**2. Historical perspective**

Atrial fibrillation was first observed as compromised heart mechanical output. By the late 1800s clinicians including Nothnagel, and later MacKenzie and Hering, noted and analyzed abnormal or absent 'a waves' in venous pressure tracings but had not specifically correlated these abnormalities with atrial dysfunction [1,2,3]. Kymographic analyses of the pulse waves of their patients allowed these investigators to report examples of irregularly irregu‐ lar pulse intervals and pulse heights, a surrogate for ventricular force generation. Towards the end of the nineteenth century physicians also came to realize that these mechanical dis‐ turbances often occurred persistently in some patients. Thus by the outset of the twentieth century these types of abnormal pressure wave recordings were grouped into the clinical conditions of *delirium cordis* or the more definitive *pulsus irregularis et inaequalis perpetuus* [4]. Vulpian, Krehl, and Hering were initial proponents of the notion that such irregularities re‐ sulted from the defective mechanical output of the atria [5,6,7]. The translational research of Cushny and Edmunds provided the first direct validation of this hypothesis when in 1907 they correlated chance observations of atrial *delirium* made in the dog laboratory with clini‐ cal recordings of *pulsus irregularis et inaequalis perpetuus* [8].

an original hypothesis centered round the seemingly logical view that a solitary ectopic de‐ polarization occurring spontaneously in a small number of heart cells confined to a specific region of the atria (*or ventricle*) could produce a 'premature' atrial (*or ventricular*) contraction. They reasoned that if such spontaneous electrical activity also could occur repeatedly and at a sufficiently rapid rate then such a 'focus' could likewise produce tachycardia or fibrilla‐ tion. Variations of this 'focal' hypothesis included multiple 'heterotopic centers' depolariz‐ ing at rates sufficient to produce flutter or fibrillation or, as Rothberger proposed [16], a single heterotopic center which depolarized at extremely rapid rates. Several early experi‐ mentalists noted that the refractory period of heart muscle must shorten to accommodate rapid ectopic activity and that such abnormal electrical activity might occur at rates fast enough to preclude regular heart muscle contraction [17], foreshadowing the idea of fibrilla‐ tory conduction. While these focal source hypotheses were logical, a molecular mechanism through which non-automatic atrial (*or ventricular*) muscle might spontaneously or automat‐ ically depolarize was not known at that time. Thus non-focal, that is reentrant hypotheses to explain arrhythmia came to the fore and now dominate this field of inquiry. Nonetheless, the challenge to identify all molecular mechanisms that cause quiescent heart muscle to ex‐ cite independently of normal sinus rhythm still remains at the center of arrhythmia research today just as it did over one hundred years ago. Thus we seek to *define mechanisms which pro‐ voke quiescent heart cells to depolarize (a) independently of normal sinus rhythm, (b) at sporadic or rapid rates, (c) in an organized manner or (d) in an apparently chaotic way, and (e) over inconstant periods of time including apparent perpetuity.* There are three such mechanisms currently

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Reentry occurs when electrical impulses conduct abnormally through the heart and re-excite quiescent heart muscle (Figure 1, center & right). Multiple experimentalists in the early twentieth century began creating this hypothesis for arrhythmia with the assumption that the mechanisms for normal electrical impulse generation and propagation they were discov‐ ering at that time fully explain the production of heart abnormal electrical activity. This hy‐ pothesis was formed from experiments Mayer published in 1906 [18] which demonstrated the fundamental event of impulse reentry. He showed that rings of excitable jellyfish tissue exposed to an external electrical impulse would produce recirculating electrical waves when unidirectional impulse block was imposed on these preparations. Subsequently in 1913 and 1914 Mines and Garrey [19,20] published similar results they acquired in heart muscle. Their data provided the initial evidence supporting the view that recirculating electrical impulses produce arrhythmia. Based on this work and their own original observations [17], Lewis, Drury and Ilescu proposed in 1921 [21] that the 'circus movement' of normal electrical activ‐ ity might explain the five characteristics of atrial fibrillation (*and other arrhythmia*) noted at the end of the preceding paragraph. This simple and elegant circus creation contributed to establishing the impulse reentry hypothesis which has since metamorphosed into the ac‐ cepted explanation for atrial fibrillation and for other clinically relevant rhythm disorders.

known and our data suggest the existence of a fourth one.

