**Meet the editor**

Wilbert S. Aronow, MD is Professor of Medicine at New York Medical College. Dr. Aronow has edited 12 books and is an author or coauthor of 1, 328 papers, 215 commentaries or Letters to the Editor, and 923 abstracts. He is currently a member of the Board of Directors of the American Society of Preventive Cardiology and a member of the American College of Chest Physicians

Cardiovascular Disease, Hypertension, and Cardiovascular Surgery Network Steering Committee. He has been a member of 88 editorial boards of medical journals, co-editor of 2 journals, deputy editor of 1 journal, executive editor of 3 journals, an associate editor for 9 journals, and a guest editor for 7 other journals.

Contents

**Preface VII**

Andrey Moskalenko

Alexander Marossy

Pascal Fallavollita

Wilbert S. Aronow

Ioana Mozos

Chapter 1 **Basic Mechanisms of Cardiac Arrhythmias 1**

Chapter 2 **Chronobiological Aspects of Impact of Apnoic Episode and**

Chapter 3 **Detection, Tracking and Related Costs of Ablation Catheters in**

**the Treatment of Cardiac Arrhythmias 71**

Chapter 4 **Ventricular Arrhythmia Risk in Noncardiac Diseases 89**

Chapter 5 **Treatment of Ventricular Arrhythmias 111**

Chapter 6 **Surgery for Atrial Fibrillation: An Overview 141**

Haralabos Parissis, B.C. Ramesh and Bassel Al-Alao

**Reoxygenation on the Electrical Myocardial Properties and Autonomic Nervous System Activity in Wistar Rats 45** Pavol Svorc, Ivana Bacova, Pavol Svorc, Jr., Monika Novakova and

## Contents

#### **Preface XI**

Chapter 6 **Surgery for Atrial Fibrillation: An Overview 141** Haralabos Parissis, B.C. Ramesh and Bassel Al-Alao

Preface

their field.

tricular arrhythmias.

ure are discussed.

during cardiac ablation interventions.

atologic, neurologic, and psychiatric disorders are discussed.

Chapter 6 discusses surgical management of atrial fibrillation.

No writing assistance was utilized in the production of this manuscript.

Financial and Competing Interests Disclosure

This book is a useful resource that every physician taking care of patients with cardiac ar‐ rhythmias should be familiar with. This book includes six chapters written by experts in

Chapter 2 discusses the chronobiological aspects of the impact of apnoic episodes on ven‐

Chapter 3 focuses on the most recent developments in navigation, detection, and tracking

Chapter 4 discusses the epidemiology and pathophysiology of ventricular arrhythmias in several noncardiac diseases, the main methods used to assess arrhythmia risk, and their as‐ sociation with long-term outcomes. Dyslipidemia, diabetes mellitus, obesity, and liver, hem‐

Chapter 5 discusses the prevalence and prognosis of ventricular arrhythmias in patients with and without heart disease. Medical therapy including use of antiarrhythmic drugs and invasive intervention for complex ventricular arrhythmias are discussed. Studies on the ef‐ fect of the automatic implantable cardioverter-defibrillator (AICD) on mortality in patients with ventricular tachyarrhythmias are discussed. Indications for implantation of an AICD for primary and for secondary prevention in patients with and without congestive heart fail‐

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

**Wilbert S. Aronow**

Valhalla, NY, USA

Cardiology Division, Department of Medicine,

Westchester Medical Center/New York Medical College,

Chapter 1 is a very comprehensive article on basic mechanisms of cardiac arrhythmias.

## Preface

This book is a useful resource that every physician taking care of patients with cardiac ar‐ rhythmias should be familiar with. This book includes six chapters written by experts in their field.

Chapter 1 is a very comprehensive article on basic mechanisms of cardiac arrhythmias.

Chapter 2 discusses the chronobiological aspects of the impact of apnoic episodes on ven‐ tricular arrhythmias.

Chapter 3 focuses on the most recent developments in navigation, detection, and tracking during cardiac ablation interventions.

Chapter 4 discusses the epidemiology and pathophysiology of ventricular arrhythmias in several noncardiac diseases, the main methods used to assess arrhythmia risk, and their as‐ sociation with long-term outcomes. Dyslipidemia, diabetes mellitus, obesity, and liver, hem‐ atologic, neurologic, and psychiatric disorders are discussed.

Chapter 5 discusses the prevalence and prognosis of ventricular arrhythmias in patients with and without heart disease. Medical therapy including use of antiarrhythmic drugs and invasive intervention for complex ventricular arrhythmias are discussed. Studies on the ef‐ fect of the automatic implantable cardioverter-defibrillator (AICD) on mortality in patients with ventricular tachyarrhythmias are discussed. Indications for implantation of an AICD for primary and for secondary prevention in patients with and without congestive heart fail‐ ure are discussed.

Chapter 6 discusses surgical management of atrial fibrillation.

Financial and Competing Interests Disclosure

The author has no relevant affiliations or financial involvement with any organization or entity with a financial interest in or financial conflict with the subject matter or materials discussed in the manuscript. This includes employment, consultancies, honoraria, stock ownership or options, expert testimony, grants or patents received or pending, or royalties.

No writing assistance was utilized in the production of this manuscript.

**Wilbert S. Aronow** Cardiology Division, Department of Medicine, Westchester Medical Center/New York Medical College, Valhalla, NY, USA

**Chapter 1**

,

**Basic Mechanisms of Cardiac Arrhythmias1**

**1.1. What should the activity of the heart and the action of the heart mean?**

*activity* of the heart" in a good accordance with the remarks above.

for shifting the system from a state A to a state B.See more below.

The term "*action of the heart*" was discussed in detail in my recent publication [1]. The terms "(any) cardiac activity" or "(any) activity of the heart" should be used only for designation any aimless functioning of the heart. On the other hand, "the action of the heart" or "the cardiac action" should be comprehended as the functioning of the heart that is directed to maintenance of physiological homeostasis, which is the target function in this case. Obviously, the action of the heart can be put into effect only due to a quantity of control loops and guidance loops2

which all together organize one and indivisible cardiovascular system. Electrical phenomena, that accompany the functioning of the heart and can be recorded by electrocardiography, are nowise satisfying the target of the cardiovascular functioning, because they are but side effects of the *autowave function of the heart* [1, 2]. In English scientific and medical literature, the electrical phenomena to accompany the functioning of the heart are referred to as "the electrical

Any action of the heart that differs from its normal action ought to be ranked among *cardiac arrhythmias*. The normal action of the heart (the normal cardiac action) should be understood as the averaged round the human population cardiac behavior in comfort conditions. The cardiac arrhythmia arising in comfort conditions is undoubtedly considered to be pathologic. However, different kinds of cardiac arrhythmia arising in conditions distant from the comfort

1This chapter is mainly based on our previous publication [2], which is revised and renewed for the aims of this book.

2 Notice that the control is used to maintain a desired output of the system under control, while the guidance is intended

© 2014 Moskalenko; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

may be either *pathologic* cardiac behavior or normal *adaptive* response of the heart.

The chapter contains some materials that have not been available previously to English-speaking readers.

Additional information is available at the end of the chapter

Andrey Moskalenko

**1. Introduction**

http://dx.doi.org/10.5772/57557

#### **Chapter 1**

## **Basic Mechanisms of Cardiac Arrhythmias1**

### Andrey Moskalenko

Additional information is available at the end of the chapter

http://dx.doi.org/10.5772/57557

#### **1. Introduction**

#### **1.1. What should the activity of the heart and the action of the heart mean?**

The term "*action of the heart*" was discussed in detail in my recent publication [1]. The terms "(any) cardiac activity" or "(any) activity of the heart" should be used only for designation any aimless functioning of the heart. On the other hand, "the action of the heart" or "the cardiac action" should be comprehended as the functioning of the heart that is directed to maintenance of physiological homeostasis, which is the target function in this case. Obviously, the action of the heart can be put into effect only due to a quantity of control loops and guidance loops2 , which all together organize one and indivisible cardiovascular system. Electrical phenomena, that accompany the functioning of the heart and can be recorded by electrocardiography, are nowise satisfying the target of the cardiovascular functioning, because they are but side effects of the *autowave function of the heart* [1, 2]. In English scientific and medical literature, the electrical phenomena to accompany the functioning of the heart are referred to as "the electrical *activity* of the heart" in a good accordance with the remarks above.

Any action of the heart that differs from its normal action ought to be ranked among *cardiac arrhythmias*. The normal action of the heart (the normal cardiac action) should be understood as the averaged round the human population cardiac behavior in comfort conditions. The cardiac arrhythmia arising in comfort conditions is undoubtedly considered to be pathologic. However, different kinds of cardiac arrhythmia arising in conditions distant from the comfort may be either *pathologic* cardiac behavior or normal *adaptive* response of the heart.

2 Notice that the control is used to maintain a desired output of the system under control, while the guidance is intended for shifting the system from a state A to a state B.See more below.

© 2014 Moskalenko; licensee InTech. This is a paper distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/3.0), which permits unrestricted use, distribution, and reproduction in any medium, provided the original work is properly cited.

1This chapter is mainly based on our previous publication [2], which is revised and renewed for the aims of this book. The chapter contains some materials that have not been available previously to English-speaking readers.

To make the proper diagnosis of arrhythmia type, one requires a deep understanding of the basic mechanisms of the cardiac action in being normal as well as in its various disorders.

tissues; the process was given the name "excitation". Since then the nervous and muscle tissues have been referred to as "excitable tissues". Further development of ideas about excitable tissues made scientists draw some extremely important generalizations of all those experi‐ mental data which were collected by the end of the 19th century. It was as long ago as 1900 [8] that T.W. Engelmann, K.F. Wenckebach and H.P. Bowditch postulated the basic properties of the myocardium, namely: 1) automaticity, 2) refractory period, 3) all-or-nothing response, 4) staircase phenomenon. It is the concept of "animal electricity" that has formed the basis for all

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 3

Here we will not dwell on the peculiarities of the physiological language used for description of biological objects, as these are written in many textbooks of physiology quite a lot and in detail (for example, see [8–10]). It should only be emphasized that, after replacing the old notion of a special "living substance", the physiological language has entirely dominated among

However, the discussion between modern investigators of the heart reveals faultiness of the cardiologic paradigm, which is constructed owing to the epoch-making discoveries made by the greatest physiologists of the 19th and 20th centuries. The faultiness appears to be caused by our rather simple comprehension how biological systems work, which arose from the historic specificity of scientific knowledge evolution. During 17–19th centuries the science development is known to be mainly grounded on the notions of determinism, with great advantage in applied mechanics to constitute their historical basis. It resulted in permeating the conception, which is referred to as *mechanistic approach*4 now, into many fields of science. Nor has medicine escaped the common lot, since all modern physiology is per se a manifes‐ tation of the mechanistic approach in biology. In accordance with scientific tradition, the phenomena observed in physiology are explained, in the frames of the mechanistic approach, as a result of different simple mechanical movements. The movement of ions through mem‐ brane of a biological cell in order to explain the action potential is a good example of the approach. Prevalent endeavors of modern cardiologists to treat cardiac disorders by adjusting

More and more researchers [11–15] are coming to an increasingly profound understanding that there is a need for an alternative or modified paradigm, in order to consider the multisystemic nature of the body's function and its environmental interface if new and more effective therapies are to be developed. Recognizing a problem is the first step to its solution...

Over the past few decades, it have been accumulated quite a large number of experimental observations and theoretical results which are poorly fit within the constraints set by the physiological language. These new discoveries were called attention to, which has resulted in both drawing new generalizations of the collected scientific knowledge and developing a new

4 To distinguish the "mechanistic approach" and "insight into mechanisms" is extremely important. In the terms of mathematical physics, the mechanistic approach is based on linear description of nature, with the principle of superpo‐ sition being correct in the frames of this approach; however, non-linear mechanisms are shown to underlie a huge number of natural phenomena (for example, see [16, 17]), and, hence, insight into such non-linear mechanisms is also very desired.

the subsequent physiological investigations.

**1.4. Cardiophysics**

biologists and medical professionals for the whole 20th century.

membrane channels using one or another drug is another such example.

