Abstract
Automaticity is the property of cardiac cells to initiate an impulse spontaneously, without need for prior stimulation. Triggered activity is impulse initiation in cardiac fibers caused by depolarizing oscillations in membrane voltage (known as afterdepolarizations) that occur consequent to one or more preceding action potentials. Reentry occurs when a propagating action potential wave fails to extinguish after initial tissue activation; instead, it blocks in circumscribed areas, circulates around the zones of block, and reenters and reactivates the site of original excitation after it recovers excitability. Reentry is the likely mechanism of most recurrent clinical arrhythmias.
Diagnosis of the underlying mechanism of an arrhythmia can be of great importance in guiding appropriate treatment strategies. Spontaneous behavior of the arrhythmia, mode of initiation and termination, and response to programmed electrical stimulation are the most commonly used tools to distinguish among the different mechanisms responsible for cardiac arrhythmias. Our present diagnostic tools, however, do not always permit unequivocal determination of the electrophysiological mechanisms responsible for many clinical arrhythmias or their ionic bases. This is further complicated by the fact that some arrhythmias can be started by one mechanism and perpetuated by another.
Keywords
arrhythmogenesis, automaticity, triggered activity, reentry, slow conduction, anisotropy
Outline
Automaticity, 51
Enhanced Normal Automaticity, 51
Abnormal Automaticity, 55
Overdrive Suppression of Automatic Rhythms, 56
Arrhythmias Caused by Automaticity, 57
Triggered Activity, 58
Delayed Afterdepolarizations and Triggered Activity, 58
Reentry, 63
Basic Principles of Reentry, 63
Requisites of Reentry, 63
Types of Reentrant Circuits, 65
Excitable Gaps in Reentrant Circuits, 68
Resetting Reentrant Tachycardias, 69
Entrainment of Reentrant Tachycardias, 73
Mechanism of Slow Conduction in the Reentrant Circuit, 74
Anisotropy and Reentry, 76
Mechanism of Unidirectional Block in the Reentrant Circuit, 78
The mechanisms responsible for cardiac arrhythmias are generally divided into categories of disorders of impulse formation (automaticity or triggered activity), disorders of impulse conduction (reentry), or combinations of both. Automaticity is the property of cardiac cells to initiate an impulse spontaneously, without need for prior stimulation. Triggered activity is impulse initiation in cardiac fibers caused by depolarizing oscillations in membrane voltage (known as afterdepolarizations) that occur consequent to one or more preceding action potentials. Reentry occurs when a propagating action potential wave fails to extinguish after initial tissue activation; instead, it blocks in circumscribed areas, circulates around the zones of block, and reenters and reactivates the site of original excitation after it recovers excitability. Reentry is the likely mechanism of most recurrent clinical arrhythmias.
Diagnosis of the underlying mechanism of an arrhythmia can be of great importance in guiding appropriate treatment strategies. Spontaneous behavior of the arrhythmia, mode of initiation and termination, and response to programmed electrical stimulation are the most commonly used tools to distinguish among the different mechanisms responsible for cardiac arrhythmias. However, our present diagnostic tools do not always permit unequivocal determination of the electrophysiological (EP) mechanisms responsible for many clinical arrhythmias or their ionic bases. In particular, it can be difficult to distinguish among several mechanisms that appear to have a focal origin with centrifugal spread of activation (automaticity, triggered activity, and microreentry). This is further complicated by the fact that some arrhythmias can be started by one mechanism and perpetuated by another.
Automaticity
Automaticity, or spontaneous impulse initiation, is the ability of cardiac cells to depolarize spontaneously, reach threshold potential, and initiate a propagated action potential, in the absence of external electrical stimulation. Altered automaticity can be caused by enhanced normal automaticity or by abnormal automaticity.
Enhanced normal automaticity refers to the accelerated generation of an action potential by normal pacemaker tissue and is found in the primary pacemaker of the heart, the sinus node, as well as in certain subsidiary or latent pacemakers that can become the functional pacemaker under certain conditions. Impulse initiation is a normal property of the primary and latent pacemakers.
Abnormal automaticity occurs in cardiac cells only when there are major abnormalities in their transmembrane potentials, in particular in steady-state depolarization of the membrane potential. This property of abnormal automaticity is not confined to any specific latent pacemaker cell type but can occur almost anywhere in the heart.
The discharge rate of normal or abnormal pacemakers can be influenced by drugs, various forms of cardiac disease, reduction in extracellular potassium (K + ), or alterations of autonomic nervous system tone.