**3. Mechanism 1: Impulse reentry**

In the early 1900s clinical and experimental string galvanometer data formed the basis for the idea that disorganized atrial electrical activity caused both the loss of venous 'a waves' and the appearance of the fine pulsatile activity which define *pulsus irregularis et inaequalis perptuus*. Specifically, string galvanometer tracings published in 1906 by Einthoven [9] and in 1908 by Hering [10] demonstrated that mechanical *pulsus irregularis et inaequalis perpetuus* occurred in humans who lacked p-waves, had F-waves, and had irregularly timed but other‐ wise normal QRS complexes. These initial reports coupled with the extensive electrocardio‐ graphic analyses of Rothberger and Winterberg published in 1909 [11] provided the electrical equivalent of the venous wave data of Cushny and Edwards. That is, the electro‐ cardiographic measurements Rothberger and Winterberg acquired from animals undergo‐ ing experimental atrial fibrillation were identical to recordings obtained from patients with *pulsus irregularis et inaequalis perpetuus*. This work together with the earlier report of MacWil‐ liam [12] that faradic stimulation produced atrial fibrillation led to the acceptance of the view that the complete disruption of atrial electrical activity caused the irregular pulse waves that characterize *pulsus irregularis*. Thomas Lewis built on and expanded this work in his elegant electrocardiographic characterization of atrial flutter and fibrillation in humans and in animals [*e.g*.,13]. By 1920 it had been accepted that the organized electrical activity observed using string galvanometers or electrocardiographs sparked rhythmic heart con‐ traction and conversely that disordered electrical activity caused abnormalities like *pulsus ir‐ regularis et inaequalis perpetuus*. Importantly, it was accepted that *pulsus irregularis* arose from disturbances that occurred specifically in the atria since hearts in atrial fibrillation often pro‐ duced normal but irregularly timed QRS complexes.

During the evolution of this explanation for clinical *pulsus irregularis et inaequalis perpetuus* experimentalists developed the initial, non-vitalist explanation for atrial fibrillation and oth‐ er cardiac rhythm disorders. Engelmann in 1896 [14] and Winterberg in 1906 [15] proposed an original hypothesis centered round the seemingly logical view that a solitary ectopic de‐ polarization occurring spontaneously in a small number of heart cells confined to a specific region of the atria (*or ventricle*) could produce a 'premature' atrial (*or ventricular*) contraction. They reasoned that if such spontaneous electrical activity also could occur repeatedly and at a sufficiently rapid rate then such a 'focus' could likewise produce tachycardia or fibrilla‐ tion. Variations of this 'focal' hypothesis included multiple 'heterotopic centers' depolariz‐ ing at rates sufficient to produce flutter or fibrillation or, as Rothberger proposed [16], a single heterotopic center which depolarized at extremely rapid rates. Several early experi‐ mentalists noted that the refractory period of heart muscle must shorten to accommodate rapid ectopic activity and that such abnormal electrical activity might occur at rates fast enough to preclude regular heart muscle contraction [17], foreshadowing the idea of fibrilla‐ tory conduction. While these focal source hypotheses were logical, a molecular mechanism through which non-automatic atrial (*or ventricular*) muscle might spontaneously or automat‐ ically depolarize was not known at that time. Thus non-focal, that is reentrant hypotheses to explain arrhythmia came to the fore and now dominate this field of inquiry. Nonetheless, the challenge to identify all molecular mechanisms that cause quiescent heart muscle to ex‐ cite independently of normal sinus rhythm still remains at the center of arrhythmia research today just as it did over one hundred years ago. Thus we seek to *define mechanisms which pro‐ voke quiescent heart cells to depolarize (a) independently of normal sinus rhythm, (b) at sporadic or rapid rates, (c) in an organized manner or (d) in an apparently chaotic way, and (e) over inconstant periods of time including apparent perpetuity.* There are three such mechanisms currently known and our data suggest the existence of a fourth one.