#### **1.2. Has the time come for alteration of the cardiologic paradigm?**

Despite major scientific, medical and technological advances over the last few decades, a cure of cardiac arrhythmias remains elusive. As a very appropriate example of the problems of traditional cardiology, which is generally based on physiological approach, is the result of the CAST [3, 4], a multicenter, double-blind, randomized controlled trial, that has revealed a higher rate of death from arrhythmia of the patients treated with antiarrhythmic agents in comparison with the patients assigned to placebo. One of the well-known Russian cardiologists having analyzed a number of multicenter trials came to the conclusion [5] that treatment with antiarrhythmic drugs is prescribed nearly at random; he shared his impression with the following words3 : "*Potentially any of the known antiarrhythmic drugs can 1) cause an antiarrhythmic effect, 2) not cause it, 3) be arrhythmogenic. And each of these cases happens unpredictably for a patient. Therefore, pharmacological tests are strongly required for selecting not only effective but, at least, harmless therapy for patients with malignant ventricular arrhythmias*." Another author impressed by the result asserted that antiarrhythmic drugs have "*cost more American lives than the Vietnam War*" [6].

Another convincing example of the same is given to us by the recent discussion about the mechanisms of cardiac fibrillation [7]. The intensity of authors' disappointment is expressed by their writing that the nature of fibrillation remains "*still so puzzling after 160 years of inquiry*". A generally accepted definition of cardiac fibrillation is lacking.

Hence, it remains to add that the history of science gives a lot of resembling examples convincing us that the actual state of affairs suggests a self-evident necessity of drastic alteration of the scientific paradigm that forms the basis of modern cardiology.

#### **1.3. The physiological description of the heart**

The discovery of "animal electricity" must undoubtedly be recognized as a very important step in understanding the causes and mechanisms of cardiac disorders. Furthermore, this discovery quickly led to the development of a new language, the *physiological language*, which appeared to be very convenient for a generalized description of such properties of living matter that had been believed to be absolutely different before.

Indeed, what common features between functions of the brain and of the muscles can be found out by somebody without special knowledge? What common, it would seem, can be between muscular power and the power of thought? However, the discovery of the "animal electricity" allowed registering a certain process that can be observed both in nervous and in muscle

3 In the original: «потенциально любой из известных антиаритмических препаратов может: а) обеспечить антиаритмический эффект; б) не обеспечить его; в) проявить аритмогенное действие. И все это индивидуально непредсказуемо. Поэтому для больных со злокачественными желудочковыми аритмиями выбор не только эффективной, но и безопасной терапии требует проведения фармакологических проб» [Голицын С.П. Грани пользы и риска при лечении желудочковых нарушений ритма сердца. Международный журнал медицинской практики 2000;(10) 56–64].

tissues; the process was given the name "excitation". Since then the nervous and muscle tissues have been referred to as "excitable tissues". Further development of ideas about excitable tissues made scientists draw some extremely important generalizations of all those experi‐ mental data which were collected by the end of the 19th century. It was as long ago as 1900 [8] that T.W. Engelmann, K.F. Wenckebach and H.P. Bowditch postulated the basic properties of the myocardium, namely: 1) automaticity, 2) refractory period, 3) all-or-nothing response, 4) staircase phenomenon. It is the concept of "animal electricity" that has formed the basis for all the subsequent physiological investigations.

Here we will not dwell on the peculiarities of the physiological language used for description of biological objects, as these are written in many textbooks of physiology quite a lot and in detail (for example, see [8–10]). It should only be emphasized that, after replacing the old notion of a special "living substance", the physiological language has entirely dominated among biologists and medical professionals for the whole 20th century.

However, the discussion between modern investigators of the heart reveals faultiness of the cardiologic paradigm, which is constructed owing to the epoch-making discoveries made by the greatest physiologists of the 19th and 20th centuries. The faultiness appears to be caused by our rather simple comprehension how biological systems work, which arose from the historic specificity of scientific knowledge evolution. During 17–19th centuries the science development is known to be mainly grounded on the notions of determinism, with great advantage in applied mechanics to constitute their historical basis. It resulted in permeating the conception, which is referred to as *mechanistic approach*4 now, into many fields of science. Nor has medicine escaped the common lot, since all modern physiology is per se a manifes‐ tation of the mechanistic approach in biology. In accordance with scientific tradition, the phenomena observed in physiology are explained, in the frames of the mechanistic approach, as a result of different simple mechanical movements. The movement of ions through mem‐ brane of a biological cell in order to explain the action potential is a good example of the approach. Prevalent endeavors of modern cardiologists to treat cardiac disorders by adjusting membrane channels using one or another drug is another such example.

More and more researchers [11–15] are coming to an increasingly profound understanding that there is a need for an alternative or modified paradigm, in order to consider the multisystemic nature of the body's function and its environmental interface if new and more effective therapies are to be developed. Recognizing a problem is the first step to its solution...

#### **1.4. Cardiophysics**

To make the proper diagnosis of arrhythmia type, one requires a deep understanding of the basic mechanisms of the cardiac action in being normal as well as in its various disorders.

Despite major scientific, medical and technological advances over the last few decades, a cure of cardiac arrhythmias remains elusive. As a very appropriate example of the problems of traditional cardiology, which is generally based on physiological approach, is the result of the CAST [3, 4], a multicenter, double-blind, randomized controlled trial, that has revealed a higher rate of death from arrhythmia of the patients treated with antiarrhythmic agents in comparison with the patients assigned to placebo. One of the well-known Russian cardiologists having analyzed a number of multicenter trials came to the conclusion [5] that treatment with antiarrhythmic drugs is prescribed nearly at random; he shared his impression with the

*effect, 2) not cause it, 3) be arrhythmogenic. And each of these cases happens unpredictably for a patient. Therefore, pharmacological tests are strongly required for selecting not only effective but, at least, harmless therapy for patients with malignant ventricular arrhythmias*." Another author impressed by the result asserted that antiarrhythmic drugs have "*cost more American lives than the Vietnam*

Another convincing example of the same is given to us by the recent discussion about the mechanisms of cardiac fibrillation [7]. The intensity of authors' disappointment is expressed by their writing that the nature of fibrillation remains "*still so puzzling after 160 years of*

Hence, it remains to add that the history of science gives a lot of resembling examples convincing us that the actual state of affairs suggests a self-evident necessity of drastic

The discovery of "animal electricity" must undoubtedly be recognized as a very important step in understanding the causes and mechanisms of cardiac disorders. Furthermore, this discovery quickly led to the development of a new language, the *physiological language*, which appeared to be very convenient for a generalized description of such properties of living matter

Indeed, what common features between functions of the brain and of the muscles can be found out by somebody without special knowledge? What common, it would seem, can be between muscular power and the power of thought? However, the discovery of the "animal electricity" allowed registering a certain process that can be observed both in nervous and in muscle

3 In the original: «потенциально любой из известных антиаритмических препаратов может: а) обеспечить антиаритмический эффект; б) не обеспечить его; в) проявить аритмогенное действие. И все это индивидуально непредсказуемо. Поэтому для больных со злокачественными желудочковыми аритмиями выбор не только эффективной, но и безопасной терапии требует проведения фармакологических проб» [Голицын С.П. Грани пользы и риска при лечении желудочковых нарушений ритма сердца. Международный журнал медицинской

*inquiry*". A generally accepted definition of cardiac fibrillation is lacking.

**1.3. The physiological description of the heart**

that had been believed to be absolutely different before.

alteration of the scientific paradigm that forms the basis of modern cardiology.

: "*Potentially any of the known antiarrhythmic drugs can 1) cause an antiarrhythmic*

**1.2. Has the time come for alteration of the cardiologic paradigm?**

2 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

following words3

практики 2000;(10) 56–64].

*War*" [6].

Over the past few decades, it have been accumulated quite a large number of experimental observations and theoretical results which are poorly fit within the constraints set by the physiological language. These new discoveries were called attention to, which has resulted in both drawing new generalizations of the collected scientific knowledge and developing a new

4 To distinguish the "mechanistic approach" and "insight into mechanisms" is extremely important. In the terms of mathematical physics, the mechanistic approach is based on linear description of nature, with the principle of superpo‐ sition being correct in the frames of this approach; however, non-linear mechanisms are shown to underlie a huge number of natural phenomena (for example, see [16, 17]), and, hence, insight into such non-linear mechanisms is also very desired.

language, the *biophysical* one. For example, while the physiological approach fails to take chaotic dynamics into account, the biophysical way of living system description, mainly based on the theory of dynamical system, has equipped scientists with reliable quantitative methods of studying enorganic phenomena of deterministic chaos. Modern scientific disciplines lead to the conclusion that often adequate comprehension of a complex system requires analyzing not the observed values, but some of its integral characteristics, which can be mathematically obtained as a combination of a number of the observed. Chaotic attractor is a good illustration of how important ideas of modern physics are for cardiology [16–18]. Whether any sort of chaotic attractors correspond to the normal cardiac activity, remains still a very good question. Other crucial phenomena that must certainly be taken into account when treatment for a cardiologic patient is provided are caused by so-called "bifurcation memory", which has attracted special attention of investigators since recently [19–21]. Recent evidence suggests that similar phenomena can be found in the heart [1, 2]. The results of investigating the bifurcation memory in a cardiac model are presented and discussed below.

consideration within the dipole hypothesis has showed [24] that the QT-duration in different leads, tQT(*l*), must be exactly equal to each other with the exception, perhaps, of some *very special cases* as well as that, at a low noise level and, consequently, the low threshold of identification the end of the T-wave, it is difficult to expect a large spread of the values tQT(*l*) measured from leads to leads in a case of vector loops with a *finite radius of curvature*. The differences in tQT(*l*) observed in practice can be explained only by algorithms used for detecting the T-wave end or the ECG isoline, by choice of the thresholds of identification in relation to the accepted rules of coding the presence of the ECG-waves, or by the actual values of the signal / noise ratio, as well as by measurement errors. Nevertheless, the authors identified a number of factors [25] that can even within the dipole hypothesis result in increasing dispersion of QT-duration both in a sequence of cardiocycles from the same leads and in a set of records of the same cardiac cycle simultaneously registered in the different leads. Two most

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 5

**1.** There is no clear correspondence between the positions of electrical and anatomical axes of the heart due to physiologically normal variations in topography of His-Purkinje

**2.** QT-dispersion also depends on the random rotations of the ventricles relative to the measuring electrodes, for example, during rotation of the heart relative to its anatomical

Hence, the investigation [24, 25] has shown that it is impossible at present to reject the hypothesis of random nature of the QTD changes, since all of these factors that generate QTD changes should be considered as random variables. Regardless of the biophysical result, it is still believed, however, that "increased QT dispersion is associated with increased risk of

The second example deals with defibrillation. Cardiologists are known to have been working on the problem of defibrillation for several decades, but desired level of success has not yet been achieved, and the fundamental mechanisms that underlie defibrillation still remain a mystery [27]. At present there is no generally accepted point of view on the mechanisms of postshock arrhythmia induction resulting from unsuccessful defibrillation. A number of factors were assumed among the possible causes of an unsuccessful defibrillation; for example: 1) residual fibrillation activity in areas of weak voltage gradient, 2) new autowave vortices generated by a shock, 3) focal ectopic activity in areas of myocardium traumatized the action of electric current that a defibrillator produces. Suggested in the last years, the new Theory of Virtual Electrodes [28, 29] helps to understand failures of the defibrillation protocols presently in use. One of the most important practical conclusions of the theory is the recommendation to use a biphasic defibrillation stimulus, which can significantly increase the effectiveness of defibrillation. It should be noted that the emergence of new look at defibrillation and the subsequent development of the theory of virtual electrodes became possible only by using one of the fresher biophysical models of such intricate active medium as the myocardium, which is referred to "bidomain model". In addition, several researches [30, 31], which also are carried out in the frames of cardiophysical approach, are aimed at developing new techniques of defibrillation based on suppression of cardiac turbulent dynamics by weak local excitations.

significant factors are following:

system.

axes.

cardiovascular death" [26].

