivity at the atriais higher in the case of integrated bipolar than in the case of dedicated bipolar. Finally, byinvoking the same physical principle according to which lead sensitivity decreases with thedistance to the electrodes, since ICD are usually implanted in the pectoral area, the sensitivityat the pectoral muscle will be higher for unipolar leads, in which the casing of the implant actsas the indifferent electrode.By calculating the discrimination indices DIAV and DIMV , the previous qualitativeobservations based on the analysis of the sensitivity distribution can be quantitativelycontrasted. As Table 3 shows, the accumulated sensitivity of bipolar leads is several ordersof magnitude higher at the ventricles than at the other non-ventricular bioelectric sources,namely the atria and near muscles. In addition to this, it can be noticed that dedicated bipolarconfigurations have a higher discrimination power than integrated bipolar configurations.Unipolar configurations, on the contrary, are characterized by a lower discrimination power,especially against muscular artifacts due to the proximity to the casing of the ICD. Ingeneral, it can be concluded from this analysis that the unipolar B configuration using theright ventricular coil and the casing of the implant, is the most vulnerable intracardiacconfiguration, whereas the dedicated bipolar configuration is the most robust configurationagainst bioelectric artifacts.

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Analysis of the Lead Sensitivity Distribution in Implantable Cardioverter Defibrillator 7

Unipolar A configuration (helix to casing)

Unipolar B configuration (coil to casing)

−5 −4 −3 −2 −1 0 1 2

Fig. 1. Sensitivity distributions of unipolar intracardiac configurations at two cross-sectionsof the heart (arbitrary units, logarithmic scale).

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Dedicated bipolar configuration (helix to ring)

Integrated bipolar configuration (helix to coil)

−5 −4 −3 −2 −1 0 1 2

Fig. 2. Sensitivity distributions of bipolar intracardiac configurations at two cross-sections ofthe heart (arbitrary units, logarithmic scale).

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Analysis of the Lead Sensitivity Distribution in Implantable Cardioverter Defibrillator 9

Discrimination power (dB)


Unipolar A -33 -13

Unipolar B -15 -2

Dedicated bipolar -61 -57

Integrated Bipolar -48 -50

Table 3. Discrimination power against atrial and muscular artifacts.

5. Conclusions

Current ICD tachyarrhythmia detection algorithms use heart rhythm criteria to determinewhether patients are suffering from a life-threatening arrhythmia. In order to extract heartrhythm, ICD currently estimate the duration of the RR interval on a beat-to-beat basisby sensing ventricular activations in EGM signals, which are continuously recorded byintracardiac leads. As a consequence, ICD overall performance depends on the abilityof intracardiac leads to measure ventricular bioelectric events and reject other biolectricevents of non-ventricular origin, which include myopotentials (Deshmukh & Anderson,1998; Kowalski et al., 2008; Sandler & Kutalek, 1994; Schulte et al., 2001) and pacing stimulusartifacts (Menz et al., 1998).It is widely acknowledged that lead design can affect EGM sensing and therefore ICDperformance. On the basis that bipolar configurations are more specific to ventricular eventsthan unipolar configurations, current ICD use bipolar leads, either dedicated or integrated,for EGM sensing, while unipolar-like leads are mainly used for cardiac defibrillation. In aprevious study, the sensitivity distribution of two unipolar and two bipolar intracardiac ICDleads were investigated in a numerical model of the ventricles (Requena-Carrión et al., 2009).This study showed quantitatively that bipolar leads concentrate their measurements morethan unipolar leads and therefore, provide with ventricular events at a more local level thanunipolar leads, which are characterized by global measurements.In the present study, the investigation previously developed in (Requena-Carrión et al., 2009)has been extended by including the analysis of the sensitivity distribution at the atria andnear muscles. Four intracardiac leads based on a current ICD commercial system have beenstudied in a computational model of the human thorax. Our analysis supports the viewthat bipolar configurations concentrate their measurement on a local level, while unipolarconfigurations provide with global measurements. In addition to this, we have been ableto analyze qualitatively the sensitivity distribution at the ventricular and atrial myocardium,showing that the sensitivity distribution of unipolar configurations is roughly of the sameorder of magnitude at the atria and at the ventricles, whereas the sensitivity distribution ofbipolar configurations drops several orders of magnitude from the ventricles to the atria. Inorder to analyze quantitatively the sensitivity to non-ventricular bioelectric sources, we haveproposed a discrimination index that compares the accumulated sensitivity at the ventricleswith the accumulated sensitivity at other non-ventricular bioelectric sources. Our resultsreveal that bipolar configurations are more specific to ventricular sources than unipolarconfigurations and hence, less vulnerable to bioelectric artifacts.

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The notion of lead sensitivity distribution can provide with a useful insight into the nature ofbioelectric signals. In combination with numerical methods, the sensitivity distribution canhelp to analyze the performance of current leads and can assist in the design of future leads.