## **3. Mechanism 1: Impulse reentry**

**2. Historical perspective**

80 Atrial Fibrillation - Mechanisms and Treatment

cal recordings of *pulsus irregularis et inaequalis perpetuus* [8].

duced normal but irregularly timed QRS complexes.

Atrial fibrillation was first observed as compromised heart mechanical output. By the late 1800s clinicians including Nothnagel, and later MacKenzie and Hering, noted and analyzed abnormal or absent 'a waves' in venous pressure tracings but had not specifically correlated these abnormalities with atrial dysfunction [1,2,3]. Kymographic analyses of the pulse waves of their patients allowed these investigators to report examples of irregularly irregu‐ lar pulse intervals and pulse heights, a surrogate for ventricular force generation. Towards the end of the nineteenth century physicians also came to realize that these mechanical dis‐ turbances often occurred persistently in some patients. Thus by the outset of the twentieth century these types of abnormal pressure wave recordings were grouped into the clinical conditions of *delirium cordis* or the more definitive *pulsus irregularis et inaequalis perpetuus* [4]. Vulpian, Krehl, and Hering were initial proponents of the notion that such irregularities re‐ sulted from the defective mechanical output of the atria [5,6,7]. The translational research of Cushny and Edmunds provided the first direct validation of this hypothesis when in 1907 they correlated chance observations of atrial *delirium* made in the dog laboratory with clini‐

In the early 1900s clinical and experimental string galvanometer data formed the basis for the idea that disorganized atrial electrical activity caused both the loss of venous 'a waves' and the appearance of the fine pulsatile activity which define *pulsus irregularis et inaequalis perptuus*. Specifically, string galvanometer tracings published in 1906 by Einthoven [9] and in 1908 by Hering [10] demonstrated that mechanical *pulsus irregularis et inaequalis perpetuus* occurred in humans who lacked p-waves, had F-waves, and had irregularly timed but other‐ wise normal QRS complexes. These initial reports coupled with the extensive electrocardio‐ graphic analyses of Rothberger and Winterberg published in 1909 [11] provided the electrical equivalent of the venous wave data of Cushny and Edwards. That is, the electro‐ cardiographic measurements Rothberger and Winterberg acquired from animals undergo‐ ing experimental atrial fibrillation were identical to recordings obtained from patients with *pulsus irregularis et inaequalis perpetuus*. This work together with the earlier report of MacWil‐ liam [12] that faradic stimulation produced atrial fibrillation led to the acceptance of the view that the complete disruption of atrial electrical activity caused the irregular pulse waves that characterize *pulsus irregularis*. Thomas Lewis built on and expanded this work in his elegant electrocardiographic characterization of atrial flutter and fibrillation in humans and in animals [*e.g*.,13]. By 1920 it had been accepted that the organized electrical activity observed using string galvanometers or electrocardiographs sparked rhythmic heart con‐ traction and conversely that disordered electrical activity caused abnormalities like *pulsus ir‐ regularis et inaequalis perpetuus*. Importantly, it was accepted that *pulsus irregularis* arose from disturbances that occurred specifically in the atria since hearts in atrial fibrillation often pro‐

During the evolution of this explanation for clinical *pulsus irregularis et inaequalis perpetuus* experimentalists developed the initial, non-vitalist explanation for atrial fibrillation and oth‐ er cardiac rhythm disorders. Engelmann in 1896 [14] and Winterberg in 1906 [15] proposed

Reentry occurs when electrical impulses conduct abnormally through the heart and re-excite quiescent heart muscle (Figure 1, center & right). Multiple experimentalists in the early twentieth century began creating this hypothesis for arrhythmia with the assumption that the mechanisms for normal electrical impulse generation and propagation they were discov‐ ering at that time fully explain the production of heart abnormal electrical activity. This hy‐ pothesis was formed from experiments Mayer published in 1906 [18] which demonstrated the fundamental event of impulse reentry. He showed that rings of excitable jellyfish tissue exposed to an external electrical impulse would produce recirculating electrical waves when unidirectional impulse block was imposed on these preparations. Subsequently in 1913 and 1914 Mines and Garrey [19,20] published similar results they acquired in heart muscle. Their data provided the initial evidence supporting the view that recirculating electrical impulses produce arrhythmia. Based on this work and their own original observations [17], Lewis, Drury and Ilescu proposed in 1921 [21] that the 'circus movement' of normal electrical activ‐ ity might explain the five characteristics of atrial fibrillation (*and other arrhythmia*) noted at the end of the preceding paragraph. This simple and elegant circus creation contributed to establishing the impulse reentry hypothesis which has since metamorphosed into the ac‐ cepted explanation for atrial fibrillation and for other clinically relevant rhythm disorders.