The following three other examples are intended to illustrate how the use of new biophysical laws has led to a substantially deeper understanding of well-known phenomena, not achiev‐ able within the frames of physiology.

Experimental results from studies in electro- and magnetocardiology gave rise to the modern biophysical conception of "*equivalent bioelectric generator*" [22], which is strongly based on classical electrodynamics. The first example is to demonstrate how the conception of "equiv‐ alent bioelectric generator" was useful for investigation of the QT dispersion problem. QT dispersion (QTD) is simply defined as the difference between the longest (QTmax) and the shortest (QTmin) QT intervals within a 12-lead ECG; since its description in 1990, it has been considered as "undergoing vigorous assessment" for the purpose of early identifying subjects at high risk of sudden cardiac death, because it was supposed that "the interlead QT interval differences within a 12-lead ECG might reflect regional differences in myocardial refractori‐ ness, and that this might predict cardiac dysrhythmias" [23]. Common sense based on the physiological concept seemed to point quite convincingly to the prognostic significance of the phenomenon of QTD, because it is expected that electrophysiological instability of activation and recovery of the myocardium must necessarily be reflected on the surface of the torso in a form of instability of ECG-patterns of the repolarization part of the cardiac cycle. In spite of that, the accurate, from the standpoint of biophysics, study of possible mechanisms of QTD, after problems of the QT-interval genesis were considered in terms of biophysical models of the cardiac electric activity, has led to the conclusion that the duration of the QT-interval (tQT) are the same in each electrocardiographic leads, and the "QT dispersion" phenomenon stems mainly from mistakes in detecting the T-wave end [24, 25]. Electrical activity of the ventricular myocardium in such models is determined only by the equivalent cardiac dipole, which the spatial vector loops QRS and T correspond to. Although the normal work of the heart can be successfully described by a dipole, multipole components are given rise to when cardiac disorders occur. It can be stated therefore that the phenomenon of QTD reflects the contribution of the multipole components in a total picture of the electrical activity of the heart. Let us denote duration of QT in different leads as tQT(*l*), where *l* belongs to a set of leads L. The theoretical consideration within the dipole hypothesis has showed [24] that the QT-duration in different leads, tQT(*l*), must be exactly equal to each other with the exception, perhaps, of some *very special cases* as well as that, at a low noise level and, consequently, the low threshold of identification the end of the T-wave, it is difficult to expect a large spread of the values tQT(*l*) measured from leads to leads in a case of vector loops with a *finite radius of curvature*. The differences in tQT(*l*) observed in practice can be explained only by algorithms used for detecting the T-wave end or the ECG isoline, by choice of the thresholds of identification in relation to the accepted rules of coding the presence of the ECG-waves, or by the actual values of the signal / noise ratio, as well as by measurement errors. Nevertheless, the authors identified a number of factors [25] that can even within the dipole hypothesis result in increasing dispersion of QT-duration both in a sequence of cardiocycles from the same leads and in a set of records of the same cardiac cycle simultaneously registered in the different leads. Two most significant factors are following:

language, the *biophysical* one. For example, while the physiological approach fails to take chaotic dynamics into account, the biophysical way of living system description, mainly based on the theory of dynamical system, has equipped scientists with reliable quantitative methods of studying enorganic phenomena of deterministic chaos. Modern scientific disciplines lead to the conclusion that often adequate comprehension of a complex system requires analyzing not the observed values, but some of its integral characteristics, which can be mathematically obtained as a combination of a number of the observed. Chaotic attractor is a good illustration of how important ideas of modern physics are for cardiology [16–18]. Whether any sort of chaotic attractors correspond to the normal cardiac activity, remains still a very good question. Other crucial phenomena that must certainly be taken into account when treatment for a cardiologic patient is provided are caused by so-called "bifurcation memory", which has attracted special attention of investigators since recently [19–21]. Recent evidence suggests that similar phenomena can be found in the heart [1, 2]. The results of investigating the bifurcation

The following three other examples are intended to illustrate how the use of new biophysical laws has led to a substantially deeper understanding of well-known phenomena, not achiev‐

Experimental results from studies in electro- and magnetocardiology gave rise to the modern biophysical conception of "*equivalent bioelectric generator*" [22], which is strongly based on classical electrodynamics. The first example is to demonstrate how the conception of "equiv‐ alent bioelectric generator" was useful for investigation of the QT dispersion problem. QT dispersion (QTD) is simply defined as the difference between the longest (QTmax) and the shortest (QTmin) QT intervals within a 12-lead ECG; since its description in 1990, it has been considered as "undergoing vigorous assessment" for the purpose of early identifying subjects at high risk of sudden cardiac death, because it was supposed that "the interlead QT interval differences within a 12-lead ECG might reflect regional differences in myocardial refractori‐ ness, and that this might predict cardiac dysrhythmias" [23]. Common sense based on the physiological concept seemed to point quite convincingly to the prognostic significance of the phenomenon of QTD, because it is expected that electrophysiological instability of activation and recovery of the myocardium must necessarily be reflected on the surface of the torso in a form of instability of ECG-patterns of the repolarization part of the cardiac cycle. In spite of that, the accurate, from the standpoint of biophysics, study of possible mechanisms of QTD, after problems of the QT-interval genesis were considered in terms of biophysical models of the cardiac electric activity, has led to the conclusion that the duration of the QT-interval (tQT) are the same in each electrocardiographic leads, and the "QT dispersion" phenomenon stems mainly from mistakes in detecting the T-wave end [24, 25]. Electrical activity of the ventricular myocardium in such models is determined only by the equivalent cardiac dipole, which the spatial vector loops QRS and T correspond to. Although the normal work of the heart can be successfully described by a dipole, multipole components are given rise to when cardiac disorders occur. It can be stated therefore that the phenomenon of QTD reflects the contribution of the multipole components in a total picture of the electrical activity of the heart. Let us denote duration of QT in different leads as tQT(*l*), where *l* belongs to a set of leads L. The theoretical

memory in a cardiac model are presented and discussed below.

4 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

able within the frames of physiology.

Hence, the investigation [24, 25] has shown that it is impossible at present to reject the hypothesis of random nature of the QTD changes, since all of these factors that generate QTD changes should be considered as random variables. Regardless of the biophysical result, it is still believed, however, that "increased QT dispersion is associated with increased risk of cardiovascular death" [26].

The second example deals with defibrillation. Cardiologists are known to have been working on the problem of defibrillation for several decades, but desired level of success has not yet been achieved, and the fundamental mechanisms that underlie defibrillation still remain a mystery [27]. At present there is no generally accepted point of view on the mechanisms of postshock arrhythmia induction resulting from unsuccessful defibrillation. A number of factors were assumed among the possible causes of an unsuccessful defibrillation; for example: 1) residual fibrillation activity in areas of weak voltage gradient, 2) new autowave vortices generated by a shock, 3) focal ectopic activity in areas of myocardium traumatized the action of electric current that a defibrillator produces. Suggested in the last years, the new Theory of Virtual Electrodes [28, 29] helps to understand failures of the defibrillation protocols presently in use. One of the most important practical conclusions of the theory is the recommendation to use a biphasic defibrillation stimulus, which can significantly increase the effectiveness of defibrillation. It should be noted that the emergence of new look at defibrillation and the subsequent development of the theory of virtual electrodes became possible only by using one of the fresher biophysical models of such intricate active medium as the myocardium, which is referred to "bidomain model". In addition, several researches [30, 31], which also are carried out in the frames of cardiophysical approach, are aimed at developing new techniques of defibrillation based on suppression of cardiac turbulent dynamics by weak local excitations.

Returning to the results of CAST and other similar investigation, we ought to remind that these results were evident directly from the very early theoretical works of those scientists who can undoubtedly be mentioned among the founders of a new branch of science, cardiophysics. First of all, I mean here the studies by Arthur Winfree [32], who has revealed the principal autowave regimes of the simplest active medium and their dependence on the basic integral parameters of the medium, as well as by Valentin Krinsky and Iury Kokoz [33], who have shown that every active medium should demonstrate the same set of principal autowave regimes, because the corresponding systems of partial differential equation can always be reduced to the simplest one. Taken together these results lead to the obvious conclusion that any manipulation with the membrane ion channels of cardiomyocytes directed to the sup‐ pression of ventricular tachycardia by forcing autowave vortices to perform uniform circular motion (which corresponds to monomorphic tachycardia) always results in to the displace‐ ment of myocardial state very far from normal, which must inevitably increase patient mortality. Note that the hypothesis about the displacement of myocardial state was confirmed later in an experimental work with lidocaine [34], in good accordance with Winfree's predic‐ tion. Another biophysical study [35] demonstrated one more reason why medicines that exhibit strongly pronounced antiarrhythmic properties when affecting single cardiomyocyte increase in 2-3 times the frequency of sudden arrhythmic death in comparison to untreated patients. At first glance, it does seem paradoxical that the same drug has antiarrhythmic effect on isolated cells and pro-arrhythmic effect on the multicellular system (the whole heart). In the computational imitating experiments, the author managed nevertheless to discover that sodium channel blockers can greatly increase the so-called vulnerable period in myocardium, which occurs because of a decrease of velocity of the excitation wave, and also because of reduction of excitability gradient. The next remark deals with ECG diagnostics. Notwith‐ standing the properties of myocardium are known to affect ECG, the investigation of the dependence of several ECG characteristics on the threshold of excitation, which was carried out by means of mathematical modeling monomorphic arrhythmias in a homogeneous twodimensional excitable medium, revealed [36] that these arrhythmias appear under both decreased and increased values of the excitation threshold. Hence, this result leads also to the conclusion that medical treatments are prescribed nearly at random when a cardiologist make his or her decision only on the base of ECG analysis without knowing about real changes of the excitation threshold. Generalizing these three biophysical conclusions about medical treatment of tachycardia, should we be surprised that the success of such treatment can hardly be called acceptable?

*cardiovascular physics*5

**2.1. Historical remarks**

cardiac action is offered in this chapter further.

Cardiovascular Biophysics Laboratory in Washington University (USA).

or *cardiophysics* (since it combines cardiology with novel achievements

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 7

of physics). Cardiophysics is an interdisciplinary science that stands at the junction of cardi‐ ology and biophysics, with researchers using the methods of, and theories from, physics to study cardiovascular system at different levels of its organization, from the molecular scale to whole organisms. Being formed historically as part of systems biology, cardiophysics is designed to reveal connections between the physical mechanisms, underlying the organization

**2. Basic biophysical mechanisms of maintaining the action of the heart**

About fifty year ago, physicists and mathematicians managed to perceive that the processes that take place in a "purely physical" systems (e.g., lasers, or even in boiling water) are similar in some of their properties to the processes observed in the physiology of excitable biological tissues. The understanding came gradually that phenomena such as irritability, conductivity, all-or-nothing response, refractory period etc. are inherent not only exclusively in biological objects, but also typical for non-living nature. It is important to comprehend that the speech here is not about some analogies, but exactly about a new scientific generalization of the accumulated scientific knowledge, and that the generalization made by researchers in respect of particular types of behavior of living and some non-living systems is based on the certain entirely real properties of such systems. This generalization led to the development of a new language, biophysical one, which are more universal and more powerful. The new language has reproduced the description of all that was already described earlier in the physiology, but it also allows in unified terms to represent a wide range of experimental data, the description of which the physiological language performed poorly. The new expanded description of the

Undoubtedly, the term "*autowave*", which refers to a large number of different biological

The first who studied actively the self-oscillations was Academician A.A. Andronov, and the term "*auto-oscillations*" in Russian terminology was introduced by him in 1928. The term "*autowaves*" was proposed in the second half of the 20th century, probably, on the analogy of the previously used "auto-oscillations". The classical axiomatic model of autowaves in myocardium was published in 1946 by Norbert Wiener and Arturo Rosenblueth [40]. During 1970-80, major efforts to study autowaves were concentrated in the Institute of Biological Physics of the USSR Academy of Sciences. A huge role in the study of autowave models of cardiac tissue belongs to D. Noble and members of his team from the University of Oxford [12, 13]. There are a lot of other researchers over the world who contributed to development of the

5 For example, there are already the Group of Nonlinear Dynamics & Cardiovascular Physics of the 1st Faculty of Mathematics and Natural Sciences in the Institute of Physics of Humboldt University of Berlin (German) and the

objects, plays one of the most important roles in the new biophysical language.

of the cardiovascular system, and biological features of its functioning.

