Triggered activity and atrial fibrillation

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In 1999, Haissaguerre et al published a landmark article showing that atrial fibrillation can be initiated by electrical activity in the pulmonary veins. Not only does it appear that electrical activity in the veins initiates fibrillation, but it also may be responsible for perpetuating fibrillation. Subsequently, similar evidence has suggested that other thoracic veins (vena cavae, coronary sinus, ligament of Marshall) initiate and perpetuate atrial fibrillation. How does electrical impulse initiation occur in the veins? The results of numerous in vivo and in vitro studies on this subject have not conclusively defined a mechanism. Impulse initiation by automaticity and triggered activity as well as impulse initiation resulting from reentry have been suggested. In this article, we focus only on those data suggesting the possibility that triggered activity initiates and/or perpetuates atrial fibrillation.

Introduction

In 1999, Haissaguerre et al published a landmark article showing that atrial fibrillation can be initiated by electrical activity in the pulmonary veins.1 Not only does it appear that electrical activity in the veins initiates fibrillation, but it also may be responsible for perpetuating fibrillation. Subsequently, similar evidence has suggested that other thoracic veins (vena cavae, coronary sinus, ligament of Marshall) initiate and perpetuate atrial fibrillation.1

How does electrical impulse initiation occur in the veins? The results of numerous in vivo and in vitro studies on this subject have not conclusively defined a mechanism. Impulse initiation by automaticity and triggered activity as well as impulse initiation resulting from reentry have been suggested. The results of ablation procedures in preventing atrial fibrillation are consistent with both mechanisms. In this article, we focus only on those data suggesting the possibility that triggered activity initiates and/or perpetuates atrial fibrillation. Our opinion from a review of the literature is that both triggered activity and reentry are involved in the genesis of atrial fibrillation but that the relative importance of each cannot be determined at present.

Triggered activity is a term used to describe impulse initiation in cardiac fibers that is dependent on afterdepolarizations.2 Afterdepolarizations are oscillations in membrane potential that follow the upstroke of an action potential. Two kinds of afterdepolarizations may cause triggered activity. One occurs early, during phase 2 or 3 repolarization of the action potential [early afterdepolarizations (EADs)]. The other is delayed until repolarization is complete or nearly complete [delayed afterdepolarizations (DADs)]. When either kind of afterdepolarization is large enough to reach the threshold potential for activation of a regenerative inward current, action potentials result and are referred to as ā€œtriggered.ā€ Therefore, a key characteristic of triggered activity is that, to occur, at least one action potential must precede it (the trigger).

Afterdepolarizations and triggered activity have been demonstrated in isolated cardiac tissues and cells using transmembrane or patch clamp recordings of electrical activity. However, the demonstration that triggered activity is a cause of arrhythmias in vivo, such as atrial fibrillation, is a major problem that is not completely solved. It has not been possible to reliably record transmembrane potentials demonstrating afterdepolarizations in vivo. Although some studies show what has been interpreted to be afterdepolarizations in monophasic action potentials, the validity of such recordings has been questioned because motion artifact can produce deflections that resemble afterdepolarizations. One method often used to demonstrate that triggered activity may be a cause of an arrhythmia is removing tissue from a region of the arrhythmic heart and showing that afterdepolarizations can be recorded from the cells of that tissue. However, the problem always exists that isolation and superfusion of cardiac tissues and cells may alter their properties. Thus, what is recorded in an isolated preparation may not always resemble what occurs in situ.

Because of these problems, it has been proposed that the mechanism of an arrhythmia in the in situ heart can be deduced from the response of the arrhythmia to cardiac pacing.3 The following is a brief summary of the stimulation protocols and the response of arrhythmias to stimulation that may identify triggered activity.