core. In this view recirculating abnormal electrical emanations disrupt normal electrical ac‐ tivity and cause arrhythmia. Allessie indeed observed 'leading circle' or 'functional' reentry under experimental conditions in which acetylcholine markedly shortened atrial action po‐ tential duration and either bursts of high frequency stimulation or ectopic impulses admin‐ istered during so-called 'vulnerable periods' induced a type of atrial fibrillation. This hypothesis of 'leading circle reentry' has evolved since 1977 and variants of it are now the dominant means to explain arrhythmia [25]. In particular, one current 'state-of-the-art' view proposes that the interaction of normal or ectopic impulses with refractory objects of an ap‐ propriate size leads to impulse fractionation and impulse reentry (Figure 1, right). This type of 'wavebreak' allows for impulse recirculation to occur around fixed anatomical sites like papillary muscles, around scar tissue or around myocardium that poorly conducts electrici‐ ty. These rotors of fractionated impulse can remain fixed in or meander through heart mus‐ cle. Elegant imaging methodologies produced from decades of engineering coupled with mathematical-biophysical modeling have theorized, searched for and characterized wave‐ break. The high frequency pin-wheel rotors of electrical activity that this model posits have sometimes been directly observed in the aftermath of high frequency burst stimulation. Their direct observation has been reported less frequently in myocardial pathologies like is‐ chemia where arrhythmia arises 'naturally' in the absence of either burst pacing or exqui‐ sitely timed ectopic stimulations. Regardless, the intellectual flexibility and elegance of the wavebreak construct allowed for the development of multiple concepts espoused as funda‐

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The current iteration of the impulse reentry hypothesis thus proposes that arrhythmia is the response of contiguous regions of discontinuously excitable and non- or poorly excitable heart muscle to an external depolarizing influence (Figure 1). That is, reentry requires (a) ex‐ tremely localized inhomogeneity in the conduction properties of heart muscle such as might occur in the border between scar tissue and viable myocardium, (b) pathological conditions that affect the biophysical properties of the voltage-dependent sodium or potassium chan‐ nels or (c) decreasing the activity of proteins like connexins which would impose conduction heterogeneities on the heart. This dominant hypothesis to explain atrial fibrillation or other arrhythmia views these disorders from a vantage point developed in the early twentieth century. Arrhythmia in this view begins primarily as a disturbance in heart electrical activi‐ ty. The fact that faradic methods like burst-pacing or stimulation during an 'electrically vul‐ nerable period' remain mainstays in inducing arrhythmia and that arrhythmia is assessed by the electrocardiograph or by other devices that measure myocyte electrical activity sus‐ tains the opinion that rhythm disorders are mainly or solely electrical problems. An alter‐ nate view might ask whether the voltage-dependent ion channels that produce heart electrical activity are themselves regulated by voltage-independent cell signaling events. Might such cell signaling events drive arrhythmia? That is, *can cardiac non-electrical sources*

The creative hypothesis proposed by Engelmann to explain arrhythmia emphasized that changes or defects in small regions of heart muscle might generate sporadic or high frequen‐ cy focal ectopic impulses. The inability to identify a candidate mechanism for focal ectopy at

mental mechanisms for arrhythmia including atrial fibrillation [25].

*cause heart electrical problems*?

**Figure 1. Impulse Reentry.***Left:* Normal heart muscle conduts impulses homogeneously. Uniform fields of excitable and refractory muscle limit impulse recirculation. *Center: Leading circle model:* Inhomogeneous rates of impulse con‐ duction (Small v large arrows) create contiguous regions of excited and quiescent myocardium with altered refractori‐ ness (Light v dark boxes). Electrical activity may recirculate in these regions if unidirectional conduction block were present. *Right: Spiral wave model:* Impulses circulating around scar could encounter local conduction inhomogeneities which cause impulse wavenreak &reentrant rotors.