In addition to remarkable progress in biophysics, another important conceptual breakthrough of science was performed in the field that now is referred to as *nonequilibrium thermodynam‐ ics*, "*physics of becoming*" [37] or *synergetics* [38], which "represents a remarkable confluence of many strands of thought, and has become a paradigm in modern culture" [39]. Biological systems are complex and nonlinear, and, therefore, demonstrate complex and nonlinear behavior, which may be chaotic, in many cases; the heart appears to be the same [14, 17, 18, 28, 30, 31].

All these examples should be recognized as proofs of birth of a new science. Thus, we ought to conclude that the 21st century seems to yield a new discipline, which is referred to as *cardiovascular physics*5 or *cardiophysics* (since it combines cardiology with novel achievements of physics). Cardiophysics is an interdisciplinary science that stands at the junction of cardi‐ ology and biophysics, with researchers using the methods of, and theories from, physics to study cardiovascular system at different levels of its organization, from the molecular scale to whole organisms. Being formed historically as part of systems biology, cardiophysics is designed to reveal connections between the physical mechanisms, underlying the organization of the cardiovascular system, and biological features of its functioning.

#### **2. Basic biophysical mechanisms of maintaining the action of the heart**

#### **2.1. Historical remarks**

Returning to the results of CAST and other similar investigation, we ought to remind that these results were evident directly from the very early theoretical works of those scientists who can undoubtedly be mentioned among the founders of a new branch of science, cardiophysics. First of all, I mean here the studies by Arthur Winfree [32], who has revealed the principal autowave regimes of the simplest active medium and their dependence on the basic integral parameters of the medium, as well as by Valentin Krinsky and Iury Kokoz [33], who have shown that every active medium should demonstrate the same set of principal autowave regimes, because the corresponding systems of partial differential equation can always be reduced to the simplest one. Taken together these results lead to the obvious conclusion that any manipulation with the membrane ion channels of cardiomyocytes directed to the sup‐ pression of ventricular tachycardia by forcing autowave vortices to perform uniform circular motion (which corresponds to monomorphic tachycardia) always results in to the displace‐ ment of myocardial state very far from normal, which must inevitably increase patient mortality. Note that the hypothesis about the displacement of myocardial state was confirmed later in an experimental work with lidocaine [34], in good accordance with Winfree's predic‐ tion. Another biophysical study [35] demonstrated one more reason why medicines that exhibit strongly pronounced antiarrhythmic properties when affecting single cardiomyocyte increase in 2-3 times the frequency of sudden arrhythmic death in comparison to untreated patients. At first glance, it does seem paradoxical that the same drug has antiarrhythmic effect on isolated cells and pro-arrhythmic effect on the multicellular system (the whole heart). In the computational imitating experiments, the author managed nevertheless to discover that sodium channel blockers can greatly increase the so-called vulnerable period in myocardium, which occurs because of a decrease of velocity of the excitation wave, and also because of reduction of excitability gradient. The next remark deals with ECG diagnostics. Notwith‐ standing the properties of myocardium are known to affect ECG, the investigation of the dependence of several ECG characteristics on the threshold of excitation, which was carried out by means of mathematical modeling monomorphic arrhythmias in a homogeneous twodimensional excitable medium, revealed [36] that these arrhythmias appear under both decreased and increased values of the excitation threshold. Hence, this result leads also to the conclusion that medical treatments are prescribed nearly at random when a cardiologist make his or her decision only on the base of ECG analysis without knowing about real changes of the excitation threshold. Generalizing these three biophysical conclusions about medical treatment of tachycardia, should we be surprised that the success of such treatment can hardly

6 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

In addition to remarkable progress in biophysics, another important conceptual breakthrough of science was performed in the field that now is referred to as *nonequilibrium thermodynam‐ ics*, "*physics of becoming*" [37] or *synergetics* [38], which "represents a remarkable confluence of many strands of thought, and has become a paradigm in modern culture" [39]. Biological systems are complex and nonlinear, and, therefore, demonstrate complex and nonlinear behavior, which may be chaotic, in many cases; the heart appears to be the same [14, 17, 18,

All these examples should be recognized as proofs of birth of a new science. Thus, we ought to conclude that the 21st century seems to yield a new discipline, which is referred to as

be called acceptable?

28, 30, 31].

About fifty year ago, physicists and mathematicians managed to perceive that the processes that take place in a "purely physical" systems (e.g., lasers, or even in boiling water) are similar in some of their properties to the processes observed in the physiology of excitable biological tissues. The understanding came gradually that phenomena such as irritability, conductivity, all-or-nothing response, refractory period etc. are inherent not only exclusively in biological objects, but also typical for non-living nature. It is important to comprehend that the speech here is not about some analogies, but exactly about a new scientific generalization of the accumulated scientific knowledge, and that the generalization made by researchers in respect of particular types of behavior of living and some non-living systems is based on the certain entirely real properties of such systems. This generalization led to the development of a new language, biophysical one, which are more universal and more powerful. The new language has reproduced the description of all that was already described earlier in the physiology, but it also allows in unified terms to represent a wide range of experimental data, the description of which the physiological language performed poorly. The new expanded description of the cardiac action is offered in this chapter further.

Undoubtedly, the term "*autowave*", which refers to a large number of different biological objects, plays one of the most important roles in the new biophysical language.

The first who studied actively the self-oscillations was Academician A.A. Andronov, and the term "*auto-oscillations*" in Russian terminology was introduced by him in 1928. The term "*autowaves*" was proposed in the second half of the 20th century, probably, on the analogy of the previously used "auto-oscillations". The classical axiomatic model of autowaves in myocardium was published in 1946 by Norbert Wiener and Arturo Rosenblueth [40]. During 1970-80, major efforts to study autowaves were concentrated in the Institute of Biological Physics of the USSR Academy of Sciences. A huge role in the study of autowave models of cardiac tissue belongs to D. Noble and members of his team from the University of Oxford [12, 13]. There are a lot of other researchers over the world who contributed to development of the

5 For example, there are already the Group of Nonlinear Dynamics & Cardiovascular Physics of the 1st Faculty of Mathematics and Natural Sciences in the Institute of Physics of Humboldt University of Berlin (German) and the Cardiovascular Biophysics Laboratory in Washington University (USA).

*theory of the autowave processes*, i.e. the processes in the *active media*. Since then, as the peculiar properties of the active media has been understood, the autowave processes attract attention of mathematicians, physicists and biologists, and it turned out, that the experience that had been gained by physiologists before gave a very useful basis for constructing the new bio‐ physical language for describing phenomena observed in the active media of different nature.

First of all, a general property of such systems, regardless of whether they are of animate or of inanimate nature, is that they consist of external energy sources distributed in the space; and such special systems were called "*active media*". From the thermodynamic point of view, these are open systems far from thermodynamic equilibrium [41]. It is the quality that compels the behavior of the active media to differ fundamentally from that of systems which have been familiar to physicists of the 19th and 20th centuries. Even the waves in active media propagate according to essentially different laws than the well-known acoustic or electromagnetic waves do. Unlike linear waves — such as sound waves, electromagnetic waves and other, which are inherent in conservative systems and mathematically described by linear second order hyperbolic equations (wave equations), — dynamics of an autowave in terms of differential equations can be described by *parabolic equation with nonlinear free member of a special form* (the

It was shown in 1973 [33] that every system of mathematical differential equations describing the process of excitation of biological tissues can be simplified with use of some standard mathematical procedures to only two equations that describe, with an acceptable accuracy, the real object for which the "exact" original system of many equations was composed. It proved that such systems are a very important kind of active media, which has been called "*active media with recovery*" (note, that nerve impulse, which serves typical example of autowaves in the active medium with recovery, was studied as far back as 1850 by Hermann von Helmholtz). Thus, the following system of two equations is recognized to be the base model of the active

1 1

where *ε* < <1.*D*2 =0 for excitable biological membranes, whereas both the diffusion coefficient, *D*1 and *D*2, are different from zero for chemical systems. For biological membranes, the meaning of the variables of state is as follows: *u* corresponds to the membrane potential, and *v* is the conductivity of the slow component of the membrane current. Although the exact description of a specific sort of active medium can take much more equations (for example, the modern model of the human myocardium consists of more than twenty equations), the most important basic properties of autowave processes are well described already within this

The next essential moment is that the active media are characterized not only by the connec‐ tions between the adjacent points of the medium (i.e. by flows of substances and / or energy,

→ (*u*

always must be self-oscillating or potentially self-oscillating. In the base model of the active

×= +D (,) *t u f uv D u* (1)

2 2 = +D (,) *t v f uv D v* (2)

→ in the system of equa‐

→ ), which

→ *t* = *f* → (*u*

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 9

→ ) is of exceptional importance, because all

e

such as heat conduction or diffusion, which is described by *DΔu*

wave processes are generated by the nonlinear dynamics of the point system *u*

tions).The concrete form of the free member *f*

equation is presented at a few lines above).

medium with recovery [41]:

basic model of active media.

#### **2.2. Mathematical aspects**

According to [41], the term "*autowaves*" is used for designation of a self-sustaining nonlinear undulatory process in a non-equilibrium (active) medium, the process remaining unchanged for sufficiently small changes in both the initial and boundary conditions and described by the system of parabolic partial differential equations with a nonlinear free member, which in its general form can be written as follows: *u* → *t* = *f* → (*u* → ) + *DΔu* → , where *u* → is a vector of state variables, *u* → *t* is the time derivative of the *u* → , *f* → (*u* → ) is a vector of free members (i.e., of nonlinear functions), *D* is a diagonal matrix of the coefficients that describe diffusion of each component, and *Δ* is the Laplace operator. Thus, the mathematical apparatus that are often used for describing autowave processes are the equations of the diffusion type with an active nonlinearity (i.e. *reaction–diffusion systems*).

It is impossible here to delve into the details of the mathematical description of autowave processes, but there are an abundance of literature on this topic (for example, see [32, 33, 40– 47]). Therefore only those aspects which are the most important for understanding the nature of cardiac arrhythmias will be touched on here. To apprehend distinctly the signification of the term "autowaves", several things should be noted.

**Figure 1.** Phase portraits (left column) and the corresponding behavior (right column) of a single element of the active medium: row **A** — excitable, row **B** — bistable, row **С** — self-oscillating element types. Rose area corresponds to *f* 1(*u*, *v*)>0, and blue color highlights the area, where *f* 1(*u*, *v*)<0. See description in the text.

First of all, a general property of such systems, regardless of whether they are of animate or of inanimate nature, is that they consist of external energy sources distributed in the space; and such special systems were called "*active media*". From the thermodynamic point of view, these are open systems far from thermodynamic equilibrium [41]. It is the quality that compels the behavior of the active media to differ fundamentally from that of systems which have been familiar to physicists of the 19th and 20th centuries. Even the waves in active media propagate according to essentially different laws than the well-known acoustic or electromagnetic waves do. Unlike linear waves — such as sound waves, electromagnetic waves and other, which are inherent in conservative systems and mathematically described by linear second order hyperbolic equations (wave equations), — dynamics of an autowave in terms of differential equations can be described by *parabolic equation with nonlinear free member of a special form* (the equation is presented at a few lines above).

*theory of the autowave processes*, i.e. the processes in the *active media*. Since then, as the peculiar properties of the active media has been understood, the autowave processes attract attention of mathematicians, physicists and biologists, and it turned out, that the experience that had been gained by physiologists before gave a very useful basis for constructing the new bio‐ physical language for describing phenomena observed in the active media of different nature.

According to [41], the term "*autowaves*" is used for designation of a self-sustaining nonlinear undulatory process in a non-equilibrium (active) medium, the process remaining unchanged for sufficiently small changes in both the initial and boundary conditions and described by the system of parabolic partial differential equations with a nonlinear free member, which in its

*D* is a diagonal matrix of the coefficients that describe diffusion of each component, and *Δ* is the Laplace operator. Thus, the mathematical apparatus that are often used for describing autowave processes are the equations of the diffusion type with an active nonlinearity (i.e.