Enhanced Normal Automaticity
Pacemaker Mechanisms
Normal automaticity involves a spontaneous, slow, progressive decline in the transmembrane potential (i.e., the membrane voltage becomes less negative) during diastole. This process is known as “spontaneous diastolic depolarization” or “phase 4 depolarization.” Once this spontaneous depolarization reaches threshold (approximately −40 mV), a new action potential is generated ( Fig. 3.1 ) ( see Chapter 1 ).
The ionic mechanisms responsible for normal pacemaker activity in the sinus node are still controversial. The fall in membrane potential during phase 4 seems to arise from a changing balance between positive inward currents, which favor depolarization, and positive outward currents, with a net gain in intracellular positive charges during diastole (i.e., a net inward depolarizing current) ( Fig. 3.2 ).
I K -decay theory.
The sinus node lacks the inward rectifier K + current (I K1 ), which acts to stabilize the resting membrane potential (E m ) in the normal working atrial and ventricular myocardium. The outward K + currents are carried by the delayed rectifier K + channels (I Kr and I Ks ), which are responsible for repolarization of the sinus node action potential; those currents decay following repolarization and channel inactivation, allowing the membrane potential to drift toward the more positive equilibrium potentials of other ions (Na + , Ca 2+ , and Cl − ). The decay of the delayed K + conductance activated during the preceding action potential was initially thought to play a major role in pacemaker activity (the I K -decay theory). This model of pacemaker depolarization lost interest after the discovery of the pacemaker current (I f ). Nonetheless, I K -decay is still believed to contribute to diastolic depolarization (especially the earliest part of the pacemaker potential) by allowing other inward currents to depolarize the myocyte during diastole. Other ionic currents gated by membrane depolarization (i.e., L-type [I CaL ] and T-type [I CaT ] Ca 2+ currents), nongated and nonspecific background leak currents, and a current generated by the Na + -Ca 2+ exchanger (I Na-Ca ), were also proposed to be involved in pacemaking.
Membrane clock.
Evidence suggests that I f (named the “funny” current because, unlike most voltage-sensitive currents, it is activated by hyperpolarization rather than depolarization) is one of the most important ionic currents involved in the rate regulation of cardiac pacemaker cells, hence its designation as the pacemaker current. I f is an inward current carried largely by Na + and, to a lesser extent, K + ions. I f channels are deactivated during the action potential upstroke and the initial plateau phase of repolarization. However, they begin to activate at the end of the action potential as repolarization brings the membrane potential to levels more negative than −40 to −50 mV, and I f is fully activated at approximately −100 mV. Once activated, I f depolarizes the membrane to a level where the Ca 2+ current activates to initiate the action potential. In its range of activation, which quite properly comprises the voltage range of diastolic depolarization, the current is inward, and its reversal occurs at approximately −10 to −20 mV because of the mixed Na + -K + permeability of I f channels. At the end of the repolarization phase of an action potential, because I f activation occurs in the background of a decaying outward (K + time-dependent) current, the current flow quickly shifts from outward to inward, thus giving rise to a sudden reversal of voltage change (from repolarizing to depolarizing) at the maximum diastolic potential. The major role of I f has been reinforced by the findings that drugs such as ivabradine targeted to block I f slow heart rate and mutations in the I f channel are associated with slowed heart rate.
The “membrane clock” (also referred to as the “voltage clock” or “ion channel clock”) refers to the time- and voltage-dependent membrane ion channels underlying pacemaking activity, including the decay of the outward rectifier K + current and the activation of several inward currents (I f , I CaL , I CaT , and I Na ).
Calcium clock.
Several studies have recently demonstrated that I f is not the only current that can initiate the diastolic depolarization process in the sinus node. In addition to voltage and time, the electrogenic and regulatory molecules on the surface membrane of sinus nodal cells are strongly modulated by Ca 2+ and phosphorylation, a finding suggesting that intracellular Ca 2+ is an important player in controlling pacemaker cell automaticity. Newer evidence points to a substantial impact of another current on the late diastolic depolarization; that is, the Na + -Ca 2+ exchanger current (I Na-Ca ) activated by submembrane spontaneous rhythmic local Ca 2+ releases from the sarcoplasmic reticulum (a major Ca 2+ store within sinus node cells) via the ryanodine receptors (RyR2). Activation of the local oscillatory Ca 2+ releases is independent of membrane depolarization and is driven by a high level of basal state phosphorylation of Ca 2+ cycling proteins. Critically timed Ca 2+ releases occur during the later phase of diastolic depolarization and instantaneously trigger Ca 2+ extrusion from the cytosol by the Na + -Ca 2+ exchanger operating in the forward mode (one Ca 2+ out for three Na + in). This generates a net inward membrane current that causes the late diastolic depolarization to increase exponentially, thus driving the membrane potential to the threshold to activate a sufficient number of voltage-gated L-type Ca 2+ channels and leading to generation of the rapid upstroke of the next action potential ( see Fig. 1.7 ). Although regulated by membrane potential and submembrane Ca 2+ , the Na + -Ca 2+ exchanger does not have time-dependent gating, as do ion channels, but generates an inward current almost instantaneously when submembrane Ca 2+ concentration increases.