The amplitude of DADs increases with a decrease in the cycle length at which action potentials occur until the afterdepolarization reaches threshold to cause triggered activity. Therefore, triggered arrhythmias caused by DADs in the in situ heart should be initiated by either overdrive pacing or programmed premature stimulation. Because automaticity is not initiated by pacing, automatic arrhythmias should be readily distinguished from triggered impulses arrhythmias (see Chapter 1 in Wit and Janse3). Reentrant arrhythmias also can be induced by the same stimulation. However, triggered activity caused by DADs is more easily induced by rapid pacing than by a single premature stimulus, whereas reentry is more easily induced by premature stimulation.

During initiation of DAD-dependent triggered rhythms, as the pacing cycle length (or coupling interval of premature impulses) decreases, the coupling interval from the last stimulated impulse to the first impulse of tachycardia should decrease (a direct relationship) because at short cycle lengths, the coupling interval of the afterdepolarizations to the proceeding action potential decreases. Such a direct relation is not expected during initiation of reentrant arrhythmias, in which slowing of conduction causes an inverse relationship.

Both triggered rhythms and reentrant rhythms can be terminated by overdrive stimulation or single premature impulses.3 Automatic rhythms caused by normal automaticity show the phenomenon of overdrive suppression but are not terminated, whereas those caused by abnormal automaticity are little affected. Another feature of the response to electrical stimulation that differentiates DAD-induced triggered activity from reentry is that reentrant rhythms, but not triggered rhythms, can be entrained.3

Arrhythmias caused by EADs, which result from prolonged action potential duration, have been shown not to be inducible by overdrive or premature stimulation, but they can be initiated by slowing the basic heart rate. However, more recent studies have suggested that, under certain circumstances, EAD-dependent triggered activity can be induced by rapid pacing in pulmonary vein preparations (see later). Electrical stimulation (premature or overdrive) in general is not expected to terminate triggered rhythms caused by EADs. The response should be similar to that of abnormal automaticity, which shows resetting but little overdrive suppression.

The response of initiators and perpetuators to electrical stimulation in vivo is mostly lacking, so proof that triggered activity is related to onset and perpetuation of atrial fibrillation is mostly circumstantial. Most of the evidence for involvement of triggered activity in atrial fibrillation comes from studies on isolated tissues and cells.

Although the pulmonary veins are the most important site for initiation of atrial fibrillation, we start with a description of triggered activity in the coronary sinus because, in our opinion, the musculature of the coronary sinus shows the most clear-cut evidence of triggered activity. Atrial myocardium extends into the coronary sinus from its orifice. Some myocytes resembling the transitional cells of the sinus node are interspersed among working atrial myocytes and connected to them by scattered gap junctions. The structure of these cells in the coronary sinus resemble the structure of cells proposed to be the automatic cells in the sinus node (Albala and Fenoglio, unpublished observations).

Rapid atrial tachycardias have been shown by mapping techniques to emanate from the coronary sinus.4 Involvement of the coronary sinus in atrial fibrillation is evidenced by the demonstration that bursts of rapid activity in the coronary sinus, faster than in the atria, occurred in response to the rapid atrial pacing that initiated atrial fibrillation.5 In some patients with atrial fibrillation, rapid repetitive activity in the musculature of the coronary sleeve may contribute to maintenance of the arrhythmia. Isolation of the coronary sinus from atrial myocardium has been shown to prevent atrial fibrillation in patients who had undergone pulmonary vein ablation that did not prevent fibrillation. Other clinical studies have shown that the initiator of atrial fibrillation can sometimes be in the vicinity of the coronary sinus.6, 7, 8

These clinical data, however, do not address the mechanism of impulse initiation in any detail. Rapid coronary sinus activity and atrial fibrillation are initiated by atrial pacing, but this does not eliminate the possibility of pacing-induced reentry. The other characteristics necessary to suggest DAD-induced triggered activity (e.g., a direct relationship between pacing cycle length and the first cycle length of the induced activity) have not been obtained. That the coronary sinus in situ is capable of triggered activity has been shown in an experimental study on the canine heart, using the characteristics of response to electrical stimulation.9, 10 Such studies in the human heart are needed to relate triggered activity to atrial fibrillation initiation and maintenance.