It is impossible here to delve into the details of the mathematical description of autowave processes, but there are an abundance of literature on this topic (for example, see [32, 33, 40– 47]). Therefore only those aspects which are the most important for understanding the nature of cardiac arrhythmias will be touched on here. To apprehend distinctly the signification of

**Figure 1.** Phase portraits (left column) and the corresponding behavior (right column) of a single element of the active medium: row **A** — excitable, row **B** — bistable, row **С** — self-oscillating element types. Rose area corresponds to

*f* 1(*u*, *v*)>0, and blue color highlights the area, where *f* 1(*u*, *v*)<0. See description in the text.

→ ) + *DΔu*

→ , where *u*

→ ) is a vector of free members (i.e., of nonlinear functions),

→ is a vector of state variables,

→ *t* = *f* → (*u*

→ , *f* → (*u*

the term "autowaves", several things should be noted.

**2.2. Mathematical aspects**

*u* →

general form can be written as follows: *u*

8 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

*t* is the time derivative of the *u*

*reaction–diffusion systems*).

It was shown in 1973 [33] that every system of mathematical differential equations describing the process of excitation of biological tissues can be simplified with use of some standard mathematical procedures to only two equations that describe, with an acceptable accuracy, the real object for which the "exact" original system of many equations was composed. It proved that such systems are a very important kind of active media, which has been called "*active media with recovery*" (note, that nerve impulse, which serves typical example of autowaves in the active medium with recovery, was studied as far back as 1850 by Hermann von Helmholtz). Thus, the following system of two equations is recognized to be the base model of the active medium with recovery [41]:

$$
\boldsymbol{\varepsilon} \cdot \boldsymbol{u}\_t = f\_1(\boldsymbol{u}, \boldsymbol{\nu}) + D\_1 \Delta \boldsymbol{u} \tag{1}
$$

$$
\Delta \mathbf{v}\_t = f\_2(\mu, \mathbf{v}) + D\_2 \Delta \mathbf{v} \tag{2}
$$

where *ε* < <1.*D*2 =0 for excitable biological membranes, whereas both the diffusion coefficient, *D*1 and *D*2, are different from zero for chemical systems. For biological membranes, the meaning of the variables of state is as follows: *u* corresponds to the membrane potential, and *v* is the conductivity of the slow component of the membrane current. Although the exact description of a specific sort of active medium can take much more equations (for example, the modern model of the human myocardium consists of more than twenty equations), the most important basic properties of autowave processes are well described already within this basic model of active media.

The next essential moment is that the active media are characterized not only by the connec‐ tions between the adjacent points of the medium (i.e. by flows of substances and / or energy, such as heat conduction or diffusion, which is described by *DΔu* → in the system of equa‐ tions).The concrete form of the free member *f* → (*u* → ) is of exceptional importance, because all wave processes are generated by the nonlinear dynamics of the point system *u* → *t* = *f* → (*u* → ), which always must be self-oscillating or potentially self-oscillating. In the base model of the active medium with recovery, the complicated nonlinear behavior of a single element is described by the free member, i.e. as the function *f* 1(*u*, *v*), which usually has **N**-shaped form (Figure 1). Three simplest types of such elements can be distinguished [17, 42, 43]; one can also say that a single element has three essentially different regimes of its behavior, because it is possible to force the element change its type. These are: *self-excited* (or *self-oscillating*), *excitable* (or *waiting*) and *trigger* (or *bistable*) regimes. Accordingly, there are three types of homogeneous active media composed of these elements.

It is reasonable that a good number of examples of combined active media, which are composed of different types of elements, can be found everywhere. The heart is just one example of a

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 11

The region of a combined active medium which consists of self-oscillatory elements is called the *pacemaker*. This region emits autowaves with a certain stable period. An example of a biological pacemaker in the heart of the human is the sinus node, which is constituted of a

In thin enough layers of the active medium, the pacemaker creates a picture in the form of ring waves diverging from a center (Figure 2). Period of pacemaker oscillations is determined by its intrinsic properties and can be arbitrary, but not less than the absolute refractory period, because a new action potential cannot arise during the absolute refractory period (see below).

If there are a number of self-oscillating elements with different periods in the medium, every element with low-frequency activity is suppressed by the element with the highest frequency [41]. For a long time physiologists have known about the hierarchy of pacemakers in the heart, and the same result was obtained mathematically in the second half of twentieth century. Pacemakers in the heart are the sinoatrial (SA) node, the atrioventricular (AV) node and the bundle of His and Purkinje fibers. The sinoatrial node normally initiates action potentials, simply because it generates impulses slightly faster than the other areas with self-oscillating activity. The remaining pacemakers normally are in a depressed state, which is reflected by physiological language as "latent pacemaker capability." If the SA node is suddenly "out of order", the fastest of the "spare" pacemakers (i.e., the AV node) enters into work, and, as a result, the heart continues its action nearly in normal regime. This duplication of parts of the

However, recent studies [49, 50] have shown that the rhythmic activity of the self-oscillating elements in the group which form the body of the pacemaker is synchronized by more complex laws, and the ascertained earlier variant of synchronization from the element with the highest frequency of the oscillations is only a special case. The problem of the control of cardiac rhythm has been considered in terms of the general theory of the synchronization of relaxation systems, and, as result, the main pathways of the control of cardiac rhythm have been revealed: (1) control with regard for the features of synchronization of relaxation systems during the formation of the unified heart rhythm due to the acceleration of the slow diastole depolariza‐ tion phase; (2) control by gradual integral increase in the duration of the slow diastole depolarization phase; (3) subsequent synchronization of the rhythm as a delay of the slow

The concept "*traveling autowave*" (or "*autowave of excitation*", or "*propagating autowave*") should be considered as generalization made in the new biophysical language of the concept "exci‐ tation wave", which is understood in the frames of physiology as an electrical wave that

highly organized combined active medium.

group of cells functioning in the self-oscillating mode.

system is aimed, evidently, to improve its reliability.

diastole depolarization phase.

**2.4. Traveling autowaves**

**2.3. Pacemakers**

The *excitable* element (row **A** of Figure 1) has only one stable steady state (the point **O**, which is the intersection of the two null isoclines; a quiescent state of the excitable element corre‐ sponds with this point). External impact over a threshold level (i.e., greater than the length of the segment **OA**), can bring the excitable element out from its steady state and force it accomplish a certain evolution (in the phase portrait shown by the orange line) before returning to its quiescent state. An excited element may affect the adjacent elements moving them out from their quiescent state. As a result, an autowave of excitation spreads through the medium. Excitable media like the working myocardium consist of such excitable elements. Hence, it becomes obvious the fallacy of popular opinion that "all cardiac cells have spontaneous firing capacity, but only at a very slow heart rate", the assertion which can be often met in books and papers.

The *bistable* element (row **B** of Figure 1) has two steady states at the points **O1** and **O2**, each of which can be whether stable or unstable, while the point O in this case is always unstable. Transitions between the two stationary states occur when an external impact exceeds a certain threshold level (the same way as it does in the excitable element). In such media there can be the *trigger wave* propagation, which switches the media from one steady state to the other. A classic case of such a switching autowave (and, perhaps, the simplest autowave phenomena) is falling dominoes. Another simple example of the bistable medium is burning paper: the switching wave propagates on it in the form of a flame, switching paper from the normal state to its ashes.

The *self-oscillating* element (row **C** of Figure 1) has no stable steady states (the point O in this case is always unstable) and therefore it permanently performs oscillations of certain fixed form, amplitude and frequency. An example of a self-oscillating medium is the sinus node of the heart, in which excitation impulses arise spontaneously. External influence can disturb these oscillations, but, after some relaxation time, all their characteristics, except for the phase, revert to the stable values, although the phase can be changed, resulting in the phase waves spread in the self-excited medium. Such phase waves can be observed in electro-garlands or in certain chemical media.

So it can be clearly seen on the phase portrait of the basic system of equations describing active medium of different types (see Figure 1) that a significant difference between these three types of behavior of an active medium is caused by the quantity and the position of its singular points. The shapes of autowaves observed in reality can be, however, very similar to each other, and therefore it can be difficult to assess correctly the type of element only by the form of its excitation impulse.

It is reasonable that a good number of examples of combined active media, which are composed of different types of elements, can be found everywhere. The heart is just one example of a highly organized combined active medium.

#### **2.3. Pacemakers**

medium with recovery, the complicated nonlinear behavior of a single element is described by the free member, i.e. as the function *f* 1(*u*, *v*), which usually has **N**-shaped form (Figure 1). Three simplest types of such elements can be distinguished [17, 42, 43]; one can also say that a single element has three essentially different regimes of its behavior, because it is possible to force the element change its type. These are: *self-excited* (or *self-oscillating*), *excitable* (or *waiting*) and *trigger* (or *bistable*) regimes. Accordingly, there are three types of homogeneous

The *excitable* element (row **A** of Figure 1) has only one stable steady state (the point **O**, which is the intersection of the two null isoclines; a quiescent state of the excitable element corre‐ sponds with this point). External impact over a threshold level (i.e., greater than the length of the segment **OA**), can bring the excitable element out from its steady state and force it accomplish a certain evolution (in the phase portrait shown by the orange line) before returning to its quiescent state. An excited element may affect the adjacent elements moving them out from their quiescent state. As a result, an autowave of excitation spreads through the medium. Excitable media like the working myocardium consist of such excitable elements. Hence, it becomes obvious the fallacy of popular opinion that "all cardiac cells have spontaneous firing capacity, but only at a very slow heart rate", the assertion which can be often met in books and

The *bistable* element (row **B** of Figure 1) has two steady states at the points **O1** and **O2**, each of which can be whether stable or unstable, while the point O in this case is always unstable. Transitions between the two stationary states occur when an external impact exceeds a certain threshold level (the same way as it does in the excitable element). In such media there can be the *trigger wave* propagation, which switches the media from one steady state to the other. A classic case of such a switching autowave (and, perhaps, the simplest autowave phenomena) is falling dominoes. Another simple example of the bistable medium is burning paper: the switching wave propagates on it in the form of a flame, switching paper from the normal state

The *self-oscillating* element (row **C** of Figure 1) has no stable steady states (the point O in this case is always unstable) and therefore it permanently performs oscillations of certain fixed form, amplitude and frequency. An example of a self-oscillating medium is the sinus node of the heart, in which excitation impulses arise spontaneously. External influence can disturb these oscillations, but, after some relaxation time, all their characteristics, except for the phase, revert to the stable values, although the phase can be changed, resulting in the phase waves spread in the self-excited medium. Such phase waves can be observed in electro-garlands or

So it can be clearly seen on the phase portrait of the basic system of equations describing active medium of different types (see Figure 1) that a significant difference between these three types of behavior of an active medium is caused by the quantity and the position of its singular points. The shapes of autowaves observed in reality can be, however, very similar to each other, and therefore it can be difficult to assess correctly the type of element only by the form of its

active media composed of these elements.

10 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

papers.

to its ashes.

in certain chemical media.

excitation impulse.

The region of a combined active medium which consists of self-oscillatory elements is called the *pacemaker*. This region emits autowaves with a certain stable period. An example of a biological pacemaker in the heart of the human is the sinus node, which is constituted of a group of cells functioning in the self-oscillating mode.

In thin enough layers of the active medium, the pacemaker creates a picture in the form of ring waves diverging from a center (Figure 2). Period of pacemaker oscillations is determined by its intrinsic properties and can be arbitrary, but not less than the absolute refractory period, because a new action potential cannot arise during the absolute refractory period (see below).