Such rhythmic, spontaneous intracellular Ca 2+ cycling has been referred to as an intracellular “calcium clock.” Phosphorylation-dependent gradation of the speed at which calcium clock cycles is the essential regulatory mechanism of normal pacemaker rate and rhythm. The robust regulation of pacemaker function is ensured by tight integration of the calcium clock and the membrane clock to form the overall “pacemaker clock.” The action potential shape and ion fluxes are tuned by membrane clocks to sustain operation of the calcium clock, which produces timely and powerful ignition of the membrane clocks to effect action potentials.
There remains some degree of uncertainty about the relative role of I f versus that of intracellular Ca 2+ cycling in controlling the normal pacemaker cell automaticity and their individual (or mutual) relevance in mediating the positive-negative chronotropic effect of neurotransmitters. Furthermore, the interactions between the membrane ion channel clock and the intracellular calcium clock and the cellular mechanisms underlying this internal calcium clock are not completely elucidated.
Automaticity in subsidiary pacemakers appears to arise via a mechanism similar to that occurring in the sinus node.
Hierarchy of Pacemaker Function
Automaticity is not limited to the cells within the sinus node. Under physiological conditions, cells in parts of the atria and within the atrioventricular node (AVN) and the His-Purkinje system (HPS) also possess pacemaking capability. However, the occurrence of spontaneous activity in these cells is prevented by the natural hierarchy of pacemaker function that causes these sites to be latent or subsidiary pacemakers. The spontaneous discharge rate of the sinus node normally exceeds that of all other subsidiary pacemakers (see Fig. 3.1 ). Therefore the impulse initiated by the sinus node depolarizes subsidiary pacemaker sites and keeps their activity depressed before they can spontaneously reach threshold. However, slowly depolarizing and previously suppressed pacemakers in the atrium, AVN, or ventricle can become active and assume pacemaker control of the cardiac rhythm if the sinus node pacemaker becomes slow or unable to generate an impulse (e.g., secondary to depressed sinus node automaticity) or if impulses generated by the sinus node are unable to activate the subsidiary pacemaker sites (e.g., sinoatrial exit block or atrioventricular [AV] block). The emergence of subsidiary or latent pacemakers under such circumstances is an appropriate fail-safe mechanism, which ensures that ventricular activation is maintained. Because spontaneous diastolic depolarization is a normal property, the automaticity generated by these cells is classified as normal .
There is also a natural hierarchy of the intrinsic rates of subsidiary pacemakers that have normal automaticity, with atrial pacemakers having faster intrinsic rates than AV junctional pacemakers, and AV junctional pacemakers having faster rates than ventricular pacemakers.
Subsidiary Pacemakers
Subsidiary atrial pacemakers.
Subsidiary pacemakers have been identified in the atrial myocardium, especially in the crista terminalis, at the junction of the inferior right atrium (RA) and inferior vena cava (IVC), near or on the eustachian ridge, near the coronary sinus (CS) os, in the atrial muscle that extends into the tricuspid and mitral valves, and in the muscle sleeves that extend into the cardiac veins (venae cavae and pulmonary veins).
Latent atrial pacemakers can contribute to impulse initiation in the atrium if the discharge rate of the sinus node is reduced temporarily or permanently. In contrast to the normal sinus node, these latent or ectopic pacemakers usually generate a fast action potential (referring to the rate of upstroke of the action potential [dV/dt]) mediated by Na + fluxes. However, when severely damaged, the atrial tissue may not be able to generate a fast action potential (which is energy dependent) but rather generates a slow, Ca 2+ -mediated action potential (which is energy independent). Automaticity of subsidiary atrial pacemakers can also be enhanced by myocardial ischemia, chronic pulmonary disease, or drugs such as digitalis and alcohol, possibly overriding normal sinus activity.
Subsidiary AV junctional pacemakers.