Lewis realized that variants of the circus hypothesis might arise in pathological settings. In particular he mentioned that the primary arrhythmogenic circuit could fragment to produce secondary or offspring ectopic sources and that local variation in the rate of conduction of ectopic impulses could provoke disorganized fibrillation [17, *see page 591 Figure III and page 592 Figures V & VI*]. Several decades later Moe, Abildskov [22], and others embellished this general circus view of impulse recirculation to explain the persistent nature of fibrillation or other high frequency arrhythmias. Based on his own data and on his careful examination of the earlier high-speed cinematographic work of Wiggers [23], Moe proposed that local var‐ iations in impulse conduction induced faradically or arising in diseased heart could cause impulses to fragment and purposelessly but persistently meander through excitable regions of atrial (*or ventricular*) muscle. Moe proposed that such 'wandering wavelets' of impulse re‐ entry were the fundamental cause of atrial fibrillation.

This 'wandering wavelet' hypothesis has been modified or superseded during the 50 years since it was first proposed. Work published by Allessie in 1977 [24] demonstrated that local variations in the refractory period of heart muscle can produce 'leading circle' reentry. In his model, impulses circulate like a pinwheel around a small region of refractory, non-excitable myocardium, producing vortices of electrical activity that emanate from a central inexcitable core. In this view recirculating abnormal electrical emanations disrupt normal electrical ac‐ tivity and cause arrhythmia. Allessie indeed observed 'leading circle' or 'functional' reentry under experimental conditions in which acetylcholine markedly shortened atrial action po‐ tential duration and either bursts of high frequency stimulation or ectopic impulses admin‐ istered during so-called 'vulnerable periods' induced a type of atrial fibrillation. This hypothesis of 'leading circle reentry' has evolved since 1977 and variants of it are now the dominant means to explain arrhythmia [25]. In particular, one current 'state-of-the-art' view proposes that the interaction of normal or ectopic impulses with refractory objects of an ap‐ propriate size leads to impulse fractionation and impulse reentry (Figure 1, right). This type of 'wavebreak' allows for impulse recirculation to occur around fixed anatomical sites like papillary muscles, around scar tissue or around myocardium that poorly conducts electrici‐ ty. These rotors of fractionated impulse can remain fixed in or meander through heart mus‐ cle. Elegant imaging methodologies produced from decades of engineering coupled with mathematical-biophysical modeling have theorized, searched for and characterized wave‐ break. The high frequency pin-wheel rotors of electrical activity that this model posits have sometimes been directly observed in the aftermath of high frequency burst stimulation. Their direct observation has been reported less frequently in myocardial pathologies like is‐ chemia where arrhythmia arises 'naturally' in the absence of either burst pacing or exqui‐ sitely timed ectopic stimulations. Regardless, the intellectual flexibility and elegance of the wavebreak construct allowed for the development of multiple concepts espoused as funda‐ mental mechanisms for arrhythmia including atrial fibrillation [25].

Leading circle

propagation Spiral wave

Heterogeneous refractoriness

**Figure 1. Impulse Reentry.***Left:* Normal heart muscle conduts impulses homogeneously. Uniform fields of excitable and refractory muscle limit impulse recirculation. *Center: Leading circle model:* Inhomogeneous rates of impulse con‐ duction (Small v large arrows) create contiguous regions of excited and quiescent myocardium with altered refractori‐ ness (Light v dark boxes). Electrical activity may recirculate in these regions if unidirectional conduction block were present. *Right: Spiral wave model:* Impulses circulating around scar could encounter local conduction inhomogeneities