If there are a number of self-oscillating elements with different periods in the medium, every element with low-frequency activity is suppressed by the element with the highest frequency [41]. For a long time physiologists have known about the hierarchy of pacemakers in the heart, and the same result was obtained mathematically in the second half of twentieth century. Pacemakers in the heart are the sinoatrial (SA) node, the atrioventricular (AV) node and the bundle of His and Purkinje fibers. The sinoatrial node normally initiates action potentials, simply because it generates impulses slightly faster than the other areas with self-oscillating activity. The remaining pacemakers normally are in a depressed state, which is reflected by physiological language as "latent pacemaker capability." If the SA node is suddenly "out of order", the fastest of the "spare" pacemakers (i.e., the AV node) enters into work, and, as a result, the heart continues its action nearly in normal regime. This duplication of parts of the system is aimed, evidently, to improve its reliability.

However, recent studies [49, 50] have shown that the rhythmic activity of the self-oscillating elements in the group which form the body of the pacemaker is synchronized by more complex laws, and the ascertained earlier variant of synchronization from the element with the highest frequency of the oscillations is only a special case. The problem of the control of cardiac rhythm has been considered in terms of the general theory of the synchronization of relaxation systems, and, as result, the main pathways of the control of cardiac rhythm have been revealed: (1) control with regard for the features of synchronization of relaxation systems during the formation of the unified heart rhythm due to the acceleration of the slow diastole depolariza‐ tion phase; (2) control by gradual integral increase in the duration of the slow diastole depolarization phase; (3) subsequent synchronization of the rhythm as a delay of the slow diastole depolarization phase.

#### **2.4. Traveling autowaves**

The concept "*traveling autowave*" (or "*autowave of excitation*", or "*propagating autowave*") should be considered as generalization made in the new biophysical language of the concept "exci‐ tation wave", which is understood in the frames of physiology as an electrical wave that

and there is a *critical value of the curvature*, above which the excitation wave propagation becomes impossible. For example, see [41, 47, 51–53]. The *critical curvature*leads, in particular, to the fact that the excitation autowaves can not pass through an aperture of sufficiently small size in a non-excitable obstacle (e.g., in the postinfarction scar). Other properties of traveling autowaves associated with critical curvature underlie different mechanisms of reentrant

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 13

Another interesting property of active media, which was found out in the earliest works, is that, for periodic autowaves, their velocity decreases with increasing frequency, and explicit expressions for calculating its value were derived. In such a way, it has been shown mathe‐ matically that the stationary propagation of autowaves is possible only as long as the wave period *T* is more than a certain value *T*min, and that there is a certain mathematical dependence of the wave velocity on the medium properties [54, 55]. When *T* <*T*min, the propagation occurs in some peculiar manner: though the excitation waves propagate without attenuation, not all of them propagate, but only, for example, every third or fourth wave, depending on *T* , which

The existence of *T*min is caused by the fact that the excitation autowave can not propagate until the recovery processes, which are described with the slow variable of the base model, has finished. This property of active media is called refractoriness, and the typical recovery time is called the refractory period.6 *Refractoriness* is the fundamental property of any object of autowave nature (especially excitable medium) not to respond on stimuli, if the object stays in the specific refractory state. In common sense, *refractory period* is the characteristic recovery time, i.e. the period of time that is associated with the motion of the image point on the left branch of the isoclinic curve *ut* =0 (i.e. the segment DO; see row **A** of Figure 1). The *relative refractory period* is understood as the immediately following interval during which initiation of the next action potential is inhibited but not impossible. In the *state of relative refractoriness*, propagation of the next autowave is possible also before the full recovery of the media, but with slightly less velocity depending on the time elapsed since the passage of the previous wave. For periodic pulse, this results in *dispersion*, which is dependence of the autowave velocity on their frequency [44, 56]. If the time interval after the passage of the previous wave is too short, then propagation of the subsequent wave is impossible, so that, for every excitable medium, there is a certain minimal interval between a couple of successive waves, the absolute refractory period. The absolute refractory period is the interval during which the next action potential absolutely cannot be initiated, no matter how large a stimulus is applied. But, even in a fully recovered excitable medium, velocity of the excitation autowaves can not exceed a certain value, which is the maximum value for the medium and which is equal to the velocity of the traveling autowave of zero curvature (i.e. with the flat front, the *flat autowave*). The

6 Let us recall that the existence of the refractory period in the cardiac muscle has been ascertained as long as 1876 by EJ Marey, who was an extremely gifted French researcher in the physiology of the heart. It was he, who also introduced this term as well as who noted that the refractory period of the cardiac muscle lasts conspicuously longer than in skeletal muscle or nerve. In 1906, A.J. Carlson was the first who used the terms "absolute refractory period" and "relative refractory

tachycardias, which will be considered in more details below.

mathematical details can be found in the suggested literature.

period"[8].

is known in cardiology as *Wenckebach periodicity*.

**Figure 2.** Spatiotemporal organization of the normal cardiac action. Green inscriptions and arrows indicate the time of arrival of the excitation wave in the corresponding region of the heart (using the data published in [48]). Blue incuts show the shape of the traveling wave ("action potential") in different areas of the heart caused by the difference in properties of the elements of the excitable medium that forms the heart tissue. Beige incut demonstrates the normal propagation of the traveling-wave of excitation from the pacemaker area in the center (from the sinus node) towards the edges (through the working myocardium) in a simple simulation model.

propagates along a muscle fiber just before its contraction. Autowaves of excitation are perhaps the most common in nature autowave phenomena, they occur in a variety of physical, chemical and biological objects. According to the earliest investigations [40–42], "traveling autowave" was a designation of the wave processes that have stable ("self-sustaining") parameters, such as speed, amplitude, and pulse shape, independently of initial conditions. It was believed also that "if two autowaves propagate toward each other, they do not pass through each other, like linear waves and solitons do it, but they annihilate in a collision" [41]. Autowaves was believed to be not able to interfere or to reflect from obstacles. These properties were considered as a significant difference of autowaves from the usual electromagnetic or sound waves.

Analysis of the systems of mathematical equations that describe the active medium has given not only a quite good explanation of the phenomena known from physiology, but also has led to the discovery of many new interesting properties of the active media, even in the earliest works. For example, the dependence of the traveling autowave velocity on the curvature of its front was obtained as a result of this analysis: the velocity decreases with increasing curvature, and there is a *critical value of the curvature*, above which the excitation wave propagation becomes impossible. For example, see [41, 47, 51–53]. The *critical curvature*leads, in particular, to the fact that the excitation autowaves can not pass through an aperture of sufficiently small size in a non-excitable obstacle (e.g., in the postinfarction scar). Other properties of traveling autowaves associated with critical curvature underlie different mechanisms of reentrant tachycardias, which will be considered in more details below.

Another interesting property of active media, which was found out in the earliest works, is that, for periodic autowaves, their velocity decreases with increasing frequency, and explicit expressions for calculating its value were derived. In such a way, it has been shown mathe‐ matically that the stationary propagation of autowaves is possible only as long as the wave period *T* is more than a certain value *T*min, and that there is a certain mathematical dependence of the wave velocity on the medium properties [54, 55]. When *T* <*T*min, the propagation occurs in some peculiar manner: though the excitation waves propagate without attenuation, not all of them propagate, but only, for example, every third or fourth wave, depending on *T* , which is known in cardiology as *Wenckebach periodicity*.

The existence of *T*min is caused by the fact that the excitation autowave can not propagate until the recovery processes, which are described with the slow variable of the base model, has finished. This property of active media is called refractoriness, and the typical recovery time is called the refractory period.6 *Refractoriness* is the fundamental property of any object of autowave nature (especially excitable medium) not to respond on stimuli, if the object stays in the specific refractory state. In common sense, *refractory period* is the characteristic recovery time, i.e. the period of time that is associated with the motion of the image point on the left branch of the isoclinic curve *ut* =0 (i.e. the segment DO; see row **A** of Figure 1). The *relative refractory period* is understood as the immediately following interval during which initiation of the next action potential is inhibited but not impossible. In the *state of relative refractoriness*, propagation of the next autowave is possible also before the full recovery of the media, but with slightly less velocity depending on the time elapsed since the passage of the previous wave. For periodic pulse, this results in *dispersion*, which is dependence of the autowave velocity on their frequency [44, 56]. If the time interval after the passage of the previous wave is too short, then propagation of the subsequent wave is impossible, so that, for every excitable medium, there is a certain minimal interval between a couple of successive waves, the absolute refractory period. The absolute refractory period is the interval during which the next action potential absolutely cannot be initiated, no matter how large a stimulus is applied. But, even in a fully recovered excitable medium, velocity of the excitation autowaves can not exceed a certain value, which is the maximum value for the medium and which is equal to the velocity of the traveling autowave of zero curvature (i.e. with the flat front, the *flat autowave*). The mathematical details can be found in the suggested literature.

propagates along a muscle fiber just before its contraction. Autowaves of excitation are perhaps the most common in nature autowave phenomena, they occur in a variety of physical, chemical and biological objects. According to the earliest investigations [40–42], "traveling autowave" was a designation of the wave processes that have stable ("self-sustaining") parameters, such as speed, amplitude, and pulse shape, independently of initial conditions. It was believed also that "if two autowaves propagate toward each other, they do not pass through each other, like linear waves and solitons do it, but they annihilate in a collision" [41]. Autowaves was believed to be not able to interfere or to reflect from obstacles. These properties were considered as a

the edges (through the working myocardium) in a simple simulation model.

12 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

**Figure 2.** Spatiotemporal organization of the normal cardiac action. Green inscriptions and arrows indicate the time of arrival of the excitation wave in the corresponding region of the heart (using the data published in [48]). Blue incuts show the shape of the traveling wave ("action potential") in different areas of the heart caused by the difference in properties of the elements of the excitable medium that forms the heart tissue. Beige incut demonstrates the normal propagation of the traveling-wave of excitation from the pacemaker area in the center (from the sinus node) towards

significant difference of autowaves from the usual electromagnetic or sound waves.

Analysis of the systems of mathematical equations that describe the active medium has given not only a quite good explanation of the phenomena known from physiology, but also has led to the discovery of many new interesting properties of the active media, even in the earliest works. For example, the dependence of the traveling autowave velocity on the curvature of its front was obtained as a result of this analysis: the velocity decreases with increasing curvature,

6 Let us recall that the existence of the refractory period in the cardiac muscle has been ascertained as long as 1876 by EJ Marey, who was an extremely gifted French researcher in the physiology of the heart. It was he, who also introduced this term as well as who noted that the refractory period of the cardiac muscle lasts conspicuously longer than in skeletal muscle or nerve. In 1906, A.J. Carlson was the first who used the terms "absolute refractory period" and "relative refractory period"[8].

A lot of active media are characterized by the pronounced *relaxantness*, i.e. the time interval of refractoriness is noticeably longer than the time interval of excitation. In the basic model of the active medium with recovery, relaxantness is determined by a small parameter *ε* [41]. For cardiac tissue, the refractory period exceeds the excitation time approximately 300 times. This leads to the fact that the excitation wave in the heart has a sharp front edge, but has no pronounced trailing edge. The presence of prolonged refractoriness allows to explain, for example, the *annihilation* of the excitation waves when they collide. Because of long refractory tail, where the excitation is not possible, two waves can not pass through each other and die.

standpoint. The so called electrical conduction system of the heart should be considered only as an illusive perception of the real complicated active media that builds the body of the heart. The illusion is caused by sincere desire to describe the heart strictly within the frames of the mechanistic approach, which requires that some specific electric wires were searched for. However, there are not any electric wires in the cardiac tissue, which rather presents the network of active elements of different types. Each of these elements can be forced change its type by influence of humoral, nervous or metabolic factors. The target function of the inherent circulatory regulation consists in maintaining the appropriate STO independently from uncontrolled influence of humoral, nervous or metabolic factors. In those cases where the regulation is untenable, pathological states develop leading to disease. For example, additional sources of autowaves, arising from pathological changes of certain areas of the myocardium,

way at various combinations of values of the individual parameters of the cardiomyocyte, but even utterly different combinations of individual parameters may result in the same clinical manifestations of cardiac disorders inasmuch as they are determined by the state of the

sodium, potassium, calcium, etc. conductivity of membrane ion channels in cardiomyocytes (as it is usual for physiologists to think) causes the normal cardiac action, but exactly that of their combinations which is optimal for the given conditions of functioning of the organism. It is likely that causes of the cases of unsuccessful pharmacological treatment of cardiac arrhythmias, which were revealed, particularly, in CAST, hide themselves somewhere here.