A large body of information describes the cellular electrophysiology of coronary sinus musculature. Mapping of isolated preparations composed of coronary sinus and atrial musculature from the canine heart showed that two different regions are capable of impulse initiation in the presence of norepinephrine, one just outside the orifice of the coronary sinus and the other well within the walls of the coronary sinus.11 The action potentials of musculature inside the coronary sinus resemble atrial action potentials but have a small plateau phase. However, the cells have a less negative resting potential that may result from a sodium leak current. In the absence of electrical stimulation, this inward current causes a progressive loss of membrane potential that may result in a loss of excitability.12 Norepinephrine causes DADs and triggered activity in musculature inside the coronary sinus (Figure 1), while causing spontaneous diastolic (pacemaker) depolarization in cells outside the coronary sinus orifice. Triggered activity in coronary sinus musculature is initiated by either a critically shortened stimulation cycle length (Figure 2) or critically timed premature impulse.11 DADs in coronary sinus are caused by a transient inward current similar to the transient inward current caused by cardiac glycosides in other tissues.13, 14 It likely is related to calcium release from the sarcoplasmic reticulum.15 Enhancing electrogenic sodium pump current during prolonged periods of triggered activity can terminate it.16

Atrial muscle extends into the pulmonary veins. An extensive literature shows that electrical activity in this pulmonary vein musculature is related to the onset and perpetuation of atrial fibrillation.1, 17 Ablation of pulmonary vein musculature can prevent atrial fibrillation. The mechanism for impulse origin in pulmonary veins is uncertain; automaticity, triggered activity, and reentry all have been proposed.18

Specialized cardiac cells that are associated with pacemaking, resembling pale (P) cells and Purkinje cells, have been described in rat19 and human pulmonary vein20 and in some21 but not all22, 23 studies on canine pulmonary veins. The link suggesting triggered activity in pulmonary veins to atrial fibrillation is that rapid pacing of the atria can initiate pulmonary vein activity. However, no other evidence from in situ studies has shown the expected features of triggered activity in response to pacing protocols that we described earlier. A majority of data suggesting a possible role of triggered activity has come from in vitro studies on tissues and cells. The results from studies on different species are somewhat varied and add to the confusion as to whether pulmonary vein musculature is capable of triggered activity.

Automaticity, DADs and triggered activity do not readily occur in in vitro preparations of canine pulmonary vein where action potentials resemble atrial muscle and are characterized by rapid upstrokes (Figure 2C, trace labeled ā€œPVā€).23, 24, 25 Pulmonary vein muscle fibers have a less negative membrane potential than does atrial muscle because of a smaller IK1, slower phase 0 upstroke velocity (Vmax) likely caused by the reduced membrane potential, and shorter action potential duration associated with larger IKr and IKs. Resting membrane potential and upstroke velocity are decreased more in the distal vein than in the proximal vein.23, 24, 25 The reduced upstrokes and structural anisotropy23, 26 along with differences in connexin expression22 and heterogeneity of action potential duration may cause reentry, a proposed mechanism for the rapid impulse initiation that can originate in the veins.27 Spontaneous activity arising just proximal to the venous ostium in the presence of isoproterenol, with an increased rate after rapid pacing (suggesting triggered activity), has been described in only one study on veins from normal dog hearts.27 Pacemaker potentials or afterdepolarizations were not evident, so a role for triggered activity is uncertain.