6. Acknowledgments

The authors would like to thank Dr. -Ing. Gunnar Seeman of Karlsruhe Institute of Technologyfor kindly providing with the detailed numerical model of the human thorax that was used inthis study.

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Nash, A., Fröhlig, G., Taborsky, M., Stammwitz, E., Maru, F., Bouwens, L. & Çeliker, C. (2005).Rejection of atrial sensing artifacts by a pacing lead with short tip-to-ring spacing,Europace 7(1): 67–72.

Natale, A., Sra, J., Axtell, K., Akhtar, M., Newby, K., Kent, V., Geiger, M. J., Brandon,M. J., Kearney, M. M. & Pacifico, A. (1996). Undetected ventricular fibrillationin transvenous implantable cardioverter-defibrillators. Prospective comparison ofdifferent lead system-device combinations, Circulation 93(1): 91–98.

Parsonnet, V., Myers, G. H. & Kresh, Y. M. (1980). Characteristics of intracardiac electrogramsII: Atrial endocardial electrograms, Pacing and Clinical Electrophysiology 3(4): 406–417.

Requena-Carrión, J., Väisänen, J., Alonso-Atienza, F., García-Alberola, A., Ramos-López, F.& Rojo-Álvarez, J. L. (2009). Sensitivity and spatial resolution of transvenous leadsin implantable cardioverter defibrillator, IEEE Transactions on Biomedical Engineering56(12): 2773 –2781.

Requena-Carrión, J., Väisänen, J., Rojo-Álvarez, J. L., Hyttinen, J., Alonso-Atienza,F. & Malmivuo, J. (2007). Numerical analysis of the resolution of surfaceelectrocardiographic lead systems, FIMH, pp. 310–319.

Rush, S. & Driscoll, D. A. (1969). EEG electrode sensitivity–an application of reciprocity, IEEETransactions on Biomedical Engineering 16(1): 15–22.

Sachse, F. B., Werner, C. D., Meyer-Waarden, K. & Dössel, O. (1998). Applications of the visibleman dataset in electrocardiology: Calculation and visualization of body surfacepotential maps of a complete heart cycle, Second Users Conference of the National Libraryof Medicine’s Visible Human Project, pp. 47–48.

Sandler, M. J. & Kutalek, S. P. (1994). Inappropriate discharge by an implantable cardioverterdefibrillator: Recognition of myopotential sensing using telemetered intracardiacelectrograms, Pacing and Clinical Electrophysiology 17(4): 665–671.

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due to oversensing of diaphragmatic myopotentials, Journal of Interventional CardiacElectrophysiology 5: 487–493.

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Modeling Defibrillation

Gernot Plank1 and Natalia Trayanova2

1Medical University of Graz, Austria2Johns Hopkins University, MD, Baltimore


1. Introduction

Cardiac fibrillation is the breakdown of the organized electrical activity in the heart intodisorganized self-sustained electrical activation patterns. Fibrillatory episodes when affectingthe ventricles, i.e. the main pumping chambers of the heart, result in loss of cardiac outputand unless timely intervention is administered, death quickly ensues. The only knowneffective therapy for lethal disturbances in cardiac rhythm is defibrillation, the delivery ofa strong electric shock to the heart. This technique, as accomplished nowadays by automatic,implantable cardioverter-defibrillator (ICD) devices, constitutes the most important means ofcombating sudden cardiac death. Several multi-center clinical trials have provided consistentevidence that ICD therapy prolongs patient life. This convincing demonstration of efficacy hasled to a nearly exponential growth, over the last decade, in the number of patients receivingimplantable devices. Currently, around 0.2 million ICDs are implanted every year throughoutthe world.Although ICD therapy has proved to be efficient and reliable in preventing sudden cardiacdeath (Bardy et al., 1993), with success rates clearly superior to other therapeutic options suchas pharmacological anti-arrhythmia therapy (Zipes et al., 1997), it is far from ideal. There areseveral known adverse effects secondary to the administration of electrical shocks, the mostprominent are linked to electroporation (DeBruin & Krassowska, 1998), (i.e. the formationof pores in the cellular membrane that allow the free and indiscriminate redistribution ofions, enzymes and large molecules between intracellular and interstitial space), and itsafter-effects which are indirectly caused by the high field strengths required to terminatearrhythmias such as ventricular fibrillation (VF) with sufficiently high probability. Moreover,psychological effects on patients play an important role. Conscious patients may perceiveshock delivery as extremely painful which leads to traumatization and reduction in qualityof life. Although pain may be tolerable in those cases where shock delivery saves humanlives, this is less likely in those cases where inadequate shocks are delivered due to highvoltage component malfunctions of the device. A recent meta-analysis of industrial reports(Maisel, 2006) concluded that such malfunctions are much more frequent than expected, withthousands of patients being affected. Further, clinical data from ICD trials suggested that 6 outof 7 shocks delivered can be classified as inadequate, indicating the amount of over-treatmentin the ICD population is significant (Zipes et al., 1997). Therefore, despite the impressiveclinical success and efficacy of ICD implant, the therapy is clearly suboptimal due to thesenumerous adverse side effects and as such research on defibrillation mechanisms remains


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to be an important topic. Achieving defibrillation reliably with shocks of much lower energythan those delivered by ICD devices today, would constitute a major step forward. Advancingour understanding towards a full appreciation of the mechanisms by which a shock interactswith the heart is the most promising approach to achieve this goal.