Hence, cardiac arrhythmia should be considered in a more general way: they occur either as a consequence of disorders of STO, or as a consequence of disorders in inherent circulatory

Since autowave processes were pointed in the role of sources of cardiac arrhythmias, the number of known types of sources of cardiac arrhythmias has increased significantly. This increase is associated not only with discovery of a number of new mechanisms of arrhythmias, but also with distinction of the mechanisms that were equated with each other before. So for *reentry*, a mechanism of arrhythmias known since the 19th century, it is accepted to distinguish now at least five types: (1) running around a ring, (2) spiral wave, (3) autowave reverberator, (4) multiple reverberators, and (5) fibrillation as chaotic behavior of autowave reverberators. In accordance with the classification of principal mechanisms of cardiac arrhythmias that was suggested in [60], the running around a ring as well as the spiral wave should be reckoned

Altered automaticity, which is the second classical mechanism of arrhythmogenesis, can be divided into (1) *altered normal* automaticity, (2) *abnormal* (or induced) automaticity, and (3)

regulation, but not as isolated disorders of the cardiac electrical activity.

**3. Basic biophysical mechanisms of cardiac arrhythmias**

among *anatomic reentry*, while the others belong to *functional reentry*.

→ ) rather than by any of the individual parameters of the myocardium. It is not

→ (*u*

→ ) may be changed in the same

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 15

can result in severe cardiac arrhythmias.

function *f*

→ (*u*

It is extremely important to understand that the function *f*

However, more recent studies [57–59] have shown that autowaves can exhibit more compli‐ cated behavior, and the properties described in the early classical works are observed only in a number of special cases. For example, it was found out that annihilation does not always occur in a collision of autowaves, but under certain conditions autowaves can pass through each other like solitons. Diffraction, reflection and splitting are also possible to observe for autowaves under certain conditions. It was shown that autowave shape and velocity may vary during its spontaneous evolution caused by the bifurcation memory [20, 21]. It was declared [20]:"The general theory of active media remains to be formulated, and practically each indepth study reveals new types of their dynamics and self-organization. There is no reason to think that these types are unique; on the contrary, the available experience indicates that, once described, a new dynamic regime or bifurcation is thereafter found in other systems, even those that have been investigated for a long time". So it can be expected that further deepening of our knowledge of the properties of autowaves will also help us to understand the failure in the treatment of cardiac arrhythmias.

#### **2.5. Spatiotemporal organization of the normal cardiac action**

The main goal of the normal cardiac action is the pumping function of the heart. It is the ordered propagation of the excitation autowave in the myocardium that maintains efficient contraction of the heart, thereby allowing blood to be pumped throughout the body. For the pumping function of the heart to be maintained effective, appropriate *spatiotemporal organization* (STO) of the excitation process is extremely important. The appropriate STO is caused by the very structure of the heart, i.e. by the special spatial arrangement of various autowave elements (cardiomyocytes) with significantly different behavior (which, as mentioned above, is descri‐ bed with use of the nonlinear free member *f* → (*u* → ) in the base model of the active medium with recovery). Due to the special spatial structure of the heart as a whole organ, well-known from courses of anatomy and physiology, the only mode of traveling waves initiated from the sinoatrial node occurs in the normal heart during the normal cardiac activity (Figure 2).

It is disorders of the spatiotemporal organization of the process of myocardial excitation and contraction that should be understood as a generalized mechanism of cardiac arrhythmias, which usually manifests with various electrical indications used by doctor to set the correct diagnosis. Note that these ideas are being developed in the concept of the autowave function of the heart [1], which has not yet received a rigorous mathematical formulation.

The simplest examples of disorders of the appropriate STO are various conduction block. The mechanism of partial conduction block has been described above from the biophysical standpoint. The so called electrical conduction system of the heart should be considered only as an illusive perception of the real complicated active media that builds the body of the heart. The illusion is caused by sincere desire to describe the heart strictly within the frames of the mechanistic approach, which requires that some specific electric wires were searched for. However, there are not any electric wires in the cardiac tissue, which rather presents the network of active elements of different types. Each of these elements can be forced change its type by influence of humoral, nervous or metabolic factors. The target function of the inherent circulatory regulation consists in maintaining the appropriate STO independently from uncontrolled influence of humoral, nervous or metabolic factors. In those cases where the regulation is untenable, pathological states develop leading to disease. For example, additional sources of autowaves, arising from pathological changes of certain areas of the myocardium, can result in severe cardiac arrhythmias.

A lot of active media are characterized by the pronounced *relaxantness*, i.e. the time interval of refractoriness is noticeably longer than the time interval of excitation. In the basic model of the active medium with recovery, relaxantness is determined by a small parameter *ε* [41]. For cardiac tissue, the refractory period exceeds the excitation time approximately 300 times. This leads to the fact that the excitation wave in the heart has a sharp front edge, but has no pronounced trailing edge. The presence of prolonged refractoriness allows to explain, for example, the *annihilation* of the excitation waves when they collide. Because of long refractory tail, where the excitation is not possible, two waves can not pass through each other and die. However, more recent studies [57–59] have shown that autowaves can exhibit more compli‐ cated behavior, and the properties described in the early classical works are observed only in a number of special cases. For example, it was found out that annihilation does not always occur in a collision of autowaves, but under certain conditions autowaves can pass through each other like solitons. Diffraction, reflection and splitting are also possible to observe for autowaves under certain conditions. It was shown that autowave shape and velocity may vary during its spontaneous evolution caused by the bifurcation memory [20, 21]. It was declared [20]:"The general theory of active media remains to be formulated, and practically each indepth study reveals new types of their dynamics and self-organization. There is no reason to think that these types are unique; on the contrary, the available experience indicates that, once described, a new dynamic regime or bifurcation is thereafter found in other systems, even those that have been investigated for a long time". So it can be expected that further deepening of our knowledge of the properties of autowaves will also help us to understand the failure in

The main goal of the normal cardiac action is the pumping function of the heart. It is the ordered propagation of the excitation autowave in the myocardium that maintains efficient contraction of the heart, thereby allowing blood to be pumped throughout the body. For the pumping function of the heart to be maintained effective, appropriate *spatiotemporal organization* (STO) of the excitation process is extremely important. The appropriate STO is caused by the very structure of the heart, i.e. by the special spatial arrangement of various autowave elements (cardiomyocytes) with significantly different behavior (which, as mentioned above, is descri‐

→ (*u*

recovery). Due to the special spatial structure of the heart as a whole organ, well-known from courses of anatomy and physiology, the only mode of traveling waves initiated from the sinoatrial node occurs in the normal heart during the normal cardiac activity (Figure 2).

It is disorders of the spatiotemporal organization of the process of myocardial excitation and contraction that should be understood as a generalized mechanism of cardiac arrhythmias, which usually manifests with various electrical indications used by doctor to set the correct diagnosis. Note that these ideas are being developed in the concept of the autowave function

The simplest examples of disorders of the appropriate STO are various conduction block. The mechanism of partial conduction block has been described above from the biophysical

of the heart [1], which has not yet received a rigorous mathematical formulation.

→ ) in the base model of the active medium with

the treatment of cardiac arrhythmias.

14 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

bed with use of the nonlinear free member *f*

**2.5. Spatiotemporal organization of the normal cardiac action**

It is extremely important to understand that the function *f* → (*u* → ) may be changed in the same way at various combinations of values of the individual parameters of the cardiomyocyte, but even utterly different combinations of individual parameters may result in the same clinical manifestations of cardiac disorders inasmuch as they are determined by the state of the function *f* → (*u* → ) rather than by any of the individual parameters of the myocardium. It is not sodium, potassium, calcium, etc. conductivity of membrane ion channels in cardiomyocytes (as it is usual for physiologists to think) causes the normal cardiac action, but exactly that of their combinations which is optimal for the given conditions of functioning of the organism. It is likely that causes of the cases of unsuccessful pharmacological treatment of cardiac arrhythmias, which were revealed, particularly, in CAST, hide themselves somewhere here.

Hence, cardiac arrhythmia should be considered in a more general way: they occur either as a consequence of disorders of STO, or as a consequence of disorders in inherent circulatory regulation, but not as isolated disorders of the cardiac electrical activity.

#### **3. Basic biophysical mechanisms of cardiac arrhythmias**

Since autowave processes were pointed in the role of sources of cardiac arrhythmias, the number of known types of sources of cardiac arrhythmias has increased significantly. This increase is associated not only with discovery of a number of new mechanisms of arrhythmias, but also with distinction of the mechanisms that were equated with each other before. So for *reentry*, a mechanism of arrhythmias known since the 19th century, it is accepted to distinguish now at least five types: (1) running around a ring, (2) spiral wave, (3) autowave reverberator, (4) multiple reverberators, and (5) fibrillation as chaotic behavior of autowave reverberators. In accordance with the classification of principal mechanisms of cardiac arrhythmias that was suggested in [60], the running around a ring as well as the spiral wave should be reckoned among *anatomic reentry*, while the others belong to *functional reentry*.

Altered automaticity, which is the second classical mechanism of arrhythmogenesis, can be divided into (1) *altered normal* automaticity, (2) *abnormal* (or induced) automaticity, and (3) *triggered activity*. Regarding *increased automaticity*7 , several new types of automatic nature were also discovered, in addition to the pacemaker activity. These are: (1) induced automaticity, (2) *leading center*, (3) triggered activity by the mechanism of *early afterdepolarization*, and (4) triggered automaticity by the mechanism of *delayed afterdepolarization*.

(i.e. line would go from the right top down to the left), and therefore we would have sponta‐ neous diastolic hyperpolarization, — however, a bistable element would fire again and again even in such a case, because of absence of the stable steady state at the point **O** on the left branch. Thus, acceptance of spontaneous diastolic depolarization as a cause of automaticity seems to be a mistake due to misunderstanding of nature of the self-oscillating automaticity.

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 17

**Figure 3.** A few examples of increased automaticity caused by transformation of an excitable element in a self-oscillat‐ ing one. Designations are as in Figure 1. It is assumed that the scale is the same in all examples. See description in the

*Altered normal automaticity* is the proper automaticity of cardiac conduction system altered by certain influences. It should be distinguished between primary and secondary permanent increase of frequency of the self-oscillating elements of cardiac conduction system. While the primary increase is conditioned by the processes that have happened inside the cardiomyocyte, and therefore may be rigid against neural and humoral influences, the secondary increase is caused by the neural and humoral influences, and, consequently, is a reversible process. A classic example of the secondary alteration is hyperthyroidism; myocardial infarction provides

*Induced automaticity* is assumed [41] to result from either transforming a waiting regime of certain myocardial area (or even a single cardiomyocyte) in a self-oscillating regime or a sufficient increase of self-oscillating activity of the latent pacemaker cells of the cardiac conduction system. In either case, causes of induced automaticity are similar; among these may be changes of characteristics and ratios of ionic currents in the cell membrane using hormones, poisons, external sources of electric current, etc. Whether the cell spontaneously generates action potential or not, depends on the ratio of incoming and outgoing ion currents. However, as has been stated above, it would be a mistake to assume that it is the spontaneous depolarization after reaching the threshold value of the transmembrane potential that leads to generating spontaneous action potential. Let's look again at Figure 1. The distance between a point of the stable steady state on a branch of the isoclinic curve *ut* =0 and the middle section of the same curve (i.e., the segment **OA** in the cases of the excitable regime, as well as the segment **O1A** or **O2C** in the cases of the triggered regime) corresponds with the threshold value; but it is evident, however, that any saying about the threshold value sounds absurdly in the

text.

with examples of the primary alteration.

And each of these mechanisms of arrhythmias can cause disarrangement of the cardiac action, manifesting themselves mostly as ectopic sources of the excitation autowaves. Using new biophysical language, we have attempted to describe below more detailed the currently known types of mechanisms of cardiac arrhythmias.