Lewis realized that variants of the circus hypothesis might arise in pathological settings. In particular he mentioned that the primary arrhythmogenic circuit could fragment to produce secondary or offspring ectopic sources and that local variation in the rate of conduction of ectopic impulses could provoke disorganized fibrillation [17, *see page 591 Figure III and page 592 Figures V & VI*]. Several decades later Moe, Abildskov [22], and others embellished this general circus view of impulse recirculation to explain the persistent nature of fibrillation or other high frequency arrhythmias. Based on his own data and on his careful examination of the earlier high-speed cinematographic work of Wiggers [23], Moe proposed that local var‐ iations in impulse conduction induced faradically or arising in diseased heart could cause impulses to fragment and purposelessly but persistently meander through excitable regions of atrial (*or ventricular*) muscle. Moe proposed that such 'wandering wavelets' of impulse re‐

This 'wandering wavelet' hypothesis has been modified or superseded during the 50 years since it was first proposed. Work published by Allessie in 1977 [24] demonstrated that local variations in the refractory period of heart muscle can produce 'leading circle' reentry. In his model, impulses circulate like a pinwheel around a small region of refractory, non-excitable myocardium, producing vortices of electrical activity that emanate from a central inexcitable

Scarred or ischemic myocardium

No change in refractoriness

which cause impulse wavenreak &reentrant rotors.

entry were the fundamental cause of atrial fibrillation.

Normal

82 Atrial Fibrillation - Mechanisms and Treatment

The current iteration of the impulse reentry hypothesis thus proposes that arrhythmia is the response of contiguous regions of discontinuously excitable and non- or poorly excitable heart muscle to an external depolarizing influence (Figure 1). That is, reentry requires (a) ex‐ tremely localized inhomogeneity in the conduction properties of heart muscle such as might occur in the border between scar tissue and viable myocardium, (b) pathological conditions that affect the biophysical properties of the voltage-dependent sodium or potassium chan‐ nels or (c) decreasing the activity of proteins like connexins which would impose conduction heterogeneities on the heart. This dominant hypothesis to explain atrial fibrillation or other arrhythmia views these disorders from a vantage point developed in the early twentieth century. Arrhythmia in this view begins primarily as a disturbance in heart electrical activi‐ ty. The fact that faradic methods like burst-pacing or stimulation during an 'electrically vul‐ nerable period' remain mainstays in inducing arrhythmia and that arrhythmia is assessed by the electrocardiograph or by other devices that measure myocyte electrical activity sus‐ tains the opinion that rhythm disorders are mainly or solely electrical problems. An alter‐ nate view might ask whether the voltage-dependent ion channels that produce heart electrical activity are themselves regulated by voltage-independent cell signaling events. Might such cell signaling events drive arrhythmia? That is, *can cardiac non-electrical sources cause heart electrical problems*?

The creative hypothesis proposed by Engelmann to explain arrhythmia emphasized that changes or defects in small regions of heart muscle might generate sporadic or high frequen‐ cy focal ectopic impulses. The inability to identify a candidate mechanism for focal ectopy at the turn of the twentieth century, the identification of impulse reentry in jellyfish, and its ascendance as a facile, malleable explanation for arrhythmia caused the focal view to fall in‐ to disfavor. By the middle of the twentieth century only few proponents supported it, in particular investigators like Rothberger, Scherf, and Kisch [16,26,27]. They continued to present data which showed that focal (*or cellular*) sites of spontaneous depolarization could provoke arrhythmia just as well as impulse reentry. From the 1920s through the 1950s Scherf repeatedly reported that focal administration of toxins like aconitine or alkaloids like vera‐ tradine incite cardiac rhythm disturbances that mimic atrial (*or ventricular*) fibrillation and atrial flutter. It is important to note that these pharmacological agents initiate arrhythmia by modifying sodium channel gating properties to disrupt this gatekeeper of the action poten‐ tial. Jervell and Lange-Nielsen published a groundbreaking report in 1957 [28] which first documented the long QT syndrome and laid the foundation for research on the genetic basis for arrhythmia. Dessertenne [29] and others greatly developed the appreciation that genetic mutation can alter the biophysical properties of voltage-dependent sodium and potassium channels in a manner analogous to the pharmacological approach of Scherf. Consequently, in addition to changes in the gross electrical properties of heart muscle proposed to underlie wavebreak and impulse reentry, pharmacological or genetic modification of ion channels came to be accepted as potential sources of clinical arrhythmia. But this toxin and genetic view have at least three critical limitations when used as evidence to support a cell-based focal hypothesis of arrhythmia

intracellular signaling and post-translational protein modification including phosphoryla‐ tion, (c) is hypothesized to depend on changes in intracellular calcium homeostasis, and (d)