1.1 Experimental approaches to investigate defibrillation mechanismsElucidating the biophysical underpinnings of defibrillation mechanisms has been a longand arduous process. The key to understanding the cardiac defibrillation process is touncover those mechanisms by which electric current delivered to the heart during shockdelivery traverses myocardial structures and interacts with the wavefronts of fibrillation.The quest for uncovering these mechanistic links between applied electric fields and evokedmembrane responses has proved to be enormously challenging. In no small part thesedifficulties can be attributed to the lack of suitable experimental methodologies which wouldallow to observe electrical events occurring before, during and after shock delivery withsufficiently high spatio-temporal resolution. Early studies relied on recordings of extracellularpotentials following the defibrillation shock, since overwhelming electrical artifacts hadprevented researchers from recording during and shortly after the shock. Although thesepioneering electrical mapping studies provided some insights which laid the basis fordeveloping the first theories such as the upper limit of vulnerability (ULV) hypothesis,there was no direct experimental evidence to prove the putative mechanisms. A majorbreakthrough occur ed with the introduction of potentiometric dyes, which allowed torecord electrical events before, during and after shock delivery at a higher spatio-temporalresolution. The ability of these optical mapping techniques to provide optical fluorescencesignals, Vopt, which are proportional to the transmembrane voltage, ∝ Vm, proved to be afurther advantage. Unlike extracellularly recorded electric potentials, Φe, which integratecontributions of bioelectric activity in the vicinity of a recording site via the volume conductorin which the heart is immersed, Vm provides a more direct measure for shock-inducedmembrane responses, although optical signals are not purely local representations of Vm ata recording site either, since fluorescence detectors collect photons emerging from withina certain scattering volume (Bishop et al., 2007). Although optical mapping setups allowto elegantly visualize shock-induced changes in tissue polarizations, these observations areconfined to record electrical activity from cardiac surfaces only. However, in a complexthree-dimensional anatomical structure such as the heart electrical events occur throughoutthe entire myocardium including the depth of the myocardial walls. Therefore, the restrictedcapabilities of current optical mapping techniques to detect events which may occur indeeper layers of the myocardial wall without any signature at the surfaces (Ashihara et al.,2008), poses a severe limitation, rendering investigations of defibrillation mechanisms byexperimental means alone a challenging endeavor.

1.2 Role of computer modelingThe absence of experimental methodology for observing shock-induced membranepolarizations in 3D inspired the theoretical community to develop and refine computermodels of the cardiac defibrillation process. Since there is insufficient direct experimentalevidence which would allow a direct verification of model predictions in the depth of themyocardium, computer models are compared against optical maps recorded at the ventricularsurfaces. Assuming that model formulations are valid quantitatively correct representationof cardiac bioelectricity, models which correctly predict experimental observations at the

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Modeling Defibrillation 3

Fig. 1. Left panel: In most experimental setups the field of view (FOV) of optical recordings,as indicated by a gray dashed rectangle, is confined to the surface. Shown are polarizationpatterns at the end of the shock delivered via plate electrodes, with the cathode being locatednext to the left ventricle (top) and the right ventricle (bottom). Right panel: Computermodels allow to observe shock-induced changes in polarization throughout the entiremyocardium, revealing important shock-induced changes in electrical state of the tissue,such as shape, size and location of the post-shock excitable gap (blue regions).

surfaces could be used with some confidence to take a look inside the depth of myocardialwalls, thus allowing to bridge the gap between experimental observations recorded atepicardial and endocardial surfaces (Fig. 1).In earlier computational studies of defibrillation mechanisms monodomain models wereemployed. Such monodomain formulations do not account explicitly for current flow in theextracellular domains. This simplification reduces model complexity and computational costsat the cost of biophysical accuracy. Although monodomain models were well established forstudying impulse propagation in the heart, their suitability in the context of simulating theprocess of defibrillation quickly turned out to be of limited value. Theoretical considerationsbased on the monodomain equations predicted shock-induced changes in transmembranevoltage, ΔVm, only along tissue boundaries and around conductive discontinuities in theheart, leaving the bulk of the myocardium essentially unaffected. However, such predictionscontradicted experimental findings which had established that a critical mass of the tissue of∼ 95% (Adgey et al., 2005; Ideker et al., 1991) has to be affected by a sufficiently strong gradientof > 5 V/cm (Frazier et al., 1989; Zhou et al., 1993) to be effective. To resolve this dilemmathe theoretical community put forward the more comprehensive bidomain model whichexplicitly accounts for current flow in both the intracellular and interstitial domains. Thebidomain model proved quickly to be an invaluable powerful tool for studying defibrillation