Some data suggest that the AVN itself has pacemaker cells, but that concept is controversial. However, it is clear that the AV junction, which is an area that includes atrial tissue, the AVN, and His-Purkinje tissue, does have pacemaker cells and is capable of exhibiting automaticity.
Subsidiary ventricular pacemakers.
In the ventricles, latent pacemakers are found in the HPS, where Purkinje fibers have the property of spontaneous diastolic depolarization. Isolated cells of the HPS discharge spontaneously at rates of 15 to 60 beats/min, whereas ventricular myocardial cells do not normally exhibit spontaneous diastolic depolarization or automaticity. The relatively slow spontaneous discharge rate of the HPS pacemakers, which further decreases from the His bundle (HB) to the distal Purkinje branches, ensures that pacemaker activity in the HPS will be suppressed on a beat-to-beat basis by the more rapid discharge rate of the sinus node and atrial and AV junctional pacemakers. However, enhanced Purkinje fiber automaticity can be induced by certain situations, such as myocardial infarction (MI). In this setting, some Purkinje fibers that survive the infarction develop moderately reduced maximum diastolic membrane potentials and therefore accelerated spontaneous discharge rates.
Regulation of Pacemaker Function
The intrinsic rate at which the sinus node pacemaker cells generate impulses is determined by the interplay of three factors: the maximum diastolic potential, the threshold potential at which the action potential is initiated, and the rate (slope) of phase 4 depolarization ( eFig. 3.1 ). A change in any one of these factors will alter the time required for phase 4 depolarization to carry the membrane potential from its maximum diastolic level to threshold and thus alter the rate of impulse initiation.
The sinus node is innervated by the parasympathetic and sympathetic nervous systems, and the balance between these systems importantly controls the pacemaker rate. The classic concept has been that of a reciprocal relationship between sympathetic and parasympathetic inputs. However, more recent investigations stress dynamic, demand-oriented interactions, and the anatomical distribution of fibers that allows both autonomic systems to act quite selectively. Muscarinic cholinergic and beta 1 -adrenergic receptors are nonuniformly distributed in the sinus node, and they modulate both the rate of depolarization and impulse propagation.
Parasympathetic activity.
Parasympathetic tone reduces the spontaneous discharge rate of the sinus node, whereas its withdrawal accelerates sinus node automaticity. Acetylcholine, the principal neurotransmitter of the parasympathetic nervous system, inhibits spontaneous impulse generation in the sinus node by increasing K + conductance. Acetylcholine acts through M 2 muscarinic receptors to activate the G i protein, which subsequently results in activation of I KACh (an acetylcholine-activated subtype of inward rectifying current) in tissues of the sinus node and AVN, as well as of the atria, Purkinje fibers, and ventricles. The increased outward repolarizing K + current leads to membrane hyperpolarization (i.e., the resting potential and the maximum diastolic potential become more negative). The resulting hyperpolarization of the membrane potential lengthens the time required for the membrane potential to depolarize to threshold and thereby decreases the automaticity of the sinus node (see eFig. 3.1 ). In addition, activation of the G i protein results in inhibition of beta receptor–stimulated adenylate cyclase activity, thus reducing cyclic adenosine monophosphate (cAMP) and inhibiting protein kinase A, with subsequent inhibition of the inward L-type Ca 2+ current (I CaL ). This results in reduction of the rate of diastolic depolarization because of less Ca 2+ entry and subsequent slowing of the pacemaker activity. Inhibition of beta receptor–stimulated adenylate cyclase activity can also inhibit the inward I f current.
Sympathetic activity.
Increased sympathetic nerve traffic and the adrenomedullary release of catecholamines increase sinus node discharge rate. Stimulation of beta 1 receptors by catecholamines enhances I CaL by increasing cAMP and activating the protein kinase A system. The increment in I CaL increases the slope of diastolic depolarization and enhances pacemaker activity (see eFig. 3.1 ). The redistribution of Ca 2+ can also increase the completeness and the rate of deactivation of the rapid (I Kr ) and slow (I Ks ) components of the delayed rectifier K + current. The ensuing decline in the opposing outward current results in a further net increase in inward current. Catecholamines can also enhance the inward I f current by shifting the voltage dependence of I f to more positive potentials, thus augmenting the slope of phase 4 and increasing the rate of sinus node firing.