Canine pulmonary vein muscle can initiate rapid activity under special experimental conditions. One condition is the simultaneous activation of parasympathetic and sympathetic nerves in vitro (Figure 2). This rapid activity is caused by EADs during phase 3 repolarization that induces triggered activity.28, 29 Although the traditional mechanism for EAD-induced triggered activity is dependent on action potential prolongation with reactivation of inward Ca2+ or Na+ current during the plateau phase, the proposed mechanism for EADs resulting from autonomic nerve activation in pulmonary veins is not dependent on action potential prolongation. The short duration of the atrial action potential in pulmonary vein muscle is associated with a peak Ca2+ transient (as deduced from force measurements) occurring during late repolarization rather than during the plateau phase. Parasympathetic nerve activation increases this disparity by accelerating repolarization to make action potential duration even shorter. Presumably [Ca2+]i from the calcium transient remains elevated at a time when the membrane potential has mostly repolarized and is negative to the equilibrium potential for the Na/Ca exchanger current. Inward exchanger current is activated under these conditions. It is proposed that sympathetic activation augments the Ca2+ transient, enhances EADs, and promotes triggering. Suppression of Na/Ca exchange suppresses EAD-induced triggered activity.28 Although the autonomic nervous system sometimes is involved in the occurrence of atrial fibrillation in experimental animals29 or in patients,30 how often its participation is obligatory is uncertain. Late phase 3 EAD-triggered activity caused by these mechanisms may occur only under limited circumstances.

From these canine studies, triggered activity does not appear to be a normal intrinsic property of normal pulmonary vein myocardium; however, the properties of the vein musculature might be altered under conditions that favor the occurrence of atrial fibrillation. For example, stretch of the atria in a sheep model of stretch-related AF causes focal activity arising in the veins.31 In a canine model of pacing-induced heart failure, atrial tachycardia and fibrillation occur that may arise in the pulmonary veins.17, 32, 33 There is evidence that atrial tachycardia in this animal model is caused by DAD-induced triggered activity, some of which arises near or in pulmonary veins, although atrial muscle also may be a source of impulse initiation. In superfused pulmonary vein preparations from a rapid-pacing induced heart failure model, both action potentials with spontaneous diastolic depolarization and automatic activity and those with phase 2 EADs have been recorded.34

In contrast to the results of studies in tissues, both DADs and EADs and triggered activity have been found to be prevalent in single pulmonary vein myocytes isolated from normal canine pulmonary vein myocardium34 as well as from myocytes from pulmonary vein obtained from dogs with pacing-induced heart failure (Figure 3).35 Reasons why triggered activity is more prevalent in single myocytes are uncertain. Electrotonic inhibition of pacemaking cells by nonpacemaking cells may occur in tissues and not in isolated myocytes.36 Additionally, isolation of single myocytes may result in abnormal calcium loading that can cause afterdepolarizations. The validity of results from isolated myocyte studies has been questioned, and some results have been attributed to experimental artifacts.24 In our opinion, studies on automaticity and triggered activity in isolated myocytes should be repeated by other laboratories.

As in the dog, rabbit pulmonary vein tissue superfused in vitro shows typical atrial action potentials, is not spontaneously active, and does not have afterdepolarizations or triggered activity.37 Addition of ryanodine to the superfusate caused depolarization of the resting potential, increase in plateau height, development of pacemaker activity, and rapid repetitive action potentials following pacing that likely were caused by DADs (Figure 4).37 This behavior is consistent with the effects of ryanodine at low concentrations in locking the sarcoplasmic reticulum Ca2+ release channel, the ryanodine receptor (RyR), in a subconductance state, causing Ca2+-independent Ca2+ release from the sarcoplasmic reticulum.38 Ca2+ leakage during diastole causes traveling Ca2+ waves, increasing Ca2+ dependent ionic currents that may cause DADs.39, 40 The inward current causing DADs in this experimental model may be an Na/Ca exchanger current.