41Modeling Defibrillation

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mechanisms, providing the sought after “missing link” (Roth & Krassowska, 1998) betweenexternally applied electric field and membrane responses in the tissue bulk. Using a bidomainmodel Sepulveda and coworkers (Sepulveda et al., 1989) demonstrated in a seminal studythat shock-induced changes in membrane polarizations can be much more complex thanpreviously anticipated. Their simulation results suggested that the tissue response in thevicinity of a strong unipolar stimulus involved the simultaneous occurrence of both positive(depolarizing) and negative (hyperpolarizing) effects in close proximity, if the anisotropyratios between intracellular and interstitial space comprising the myocardium are unequal,i.e. both spaces are anisotropic, but to a different degree. In the absence of unequal anisotropyratios, as it is the case with monodomain models which inherently assume equal anisotropies,no polarizations of opposite polarity can occur (Fig. 2). This prediction of the existence of

Fig. 2. Unequal anisotropy ratios between intracellular and interstitial space is a necessarycondition for the existence of bulk VEPs. A) A unipolar anodal stimulus is delivered to thecenter of a tissue sheet of equal anisotropy ratios. Shock induced polarizations of only onepolarity (hyperpolarizing) are observed and the tissue affected by the shock is limited theimmediate vicinity of the electrode. B) The exact same shock delivered to tissue of unequalanisotropy ratios induced polarizations of both polarities and the area of tissue affectedextends far beyond the electrotonic space constant. Dashed lines indicate the longitudinalaxis of myocyte orientation.

“virtual electrodes” departed from the established view that tissue responses should onlybe depolarizing if the stimulus is cathodal, or hyperpolarizing if the stimulus is anodal.Optical mapping studies that followed convincingly confirmed these theoretical predictions(Wikswo Jr et al., 1995). Since, “virtual electrode polarization” (VEP) has been documentedin experiments involving various stimulus configurations (Efimov, Aguel, Cheng, Wollenzier& Trayanova, 2000; Efimov et al., 1997; Efimov, Gray & Roth, 2000; Evans et al., 2002; Knisleyet al., 1999).

1.3 Current understanding of defibrillation mechanismsConceptually, defibrillation can be considered to be a two-step process. First, the appliedshock drives currents that traverse the myocardium and cause complex polarization changesin transmembrane potential distribution (Sobie et al., 1997). Secondly, post-shock activemembrane reactions are invoked that eventually result either in termination of fibrillationin the case of shock success, or in reinitiation of fibrillatory activity in the case of shock

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Modeling Defibrillation 5

failure. Using computer models to analyze the etiology of VEP patterns during the shockapplication phase revealed that shape, location, polarity, and intensity of shock-inducedVEP are determined by both the cardiac tissue structure as well as the configuration ofthe applied field (Knisley et al., 1999; Rodriguez et al., 2005; Sobie et al., 1997). Based ontheoretical considerations VEPs can be classified either as “surface VEP”, which penetratesthe ventricular wall over a few cell layers, or as “bulk VEP” where polarizations arisethroughout the ventricular wall (Entcheva et al., 1999; Trayanova et al., 1998). Analysis of thebidomain equations revealed that a necessary condition for the existence of the bulk VEP isthe presence of unequal anisotropies in the myocardium. Sufficient conditions include eitherspatial non-uniformity in applied electric field, or non-uniformity in tissue architecture, suchas fiber curvature, fiber rotation, fiber branching and anastomosis, and local changes in tissueconductivity due to resistive heterogeneities (Plank et al., 2005) (Fig. 3).The cellular response depends on VEP magnitude and polarity as well as on pre-shock stateof the tissue. APD can be either extended (by positive VEP) or shortened (by negative VEP)to a degree that depends on VEP magnitude and shock timing, with strong negative VEPcompletely abolishing (de-exciting) the action potential thus creating post-shock excitablegaps. As demonstrated in bidomain modeling studies (Ashihara et al., 2008; Roth, 1995), thepost-shock VEP pattern is also the major determinant of the origin of post-shock activations.In those regions where shock-induced virtual anodes and virtual cathodes are in closeproximity, a “break” excitation at shock-end (i.e, the “break” of the shock) can be elicited.The virtual cathode serves as an electrical stimulus eliciting a regenerative depolarization anda propagating wave in the newly created excitable area. Whether or not break excitationsarise depends on whether the transmembrane potential gradient across the border spans thethreshold for regenerative depolarization (Cheng, Mowrey, Van Wagoner, Tchou & Efimov,1999). The finding of break excitations, combined with the fact that positive VEP can result in“make” excitations (where “make” refers to the onset of a shock) in regions where tissue is ator near diastole, resulted in a novel understanding of how a strong stimulus can trigger thedevelopment of new activations.According to VEP theory, mechanisms for shock success or failure are multifactorialdepending mainly on post-shock distribution of Vm as well as timing and speed ofpropagation of shock-induced wavefronts. Whether the depolarization of the post-shockexcitable gap is achieved in time critically depends on number and conduction velocityof post-shock activations, as well as the available time window which is bounded by theinstant at which refractory borders enclosing the excitable regions recover excitability. Allfactors depend, ultimately, on shock strength. Increasing shock strength results in highervoltage gradients across borders between regions of opposite polarity, leading to morebreak-excitations (Cheng, Mowrey, Van Wagoner, Tchou & Efimov, 1999) which then startto traverse the post-shock excitable gap earlier (Skouibine et al., 2000a) and at a faster velocity(Cheng, Mowrey, Van Wagoner, Tchou & Efimov, 1999), as well as extending refractoriness toa larger degree (Knisley et al., 1994).