In addition to altering ionic conductance, changes in autonomic tone can produce changes in the rate of the sinus node by shifting the primary pacemaker region within the pacemaker complex. Mapping of activation indicates that, at faster rates, the sinus node impulse usually originates in the superior portion of the sinus node, whereas at slower rates, it usually arises from a more inferior portion of the sinus node. The sinus node can be insulated from the surrounding atrial myocytes, except at a limited number of preferential exit sites. Shifting pacemaker sites can select different exit pathways to the atria. As a result, autonomically mediated shifts of pacemaker regions can be accompanied by changes in the sinus rate. Vagal fibers are denser in the cranial portion of the sinus node, and stimulation of the parasympathetic nervous system shifts the pacemaker center to a more caudal region of the sinus node complex, thus resulting in slowing of the heart rate. In contrast, stimulation of the sympathetic nervous system or withdrawal of vagal stimulation shifts the pacemaker center cranially, resulting in an increase in heart rate.
Atrial, AV junctional, and HPS subsidiary pacemakers are also under similar autonomic control, with the sympathetic nervous system enhancing pacemaker activity through beta 1 -adrenergic stimulation and the parasympathetic nervous system inhibiting pacemaker activity through muscarinic receptor stimulation.
Other influences.
Adenosine binds to A1-receptors, thus activating I KACh and increasing outward I K in a manner similar to that of marked parasympathetic stimulation. It also has similar effects on I f channels.
Digitalis exerts two effects on the sinus rate. It has a direct positive chronotropic effect on the sinus node, resulting from depolarization of the membrane potential caused by inhibition of the Na + -K + exchange pump. The reduction in the maximum diastolic membrane potential shortens the time required for the membrane to depolarize to threshold and thereby accelerates the spontaneous discharge rate. However, digitalis also enhances vagal tone, which decreases spontaneous sinus discharge.
Enhanced subsidiary pacemaker activity may not require sympathetic stimulation. Normal automaticity can be affected by certain other factors associated with heart disease. Inhibition of the electrogenic Na + -K + exchange pump results in a net increase in inward current during diastole because of the decrease in outward current normally generated by the pump, and therefore it can increase automaticity in subsidiary pacemakers sufficiently to cause arrhythmias. This can occur when adenosine triphosphate (ATP) is depleted during prolonged hypoxia or ischemia or in the presence of toxic amounts of digitalis. Hypokalemia can reduce the activity of the Na + -K + exchange pump, thereby reducing the background repolarizing current and enhancing phase 4 diastolic depolarization. The end result would be an increase in the discharge rate of pacemaking cells. In addition, the flow of current between partially depolarized myocardium and normally polarized latent pacemaker cells can enhance automaticity. This mechanism has been proposed to be a cause of some of the ectopic complexes that arise at the borders of ischemic areas in the ventricle. Slightly increased extracellular K + can reduce the maximum diastolic potential (i.e., becomes less negative), thereby also increasing the discharge rate of pacemaking cells. However, a greater increase in extracellular K + renders the heart inexcitable by depolarizing the membrane potential and inactivating the Na + current (I Na ).
Evidence indicates that active and passive changes in the mechanical environment of the heart provide feedback to modify cardiac rate and rhythm and are capable of influencing both the initiation and spread of cardiac excitation. This direction of the crosstalk between cardiac electrical and mechanical activity is referred to as mechanoelectric feedback and is thought to be involved in the adjustment of heart rate to changes in mechanical load, which would help to explain the precise beat-to-beat regulation of cardiac performance. Acute mechanical stretch enhances automaticity, reversibly depolarizes the cell membrane, and shortens the action potential duration. Feedback from cardiac mechanics to electrical activity involves mechanosensitive ion channels and ATP-sensitive K + channels. In addition, Na + and Ca 2+ entering the cells via nonselective ion channels are thought to contribute to the genesis of stretch-induced arrhythmia.
Abnormal Automaticity
In the normal heart, automaticity is confined to the sinus node and other specialized conducting tissues. Working atrial and ventricular myocardial cells do not normally exhibit spontaneous diastolic depolarization and do not initiate spontaneous impulses, even when they are not excited for long periods of time by propagating impulses. Although these cells do have an I f , the range of activation of this current in these cells is much more negative (−120 to −170 mV) than in Purkinje fibers or in the sinus node. As a result, during physiological E m (−85 to −95 mV), the I f is not activated and ventricular cells do not depolarize spontaneously. However, when the resting potentials of these cells are depolarized sufficiently, to approximately −70 to −30 mV, spontaneous diastolic depolarization can occur and cause repetitive impulse initiation, a phenomenon called depolarization-induced automaticity or abnormal automaticity (see eFig. 3.1 ). Similarly, cells in the Purkinje system, which are normally automatic at high levels of membrane potential, show abnormal automaticity when the membrane potential is reduced to approximately −60 mV or less, as can occur in ischemic regions of the heart. When the steady-state membrane potential of Purkinje fibers is reduced to levels more positive to −60 mV, the I f channels that participate in normal pacemaker activity in Purkinje fibers are closed and nonfunctional, and automaticity is therefore not caused by the normal pacemaker mechanism. However, it can be caused by an “abnormal” mechanism. In contrast, enhanced automaticity of the sinus node, subsidiary atrial pacemakers, or the AVN caused by a mechanism other than acceleration of normal automaticity has not been demonstrated clinically.