Other sites of triggered activity that may be related to the onset and perpetuation of atrial fibrillation include vena cavae, ligament of Marshall, atrial muscle, and mitral valves. Ectopic activity has been recorded from the cardiac muscle that extends into the vena cavae41 associated with onset of atrial fibrillation.42 Isoproterenol infusion and burst pacing, both of which can cause triggered activity, initiated atrial fibrillation with onset attributed to vena cava activity because the atrial fibrillation was prevented by ablation at the vein orifice. Isolated cardiomyocytes from the vena cavae have been shown to have pacemaker activity, DADs, and triggered activity.43

An electrically active muscle sleeve occurs in the ligament of Marshall, continuous with the muscle sleeve around the coronary sinus.44 Rapid activity in this muscle sleeve has been shown to precede the onset of atrial fibrillation in some patients with ablation of the ligament preventing fibrillation.45, 46 Action potentials recorded from the ligament in vitro resemble working atrial myocardial action potentials.1 A role of triggered activity in the focal impulse initiation seen in situ has not been established.

DADs and triggered activity in the presence of catecholamines readily occur in the atrial muscle that extends into the mitral valve.47 Although a role for valve impulse initiation in atrial fibrillation has not been described, a relationship is possible. Under certain circumstances, triggered activity can also occur in working atrial muscle,48 particularly in the presence of underlying disease such as a cardiomyopathy.49

Section snippets

Conclusion

Although it is well accepted that electrical activity originating in the pulmonary and other thoracic veins is sometimes intimately related to the onset and perpetuation of atrial fibrillation, the mechanism for impulse initiation is uncertain. Triggered activity does not appear to be a normal property of the atrial muscle that lines the pulmonary veins, although it may be a normal property of coronary sinus muscle. Thus, studies on normal canine hearts, although they define the normal

References (49)

  • P.S. Chen et al.

    Coronary sinus as an arrhythmogenic structure

    J Cardiovasc Electrophysiol

    (2002)
  • D. Katritsis et al.

    Conduction delay within the coronary sinus in Humans: implications for atrial arrhythmias

    J Cardiovasc Electrophysiol

    (2002)
  • P. Sandres et al.

    Electrical disconnection of the coronary sinus by radiofrequency catheter ablation to isolate a trigger of atrial fibrillation

    J Cardiovasc Electrophysiol

    (2004)
  • N. Johnson et al.

    Characteristics of initiation and termination of catecholamine-induced triggered activity in atrial fibers of the coronary sinus

    Circulation

    (1986)
  • G. Malfatto et al.

    The response to overdrive pacing of triggered atrial and ventricular arrhythmias in the canine heart

    Circulation

    (1988)
  • A.L. Wit et al.

    Triggered and automatic activity in the canine coronary sinus

    Circ Res

    (1977)
  • P.A. Boyden et al.

    The basis for the membrane potential of quiescent cells of the canine coronary sinus

    J Physiol

    (1983)
  • G.N. Tseng et al.

    Effects of reducing [Na+]o on catecholamine-induced delayed afterdepolarizations in atrial cells

    Am J Physiol Heart Circ Physiol

    (1987)
  • R.S. Aronson et al.

    The effects of caffeine and ryanodine on the electrical activity of the canine coronary sinus

    J Physiol

    (1985)
  • A.L. Wit et al.

    Electrogenic sodium extrusion can stop triggered activity in the canine coronary sinus

    Circ Res

    (1981)
  • S. Nattel

    Basic electrophysiology of the pulmonary veins and their role in atrial fibrillation: precipitators, perpetuators, and perplexers

    J Cardiovasc Electrophysiol

    (2003)
  • F. Masani

    Node-like cells in the myocardial layer of the pulmonary vein of rats: an ultrastructural study

    J Anat

    (1986)
  • A. Perez-Lugones et al.

    Evidence of specialized conduction cells in human pulmonary veins of patients with atrial fibrillation

    J Cardiovasc Electrophysiol

    (2003)
  • C.-C. Chou et al.

    Intracellular calcium dynamics and anisotropic reentry in isolated canine pulmonary veins and left atrium

    Circulation

    (2005)
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