2. Computationally modeling defibrillation and shock-induced arrhythmogenesis

Comprehensive mechanistic insight into defibrillation remains a major scientific frontier andthe 3D bidomain model is an important tool to complement and interpret experimentalobservations. The quest to unravel how shocks could succeed in terminating fibrillationor how they could re-instate arrhythmia has driven the technological aspects of computersimulations of 3D bidomain activity. In order to be able to simulate electrical processes

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Fig. 3. An important insight learned from the bidomain model is that the etiology of VEPs isdetermined by both field configuration as well as tissue structure. Shown are shock-inducedpolarization patterns as a function of field and tissue configuration. Top panels: Shown arethe extracellular electric potentials Φe as induced by two point-like electrodes (left) andline-like electrodes (right). Red(blue) indicates cathodal (anodal) stimulus. Left panels: Twotissue configurations are shown, a homogeneous configuration with straight fibers only(top), and a configuration where fiber orientation varies as a function of space (bottom).Preferred longitudinal axes of the tissue is indicated by dashed lines. Central panels:Shock-induced polarization patterns for all possible combinations between field and tissueconfiguration. In the case of plate electrodes with a homogeneous tissue structure onlysurface polarizations close to the electrode locations are observed. The bulk of the tissueremains essentially unaffected.

driven by the delivery of shocks to the ventricles, computational research has managed toovercome tremendous difficulties associated with obtaining solutions of very large systemsof unknowns, involving stiff equations and computational meshes of irregular geometry. Abrief overview of the computational approaches involved in conducting simulations of shockadministration and post-shock arrhythmogenesis is presented below.

2.1 Simulating cardiac bioelectric activity at the tissue and organ levelComputer models of cardiac biolelectric activity are built upon first principles which representthe movement of ions in within the myocardial tissue. A building block of central importance

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Modeling Defibrillation 7

are cardiac myocytes which make up the tissue. A myocyte is of roughly cylindrical shape,∼100μm long and 10-20μm in diameter. The intracellular spaces of adjacent myocytes areinterconnected by specialized connexins referred to as gap junctions (Desplantez et al., 2007).The connexin expression over the cell is heterogeneous with a higher density of gap junctionsat the intercalated discs located at the cell ends (along the long axis of the cell) and a lowerdensity along the lateral boundaries (Gourdie et al., 1991; Hoyt et al., 1989), and differentconnexins of varying conductance are expressed in different regions of the heart (Severs et al.,2008). As a consequence of the elongated cellular geometry as well as the directionally varyinggap junction density current flows more readily along the longitudinal axes of the cells thantransverse to it. This property is referred to as anisotropy. Cardiac tissue is composed of twospaces: an intracellular space formed by the interconnected network of myocytes, and the cleftspaces between myocytes referred to as interstitial space which is made up of the extracellularmatrix and the interstitial fluid. The extracellular matrix consists of networks of collagenfibers which determine the passive mechanical properties of the myocardium. Electrically, itis assumed that the preferred directions are co-aligned between the two spaces, but that theconductivity ratios between the principal axes are unequal between the two domains (Clerc,1976; Hooks et al., 2007; Roberts & Scher, 1982; Roth, 1997). All parameters influencing theelectrical properties of the tissue, such as density and conductance of gap junctions, cellulargeometry, orientation and cell packing density, and the composition of the interstitial space,are heterogeneous and may vary at all size scales, from the cellular level up to the organ.As a consequence, direction and speed of a propagating electric wave is constantly modifiedby interactions with discontinuous spatial variations in material properties at various sizescales. At a finer size scale below the space constant, λ, of the tissue, i.e. <1mm, the tissueis best characterized as a discrete network in which the electrical impulse propagates in adiscontinuous manner (Kleber & Rudy, 2004; Spach & Heidlage, 1995). At a larger moremacroscopic size scale (� λ) the tissue behaves as a continuous functional syncytium wherethe effects of small-scale discontinuities are assumed to play a minor role.Theoretically, the idea of modeling an entire heart by using models of a single cell asthe basic building block is conceivable. However, the associated computational costs areprohibitive with current computing hardware, since a single heart consists of roughly 5billion cells. Although a few high resolution modeling studies have been conducted wheresmall tissue preparations were discretized at a sub-cellular resolution (Hooks et al., 2007;Roberts et al., 2008; Spach & Heidlage, 1995), in general the spatial discretization stepswere chosen based on the spatial extent of electrical wave fronts and not on the size scalesof the tissue’s micro-structures. For this sake cardiac tissue is treated as a continuum forwhich appropriate material parameters have to be determined which translate the discretecellular matrix into an electrically analog macroscopic representation. In principle, this isachieved by averaging material properties over suitable length scales such that both potentialand current solution match between homogenized and discrete representation. A rigorousmathematical framework for this procedure is provided by homogenization theory whichhas been applied by several authors to the bidomain problem (Hand et al., 2009; Henriquez,1993; Neu & Krassowska, 1993; Pennacchio M. et al., 2006). Homogenization is a two-stepprocess where the intracellular and interstitial domain are homogenized in a first step andthe two respective domains are spread out and overlapped to fill the entire tissue domain.This concept of interpenetrating domains states that everywhere within the entire myocardialvolume intracellular space, extracellular space and the cellular membrane coexist (Fig. 4).