A low level of membrane potential is not the only criterion for defining abnormal automaticity. If this were so, the automaticity of the sinus node would have to be considered abnormal. Therefore an important distinction between abnormal and normal automaticity is that the membrane potentials of fibers showing the abnormal type of activity are reduced from their own normal level. For this reason, automaticity in the AVN (e.g., where the membrane potential is normally low) is not classified as abnormal automaticity.
Several different mechanisms probably cause abnormal pacemaker activity at low membrane potentials, including activation and deactivation of the delayed rectifier I K , intracellular Ca 2+ release from the sarcoplasmic reticulum that causes activation of inward Ca 2+ current as well as I Na (through the Na + -Ca 2+ exchanger), and a potential contribution by I f . It has not been determined which of these mechanisms are operative in the different pathological conditions in which abnormal automaticity can occur.
The upstroke of the spontaneously occurring action potentials generated by abnormal automaticity can be caused by Na + or Ca 2+ inward currents or possibly a combination of the two. In the range of diastolic potentials between approximately −70 and −50 mV, repetitive activity is dependent on extracellular Na + concentration and can be decreased or abolished by Na + channel blockers. In a diastolic potential range of approximately −50 to −30 mV, Na + channels are predominantly inactivated; repetitive activity depends on extracellular Ca 2+ concentration and is reduced by L-type Ca 2+ channel blockers.
The intrinsic rate of a focus with abnormal automaticity is a function of the membrane potential. The more positive the membrane potential, the faster the automatic rate (see eFig. 3.1 ). Abnormal automaticity is less vulnerable to suppression by overdrive pacing (see later). Therefore even occasional slowing of the sinus node rate can allow an ectopic focus with abnormal automaticity to fire without a preceding long period of quiescence. Catecholamines can increase the rate of discharge caused by abnormal automaticity and therefore can contribute to a shift in the pacemaker site from the sinus node to a region with abnormal automaticity.
The decrease in the membrane potential of cardiac cells required for abnormal automaticity to occur can be induced by a variety of factors related to cardiac disease, such as ischemia and infarction. However, the circumstance under which membrane depolarization occurs can influence the development of abnormal automaticity. For example, an increase in extracellular K + concentration, as occurs in acutely ischemic myocardium, can reduce membrane potential; however, normal or abnormal automaticity in working atrial, ventricular, and Purkinje fibers usually does not occur because of an increase in K + conductance (and hence net outward current) that results from the increase in extracellular K + concentration.
Overdrive Suppression of Automatic Rhythms
The sinus node maintains its dominance over subsidiary pacemakers in the AVN and the Purkinje fibers likely by several mechanisms. During sinus rhythm in a normal heart, the intrinsic automatic rate of the sinus node is faster than that of the other potentially automatic cells. Consequently, the latent pacemakers are excited by propagated impulses from the sinus node before they have a chance to depolarize spontaneously to threshold potential. The higher frequency of sinus node discharge also suppresses the automaticity of other pacemaker sites by a mechanism called overdrive suppression. The diastolic (phase 4) depolarization of the latent pacemaker cells with the property of normal automaticity is actually inhibited because the cells are repeatedly depolarized by the impulses from the sinus node. Electrotonic interaction between the pacemaker cells and the nonpacemaker cells in the surrounding myocardium via intercalated discs and gap junctions can also hyperpolarize the latent pacemakers and contribute to their suppression ( Fig. 3.3 ).