#### **3.1. Increased automaticity**

The term "cardiac automaticity" refers to a biological event characterized by spontaneous process of action potential generation in separate groups of myocardial cells. "Spontaneous" should be understood as being conditioned by intrinsic dynamics, and developing or occurring without apparent external influence, force, cause, or treatment. A spontaneous process is capable of proceeding in a given direction without needing to be driven by an outside source of energy. It is accepted that three different mechanisms may independently underlie cardiac automaticity. These are: (1) the *proper automaticity* of specialized cells of cardiac conduction system, (2) induced automaticity arising or growing under external influences, and (3) triggered activity, which is the automaticity provoked by a series of electrical stimuli.

About the proper automaticity of cardiac conduction system was already told above; it underlies normal cardiac function. It is widely thought that the proper automaticity of specialized myocardiocytes is defined by the capability of cardiac cells to undergo spontaneous diastolic depolarization and to initiate an electrical impulse in the absence of external electrical stimulation. This is so indeed that the specialized conduction system of the heart has the special property of depolarizing without any external influence with a slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end of one action potential and the beginning of the next action potential. But let's look intently again at Figure 1. Process of spontaneous depolarization corresponds with the motion of the image point from the point D down the left branch of the isoclinic curve *ut* =0. It is easy to perceive that a self-oscillating element differs from an excitable or from a bistable element only by the absence of the stable steady state at the point **O**. This difference results in birth of a limit cycle8 , which force the element fire again and again. Hence, it is the limit cycle that should be recognized as the cause of the proper automaticity of the specialized myocardiocytes! And what is more, it is likely that a dynamic system described by the base model can be constructed in such manner that the left branch of the isoclinic curve *ut* =0 would go in the other direction

7 Some people find it difficult to discern the difference between enhanced and increased cardiac automaticity. It seems that to distinguish between enhanced and increased cardiac automaticity is useful for some reasons. While enhanced cardiac automaticity is referred to reactions of normal adaptation (such as influence of autonomic nervous system because of stress), increased cardiac automaticity is addressed rather to pathological alterations of cardiac tissue properties. Some authors prefer using the term "abnormal induced automaticity" instead of "increased cardiac automaticity" (see for example [60]).

8 In mathematics, in the study of dynamical systems with two-dimensional phase space, a limit cycle is a closed trajectory in phase space.

(i.e. line would go from the right top down to the left), and therefore we would have sponta‐ neous diastolic hyperpolarization, — however, a bistable element would fire again and again even in such a case, because of absence of the stable steady state at the point **O** on the left branch. Thus, acceptance of spontaneous diastolic depolarization as a cause of automaticity seems to be a mistake due to misunderstanding of nature of the self-oscillating automaticity.

*triggered activity*. Regarding *increased automaticity*7

16 Cardiac Arrhythmias - Mechanisms, Pathophysiology, and Treatment

types of mechanisms of cardiac arrhythmias.

**3.1. Increased automaticity**

cycle8

example [60]).

in phase space.

triggered automaticity by the mechanism of *delayed afterdepolarization*.

also discovered, in addition to the pacemaker activity. These are: (1) induced automaticity, (2) *leading center*, (3) triggered activity by the mechanism of *early afterdepolarization*, and (4)

And each of these mechanisms of arrhythmias can cause disarrangement of the cardiac action, manifesting themselves mostly as ectopic sources of the excitation autowaves. Using new biophysical language, we have attempted to describe below more detailed the currently known

The term "cardiac automaticity" refers to a biological event characterized by spontaneous process of action potential generation in separate groups of myocardial cells. "Spontaneous" should be understood as being conditioned by intrinsic dynamics, and developing or occurring without apparent external influence, force, cause, or treatment. A spontaneous process is capable of proceeding in a given direction without needing to be driven by an outside source of energy. It is accepted that three different mechanisms may independently underlie cardiac automaticity. These are: (1) the *proper automaticity* of specialized cells of cardiac conduction system, (2) induced automaticity arising or growing under external influences, and (3)

triggered activity, which is the automaticity provoked by a series of electrical stimuli.

About the proper automaticity of cardiac conduction system was already told above; it underlies normal cardiac function. It is widely thought that the proper automaticity of specialized myocardiocytes is defined by the capability of cardiac cells to undergo spontaneous diastolic depolarization and to initiate an electrical impulse in the absence of external electrical stimulation. This is so indeed that the specialized conduction system of the heart has the special property of depolarizing without any external influence with a slow, positive increase in voltage across the cell's membrane (the membrane potential) that occurs between the end of one action potential and the beginning of the next action potential. But let's look intently again at Figure 1. Process of spontaneous depolarization corresponds with the motion of the image point from the point D down the left branch of the isoclinic curve *ut* =0. It is easy to perceive that a self-oscillating element differs from an excitable or from a bistable element only by the absence of the stable steady state at the point **O**. This difference results in birth of a limit

, which force the element fire again and again. Hence, it is the limit cycle that should be recognized as the cause of the proper automaticity of the specialized myocardiocytes! And what is more, it is likely that a dynamic system described by the base model can be constructed in such manner that the left branch of the isoclinic curve *ut* =0 would go in the other direction

7 Some people find it difficult to discern the difference between enhanced and increased cardiac automaticity. It seems that to distinguish between enhanced and increased cardiac automaticity is useful for some reasons. While enhanced cardiac automaticity is referred to reactions of normal adaptation (such as influence of autonomic nervous system because of stress), increased cardiac automaticity is addressed rather to pathological alterations of cardiac tissue properties. Some authors prefer using the term "abnormal induced automaticity" instead of "increased cardiac automaticity" (see for

8 In mathematics, in the study of dynamical systems with two-dimensional phase space, a limit cycle is a closed trajectory

, several new types of automatic nature were

**Figure 3.** A few examples of increased automaticity caused by transformation of an excitable element in a self-oscillat‐ ing one. Designations are as in Figure 1. It is assumed that the scale is the same in all examples. See description in the text.

*Altered normal automaticity* is the proper automaticity of cardiac conduction system altered by certain influences. It should be distinguished between primary and secondary permanent increase of frequency of the self-oscillating elements of cardiac conduction system. While the primary increase is conditioned by the processes that have happened inside the cardiomyocyte, and therefore may be rigid against neural and humoral influences, the secondary increase is caused by the neural and humoral influences, and, consequently, is a reversible process. A classic example of the secondary alteration is hyperthyroidism; myocardial infarction provides with examples of the primary alteration.

*Induced automaticity* is assumed [41] to result from either transforming a waiting regime of certain myocardial area (or even a single cardiomyocyte) in a self-oscillating regime or a sufficient increase of self-oscillating activity of the latent pacemaker cells of the cardiac conduction system. In either case, causes of induced automaticity are similar; among these may be changes of characteristics and ratios of ionic currents in the cell membrane using hormones, poisons, external sources of electric current, etc. Whether the cell spontaneously generates action potential or not, depends on the ratio of incoming and outgoing ion currents. However, as has been stated above, it would be a mistake to assume that it is the spontaneous depolarization after reaching the threshold value of the transmembrane potential that leads to generating spontaneous action potential. Let's look again at Figure 1. The distance between a point of the stable steady state on a branch of the isoclinic curve *ut* =0 and the middle section of the same curve (i.e., the segment **OA** in the cases of the excitable regime, as well as the segment **O1A** or **O2C** in the cases of the triggered regime) corresponds with the threshold value; but it is evident, however, that any saying about the threshold value sounds absurdly in the case of the self-oscillating regime because no threshold value exists in this case. The illusion that generating spontaneous action potential is caused by the spontaneous depolarization of cardiac cells has spread widely among physiologists only because of their firm intention to stay strictly within the frames of the mechanistic approach. The real cause of transition of an active element from waiting in a self-oscillating regime is such a deformation of its phase portrait which leads to a shift of the point **O** onto the middle section of the isoclinic curve. Changes of the threshold level also occur as a result of one or another deformation of the phase portrait. Specific causes of the phase portrait deformation are similar in either case; these are again poisons, external electric power sources, and other unpleasant things which are almost certain to disagree with a human being, sooner or later.

oscillations that occur during or immediately following a preceding AP (for more details, see [8, 60]). Based on their temporal relationship, two types of afterdepolarizations are described: early afterdepolarizations (EADs), which occur during phase 2 or 3 of the AP, and delayed afterdepolarizations (DADs), which occur after completion of the repolarization phase. There has been increasing recognition of the role played by TA caused by either EADs or DADs in the genesis of clinical arrhythmias [66, 67–69]. It is widely accepted that phenomena of either type of afterdepolarizations are caused by a variety of conditions that raise the diastolic intracellular Ca2+ concentration, resulting in Ca2+ mediated oscillations that can trigger a new AP if they reach the excitation threshold. It has been found [70] that the active pumping of

level is involved in the mechanism of DADs. Therefore, the depolarization is observed after treatment of the myocardium with catecholamines [71], which accelerate the pump, as well as

to the accumulation of intracellular sodium ions and, hence, enhances the intensity of Na+ /

sarcoplasmic reticulum, as well as a number of other processes of molecular level are believed

Although the cause of TA is believed to be the transmembrane potential oscillations exceeding the excitation threshold, closer examination of the phase portrait of the basic model is forcing doubt this widespread opinion. As it has already been argued logically above, the excitation threshold can not play any role for self-oscillatory elements, as it simply does not exist in this regime. This fact motivates to search other, more sensible, explanation. Let's assume that the effect of catecholamines and glycosides results in a significant deformation of the phase portrait, and it is the deformation that is the true cause for the change in behavior of the active elements from waiting into a self-oscillating regime, manifesting it in the triggered activity. An important factor in support of this assumption is the following. In the waiting regime, we have a stable solution of node type at the steady point O; a local *bifurcation* of vector fields on the plane occurs while transiting from the waiting regime into the self-oscillating regime, in which the steady point O loses stability, and a new solution, a limit cycle, arises.10 Thus, in process of the transition of the steady point O from the left branch to the middle section of the isoclinic curve, the system passes through the state, which is referred to as bifurcation; the bifurcation point is situated at the minimum of the N-shaped isocline. Assume that, under the influence of various substances, the null-isocline *f* 2(*u*, *v*)=0 moves by parallel displacement along the abscissa from left to right in a linear dependence on the concentration of biologically active substances. What will be observed when the system comes to be near the bifurcation condition? Left from the bifurcation point damped oscillations will be observed, which is in a quite good correspondence with afterdepolarizations without TA. On the right we will observe oscillations with increasing amplitude (the movement by escalating spiral, gradually leading off system onto the right branch of the isocline). In other words, the assumption lead to the conclusion that the base system near the bifurcation point behaves just exactly as it is observed

10 The appearance or the disappearance of a periodic orbit through a local change in the stability properties of a steady

point is known as the Hopf bifurcation. For more details, see elsewhere [75].

/ K+

/ Ca2+ exchange current of abnormally increased

pump promotes also the release of Ca2+ from the

/ K+ pump, and this leads in turn

Basic Mechanisms of Cardiac Arrhythmias http://dx.doi.org/10.5772/57557 19

calcium ions into cardiomyocytes by the Na+

Ca2+ pump [74]. Inhibition of the Na+

to underlie TA [60].

in experiments with TA.

with glycosides (e.g., digitalis) [72, 73], which inhibit the Na+

Figure 3 gives schematically several examples of the deformation of the phase portrait which leads to induced automaticity. The example D is of special interest, because it assumes that two different attractors exist primordially on the phase portrait.9 While external stimulus remains near the threshold value, the active element behaves in the waiting regime (the attractor at the left side), but the stimulus that sufficiently exceeds the threshold value will throw it in the self-oscillating regime (the attractor at the right side).

It should only be added that latent pacemakers may become sources of arrhythmias, even when their proper automaticity is maintained on the normal level, but, in the cardiac tissue damaged with disease, a low frequency pacemaker is not synchronized by the waves coming from the sinoatrial node. As a result, the distorted ventricular complexes generated by such a source appear out of turn on the background of normal ECG. Mechanism of such arrhythmia (which is a variant of ventricular extrasystole) could be so-called unidirectional block in a damaged site of myocardium [52], when the autowave excitation is capable of spreading in one direction, but is damped propagating in opposite direction. There may be different causes of such unidirectional block; one of these may be the critical curvature, which was discussed above.