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Fig. 4. a) Cardiac tissue is made up of discrete myocytes which are interconnected via gapjunctions. b) Discrete structures in both the intracellular as well as the interstitial space arehomogenized to arrive at a continuum representation, which matches electrical propertiesbetween discrete microscopic size scale and continuous macroscopic size scale. Further, bothhomogenized domains are overlapped, separated by a membrane at each point in space(interpenetrating domains). c) Discrete representation of both conductive domains andmembrane, as discretized by a finite difference approach.

2.2 Governing equationsThe bidomain equations(Plonsey, 1988) describe the electrical behavior of cardiac tissue as asyncytium, where all tissue parameters are accounted for in an averaged sense. The domainsof interest, intracellular and extracellular, and the cellular membranes which physicallyseparate the two domains, are distributed over the entire tissue volume. The bidomainequations state that currents that enter the intracellular or extracellular spaces by crossing thecell membrane represent the sources for the intracellular potential, φi, and the extracellularpotential, φe,

∇ ·σi∇φi = βIm (1)

∇ ·σe∇φe = −βIm − Ie (2)

Im = Cm∂Vm

∂t+ Iion(Vm,η)− Istim (3)

Vm = φi − φe, (4)

where σi and σe are the intracellular and extracellular conductivity tensors, respectively, βis the bidomain membrane surface to volume ratio, Im is the transmembrane current density,Istim is the current density of the transmembrane stimulus used to initiate an action potential,Ie is the current density of the extracellular stimulus, Cm is the membrane capacitance per unitarea, Vm is the transmembrane potential, and Iion is the density of the total current flowingthrough the membrane ionic channels, pumps and exchangers, which depends on Vm and aset of state variables, η. At the tissue boundaries, electrical isolation is assumed, which isaccounted for by imposing no-flux boundary conditions on φe and φi.If, however, cardiac tissue is surrounded by a conductive medium, such as blood in theventricular cavities or a perfusing bath (Tyrode solution) in which the heart is submerged,then Laplace equation has to be additionally solved

∇ · σb∇φe = 0, (5)

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Modeling Defibrillation 9

where σb is the isotropic conductivity of the conductive medium. In this case no-flux boundaryconditions are assumed at the boundaries of the conductive medium, whereas continuity ofthe normal component of the extracellular current and continuity of φe are enforced at thetissue-bath interface. The no-flux boundary conditions for φi remain the same.For most applications the bidomain equations are recast into other forms by substituting eq.(4)into (1) and (2) and executing algebraic transformations. Several ways to recast the bidomainequations have been proposed; a systematic overview of the different linear transformationsis found in (Hooke et al., 1994). A widely used transformation is to add eqs. (1) and (2) andreplace φi by Vm + φe (Pollard et al., 1992)

∇ · (σi +σe)∇φe = −∇ ·σi∇Vm − Ie (6)

∇ ·σi∇Vm = −∇ ·σi∇φe + βIm, (7)

which retains Vm and φe as the independent variables. For comparison of tissue and organlevel simulations with experimental data this is advantageous since φe can be measured viaelectrical mapping techniques and optical mapping techniques allow to record signals Vopt ∝Vm.