The mechanism of overdrive suppression is mediated mostly by enhanced activity of the Na + -K + exchange pump that results from driving a pacemaker cell faster than its intrinsic spontaneous rate. During normal sinus rhythm (NSR), latent pacemakers are depolarized at a higher frequency than their intrinsic rate of automaticity. The increased frequency of depolarizations leads to an increase in intracellular Na + , which enters the cell with every action potential. The increased intracellular Na + stimulates the Na + -K + exchange pump. Because the Na + -K + exchange pump is electrogenic (i.e., moves more Na + outward than K + inward), it generates a net outward (hyperpolarizing) current across the cell membrane. This drives the membrane potential more negative, thereby offsetting the depolarizing I f being carried into the cell and slowing the rate of phase 4 diastolic depolarization. This effectively prevents the I f from depolarizing the cell to its threshold potential and thereby suppresses spontaneous impulse initiation in these cells.
When the dominant (overdrive) pacemaker is stopped, suppression of subsidiary pacemakers continues because the Na + -K + exchange pump continues to generate the outward current as it reduces the intracellular Na + levels toward normal. This continued Na + -K + exchange pump–generated outward current is responsible for the period of quiescence, which lasts until the intracellular Na + concentration, and hence the pump current, becomes low enough to allow subsidiary pacemaker cells to depolarize spontaneously to threshold. Intracellular Na + concentration decreases during the quiescent period because Na + is constantly being pumped out of the cell and little is entering. The spontaneous rate of the suppressed cell remains lower than it would be otherwise until the intracellular Na + concentration has a chance to decrease. Intracellular Na + concentration and pump current continue to decline even after spontaneous discharge begins because of the slow firing rate, thus causing a gradual increase in the discharge rate of the subsidiary pacemaker. At slower rates and shorter overdrive periods, the Na + load is of lesser magnitude, as is the activity of the Na + -K + pump, resulting in a progressively rapid diastolic depolarization and warm-up. The higher the overdrive rate or the longer the duration of overdrive, the greater the enhancement of pump activity will be, so that the period of quiescence after the cessation of overdrive is directly related to the rate and duration of overdrive.
The sinus node itself also is vulnerable to overdrive suppression. However, when overdrive suppression of the normal sinus node occurs, it is generally of lesser magnitude than that of subsidiary pacemakers overdriven at comparable rates. The sinus node action potential upstroke is largely dependent on the slow inward current carried by I CaL , and far less Na + enters the fiber during the upstroke than occurs in latent pacemaker cells such as the Purkinje fibers. As a result, the accumulation of intracellular Na + and enhancement of Na + -K + exchange pump activity occur to a lesser degree in sinus node cells after a period of overdrive; therefore there is less overdrive suppression caused by enhanced Na + -K + exchange pump current. The relative resistance of the normal sinus node to overdrive suppression is important in enabling it to remain the dominant pacemaker, even when its rhythm is perturbed transiently by external influences such as transient shifts of the pacemaker to an ectopic site. However, the diseased sinus node can be much more easily overdrive suppressed, such as in the so-called tachycardia-bradycardia syndrome.
Abnormally automatic cells and tissues at reduced levels of membrane potential are less sensitive to overdrive suppression than are cells and tissues that are fully polarized, with enhanced normal automaticity. The amount of overdrive suppression of spontaneous diastolic depolarization that causes abnormal automaticity is directly related to the level of membrane potential at which the automatic rhythm occurs. At low levels of membrane potential, Na + channels are inactivated, decreasing the fast inward I Na ; therefore there are reductions in the amount of Na + entering the cell during overdrive and the degree of stimulation of the Na + -K + exchange pump. The more polarized the membrane is during phase 4, the larger the amount will be of Na + entering the cell with each action potential and the more overdrive suppression will occur. As a result of the lack of overdrive suppression of abnormally automatic cells, even transient sinus pauses can permit an ectopic focus with a slower rate than the sinus node to capture the heart for one or more beats. However, even in situations in which the cells can be sufficiently depolarized to inactivate the I Na and limit intracellular Na + load, overdrive suppression can still be observed because of increased intracellular Ca 2+ loading. Such Ca 2+ loading can activate Ca 2+ -dependent K + conductance (favoring repolarization) and promote Ca 2+ extrusion through the Na + -Ca 2+ exchanger and Ca 2+ channel phosphorylation, thus increasing Na + load and thus Na + -K + exchange pump activity. The increase in intracellular Ca 2+ load can also reduce the depolarizing I CaL by promoting Ca 2+ -induced inactivation of the Ca 2+ current.
In addition to overdrive suppression being of paramount importance for maintenance of NSR, the characteristic response of automatic pacemakers to overdrive is often useful to distinguish automaticity from triggered activity and reentry.