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The groundbreaking work of Arvanataki in 1939 [31] provided the initial evidence for after‐ depolarization. This series of papers demonstrated that spontaneous electrical activity oc‐ curred in a wide range of excitable cells including snail muscle when these preparations were stimulated at extremely rapid rates and the pacing stimulus then was abruptly stop‐ ped. Studies reported by Bozler in 1943 [32] expanded on this breakthrough work, demon‐ strating that cardiac muscle also can afterdepolarize. The two types of afterdepolarization

Early afterdepolarization occurs either during the Phase II plateau or during Phase III repo‐ larization of a prolonged action potential. Increased late sodium current [33] or decreased potassium channel activity, lowered 'repolarization reserve' [34], may prolong the duration of the action potential. Numerous studies show that early afterdepolarization occurs more readily with increased late sodium current compared to decreased repolarization reserve even though action potential durations are similarly prolonged. Interesting to a focal view of arrhythmia described later on, stimulating Gαq receptors greatly increases the frequency at which early afterdepolarization occurs in muscles with decreased repolarization reserve. The molecular basis for this curious effect has not been conclusively established. Early after‐ depolarization occurs most often at low rates of muscle stimulation and materializes much less frequently as the stimulation rate increases toward normal. Thus arrhythmia that arises in settings of bradycardia or in conditions where heart rate is highly variable is often ascri‐ bed to early afterdepolarization. In addition, early afterdepolarization is a likely source for premature atrial (*or ventricular*) contraction and more complex arrhythmia when genetic mu‐

tation or pharmacological intervention prolongs the myocardial QT interval.

lated ectopic event lead to sustained tachycardic or fibrillary activity?

Delayed afterdepolarization is the second type of triggered activity. By contrast to early af‐ terdepolarization, muscle or myocytes with normal action potentials that have returned to their Phase IV resting potential generate this type of abnormal impulse. Delayed afterdepo‐ larization usually arises following high frequency burst stimulation of heart or myocytes or when heart calcium stores are greatly increased. Depending on the precise experimental condition, afterdepolarization can occur as a solitary event, as a few afterdepolarizations or as ectopy that lasts for seconds or longer. This latter type of event has been termed 'sus‐ tained triggered activity' [33]. Hypotheses for afterdepolarization must explain isolated events, sustained activity, and the transition between the two. That is, how can a single iso‐

Schmitt and Erlanger initially explained premature contraction of intact muscle using the impulse reentry hypothesis [35]. In their view, electrical impulses might recirculate through junctions in the Purkinje system or around a region of the heart if both somehow came to possess unidirectional impulse block and altered conduction properties. They envisioned a scenario wherein recirculation could occur once or in a sustained manner depending on the electrical characteristics of the recirculating loop. The observation of afterdepolarization in isolated myocytes indicated that mechanisms besides the gross physiological ones of reentry

needs a preceding action potential as a triggering event.

are designated as early or delayed events.

Toxins and alkaloids modify the biophysical properties of the sodium channel to provoke arrhythmic activity. These changes in channel properties at the site of toxin administration may provoke conditions that favor impulse reentry. Thus these pharmacological approaches might incite arrhythmia in a reentrant manner analogous to faradic sources.

Mutations of voltage-dependent ion channels also might create conditions for functional or anatomic impulse reentry. Indeed reentry is invoked to explain genetically-linked arrhyth‐ mia including the long QT syndromes [30].

Even if toxin-induced arrhythmia were purely a focal event, this approach to induce ar‐ rhythmia does not identify the cellular process which might alter the biophysical properties of the sodium or other voltage-dependent ion channels to recapitulate the arrhythmogenic effects of aconitine or veratradine.

The development of a robust focal explanation for arrhythmia requires the identification of cellular mechanisms that destabilize quiescent atrium (*or ventricle*) to produce sporadic, ta‐ chycardic or fibrillatory ectopic electrical activity. There are two mechanisms now accepted to generate such abnormal electrical impulses.