2.3 Computational considerationsLarge-scale computational studies employing the bidomain model in general, anddefibrillation studies in particular, have remained a challenge even though computer speedand memory have dramatically increased. There are numerous factors which render anynumerical solution of the bidomain equations computationally challenging. First, theupstroke of the action potential is very fast, lasting only ∼ 1ms. These fast transients translateinto a steep propagating wavefront in space where the depolarization wavefront extendsonly a few hundreds of μm. As a consequence, both spatially fine-grained computationalgrids and a high temporal resolution is required to faithfully capture wavefront propagation.Further, the discretized domain of interest has to be chosen large enough to support reentrantwave propagation when studying the formation, maintenance and termination of cardiacarrhythmias. With constraints on spatial discretization as mentioned above, the results is alarge system, on the order of 0.1 to 100 million degrees of freedom. Finally, the maximum timestep which can be taken to advance the solution of the bidomain equations in time is limited,either by stability (Courant et al., 1928) or accuracy constraints. Since the physiologicalprocesses of interest take place over seconds or minutes, temporal step size limits necessitatea large number of time steps, typically in the range from tens to hundreds of thousands.Beyond the high computational load imposed by bidomain simulations in general, there arenumerous additional methodological challenges which need to be addressed when usingcomputer models for studying the delivery of defibrillation shocks. To model the effectof extracellularly applied fields, the use of unstructured grids for anatomically realisticmodels of the heart is mandatory as to allow smooth representation of the organ’s surfaces.Jagged boundaries, which inevitably form along the organ surfaces when regular structuredor block structured grids are employed, cause spurious polarizations upon delivery of adefibrillation-strength shock. Further, even finer spatial discretization may be required sincelarge transmembrane voltage gradients are induced by the shock; for instance, in a passive2D bidomain study (Aguel et al., 1999) a voltage drop of 1V over a distance as short as 100μm has been reported. Another serious difficulty is the use of state-of-the-art ionic modelswhich incorporate now up to several tens of state variables of ever increasing stiffness. Thesemodels are developed and tested within the normal physiological range of action potentials,

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however, during the shock administration transmembrane voltages may rise significantlybeyond this range, even when ionic models are augmented with additional currents suchas electroporation currents (DeBruin & Krassowska, 1998) or hypothetical potassium currents(Cheng, Tung & Sobie, 1999). Although these currents kick in at elevated transmembranevoltages to cap the rise of Vm at a few hundreds of mV, transmembrane voltages still riseswell beyond the physiological range which could potentially entail undesirable behavior ofthe model equations. Moreover, due to the even faster transients in state variables duringshock onset enforce, even smaller time steps may be required, making computations duringthe shock very burdensome. Typically, modifications are required to render an ionic modelsuitable for defibrillation studies (Ashihara & Trayanova, 2004; Skouibine et al., 2000b).Finally, due to the nature of defibrillation, where shock success depends on a multitude ofparameters such as shock strength and timing, pulse shape and polarity or electrode geometryand location, a large number of simulations is required to sweep the parameter space. Forinstance, a standard problem is to determine the window of vulnerability for a given electrodeconfiguration, that is, for which range of shock strength and coupling intervals the tissue isvulnerable to arrhythmia induction. Such studies involve the construction of vulnerabilitygrids where N timings and M shock strengths have to be tested. Therefore a total of N × Mshocks need to be computed and N × M simulations of post-shock evolution need to beperformed to determine arrhythmia inducibility for each combination.

2.4 Spatial discretizationVarious spatial discretization techniques have been applied to the cardiac bidomain problem,most notably the finite difference method (FDM) (Potse et al., 2006; Skouibine et al., 2000a),the finite volume method (FVM) (Harrild & Henriquez, 1997; Trew, Le Grice, Smaill &Pullan, 2005) and the finite element method (FEM) (Rogers & McCulloch, 1994; Vigmondet al., 2002), although other non-standard techniques such as the interconnected cable modelhave been employed successfully as well (Leon & Roberge, 1991; Wang et al., 1996). Ingeneral, the FDM is easiest to implement, but the method does not accommodate complexboundaries as naturally as the FEM or the FVM do. Although suggestions were made toovercome this limitation by employing the phase-field approach (Fenton et al., 2005) or othergeneralizations (Buist et al., 2003; Trew, Smaill, Bullivant, Hunter & Pullan, 2005), the FDMlooses its most appealing advantage, the ease of implementation. FEM and FVM are both verywell suited for spatial discretizations of complex geometries with smooth representations ofthe boundaries, which is a key feature when polarization patterns induced via extracellularlyapplied currents are to be studied. Both FVM and FEM have been used to model electricalactivity in anatomical realistic models of the atria (Harrild & Henriquez, 2000; Seemann et al.,2006; Vigmond et al., 2004; Virag et al., 2002) as well as the ventricles (Ashihara et al., 2008;Plank et al., 2009; Potse et al., 2006; Ten Tusscher et al., 2007). Mesh generation requirementsare similar for both techniques, that is, the domain of interest has to be tessellated into a set ofnon-overlapping and conformal geometric primitives (Fig. 5). With the FVM, quadrilateralsin 2D (Harrild & Henriquez, 1997) and hexahedral elements in 3D (Harrild & Henriquez,2000; Trew, Le Grice, Smaill & Pullan, 2005) have been preferred, whereas with the FEM,triangles and quadrilaterals were used in 2D and tetrahedral (Plank et al., 2009) or hexahedralelements in 3D (Munteanu et al., 2009; Seemann et al., 2006). Typically, monolithic meshesconsisting of one element type only were used, but exception exist (Prassl et al., 2009; Rochaet al., 2011) where hybrid meshes consisting of tetrahedra, hexahedra, pyramids and prismswere used. Further, most FEM studies relied on the Galerkin FEM where linear test functions

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with tetrahedral elements (Franzone et al., 2006; Sundnes et al., 2006; Vigmond et al., 2002),isoparametric trilinear test functions with hexahedral elements (Munteanu et al., 2009) orcubic-hermite hexahedral elements (Rogers & McCulloch, 1994; Saucerman et al., 2004) wereused.Independently of the spatial discretization technique, the choice of space step, h, is of majorimportance. It is known since very early modeling studies that the solution of the bidomainequations does depend, to a certain degree, on h, even with very fine spatial discretizations(Pollard et al., 1993). This sensitivity has to be attributed to the non-linearity and stiffness ofthe reaction term which entails an extremely fast upstroke of the cardiac action potential,lasting ∼ 1 ms only. When propagating, a fast upstroke in time translates into a steepwavefront in space. Depending on tissue conductivity and cellular excitability, physiologicalconduction velocities range between 0.2 - 0.7 m/s within the myocardium which translates anupstroke duration of 1 ms duration into a wavefront that extends 200-700 μm in space. Underpathological situations where tissue conductivity and/or excitability is reduced, conductionvelocity may be substantially slower, leading to wavefronts where the spatial extent may beeven below 100 μm. The spatial extent of a wavefront along a direction ζ is proportional tothe space constant, λζ ,

λζ =


σiζ σeζ

σiζ + σeζ. (8)

It has been shown that for sufficiently small effective discretizations, Hζ = λζ /hζ < 0.15,solutions converge with deviations in conduction velocity <1% (Pollard et al., 1993). Inpractice, a trade-off has to be made between accuracy and computational tractability. In tissueand organ scale modeling studies a standard choice for h, or for an average discretization h̄when unstructured grids are considered, is 250μm, but finer (Plank et al., 2009) as well ascoarser discretizations (Ashihara et al., 2008; Saucerman et al., 2004) have been reported aswell. With very coarse discretizations, h >500 μm, and physiologically realistic models ofcellular dynamics simulations deviate substantially from results obtained at finer resolutions.Conduction velocities at such coarse grids are underestimated to different degrees as afunction of direction, leading to wavefront distortions (Clayton et al., 2011), even conductionblock may occur as a numerical side effect due to spatial undersampling.

2.5 Construction of models of cardiac anatomyIn order to construct geometrically-realistic models of cardiac anatomy, such information mustbe first obtained via various different imaging modalities, to then be processed and used inmodel construction. In the past decade or so, efforts have been focused towards developingtechniques to construct 3D computational cardiac models directly from non-invasive 3Dimaging modalities such as magnetic resonance (MR). In the last few years, the advent ofstronger magnets and refined scanning protocols has significantly increased the resolution ofanatomical MR scans, such that small mammalian hearts now can have MR voxel dimensionsof ≈ 20 − 25 μm (Burton et al., 2006; Plank et al., 2009). An example of a high resolutionanatomical MR scan of a rabbit heart with voxel resolution ≈ 25 μm isotropic is shownin Fig. 5. As a result of this increase in attainable resolution, anatomical MR imaging isnow capable of providing a wealth of information regarding fine-scaled cardiac structuralcomplexity. Such MR data is currently allowing accurate identification of microscopic featuressuch as the coronary vasculature, extracellular cleft spaces and the free-running Purkinjesystem, as well as macroscopic structures such as trabeculations and papillary muscles.In addition, information regarding the organization of cardiomyocytes into cardiac fibers

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(Streeter et al., 1969), as well as the laminar structure of the myocardial wall (LeGrice et al.,1995) is required to account for orthotropic tissue properties. Such data is unattainable withnormal anatomical MR imaging, however, the eigenaxes of the tissue can be estimated in 3Dusing diffusion-tensor MR imaging (DT-MRI).This information must then be processed and transformed into a usable format to facilitatethe generation of anatomically-detailed computational cardiac models. A first processing stepis to faithfully extract the complex geometrical information present in the image stacks. Thisprocedure, referred to as segmentation, involves labeling voxels based-on their associationwith different regions, types of tissue, objects or boundaries within the image. Ideally,computational algorithms are employed, which automatically segment regions of interestwithin the image with little or no manual input. For generating a computational model itis required to discriminate those voxels in the MR data set which belong to cardiac ‘tissue’from those which represent non-tissue or