Arrhythmias Caused by Automaticity
Inappropriate Sinus Node Discharge
Examples of these arrhythmias include inappropriate sinus bradycardia, sinus arrest, inappropriate sinus tachycardia, and inappropriate respiratory sinus arrhythmia. Such arrhythmias result simply from an alteration in the rate of impulse initiation by the normal sinus node pacemaker, without a shift of impulse origin to a subsidiary pacemaker at an ectopic site, although there can be shifts of the pacemaker site within the sinus node itself during alterations in sinus rate. These arrhythmias are often a result of the actions of the autonomic nervous system on the sinus node.
Escape Ectopic Automatic Rhythms
Impairment of the sinus node can allow a latent pacemaker to initiate impulse formation. This would be expected to happen when the rate at which the sinus node overdrives subsidiary pacemakers falls considerably below the intrinsic rate of the latent pacemakers or when the inhibitory electrotonic influences between nonpacemaker cells and pacemaker cells are interrupted.
The rate at which the sinus node activates subsidiary pacemakers can be decreased in certain situations, including sinus node dysfunction, with depressed sinus automaticity (secondary to increased vagal tone, drugs, or intrinsic sinus node disease), sinoatrial exit block, AV block, and parasystolic focus. The sinus node and AVN are most sensitive to vagal influence, followed by atrial tissue, with the ventricular conducting system being least sensitive. Moderate vagal stimulation allows the pacemaker to shift to another atrial site, but severe vagal stimulation suppresses the sinus node and blocks conduction at the AVN and therefore can allow a ventricular escape pacemaker to become manifest.
Interruption of the inhibitory electrotonic influences between nonpacemaker cells and pacemaker cells allows those latent pacemakers to fire at their intrinsic rate. Uncoupling can be caused by fibrosis or damage (e.g., infarction) of the tissues surrounding the subsidiary pacemaker cells or by reduction in gap junction conductance secondary to increased intracellular Ca 2+ , which can be caused by digitalis. Some inhibition of the sinus node is still necessary for the site of impulse initiation to shift to an ectopic site that is no longer inhibited by uncoupling from surrounding cells because the intrinsic firing rate of subsidiary pacemakers is still slower than that of the sinus node.
Accelerated Ectopic Automatic Rhythms
Accelerated ectopic automatic rhythms are caused by enhanced normal automaticity of subsidiary pacemakers. The rate of discharge of these latent pacemakers is then faster than the expected intrinsic automatic rate. Once the enhanced rate exceeds that of the sinus node, the enhanced ectopic pacemaker prevails and overdrives the sinus node and other subsidiary pacemakers. A premature impulse caused by enhanced automaticity of latent pacemakers comes early in the normal rhythm. In contrast, an escape beat secondary to relief of overdrive suppression occurs late in normal rhythm.
Enhanced automaticity is usually caused by increased sympathetic tone, which steepens the slope of diastolic depolarization of latent pacemaker cells and diminishes the inhibitory effects of overdrive. Such sympathetic effects can be localized to subsidiary pacemakers in the absence of sinus node stimulation. Other causes of enhanced normal automaticity include periods of hypoxemia, ischemia, electrolyte disturbances, and certain drug toxicities. There is evidence that in the subacute phase of myocardial ischemia, increased activity of the sympathetic nervous system can enhance automaticity of Purkinje fibers, thus enabling them to escape from sinus node domination.
Parasystole
Parasystole is a result of interaction between two fixed rate pacemakers having different discharge rates. Parasystolic pacemakers can exist in either the atrium or the ventricle. The latent pacemaker is protected from being overdriven by the dominant rhythm (usually NSR) by intermittent or constant entrance block (i.e., impulses of sinus origin fail to depolarize the latent pacemaker secondary to block in the tissue surrounding the latent pacemaker focus).
Various mechanisms have been postulated to explain the protected zone surrounding the ectopic focus. It is possible that the depolarized level of membrane potential at which abnormal automaticity occurs can cause entrance block, leading to parasystole. This would be an example of an arrhythmia caused by a combination of an abnormality of impulse conduction and impulse initiation. However, such block must be unidirectional, so that activity from the ectopic pacemaker can exit and produce depolarization whenever the surrounding myocardium is excitable. The protected pacemaker is said to be a parasystolic focus. In general, under these conditions, a protected focus of automaticity of this type fires at its own intrinsic frequency, and the intervals between the discharges of each pacemaker are multiples of its intrinsic discharge rate (sometimes described as fixed parasystole ). Therefore on the surface electrocardiogram (ECG) the coupling intervals of the manifest ectopic beats wander through the basic cycle of the sinus rhythm. Accordingly, the traditional ECG criteria used to recognize the fixed form of parasystole include: (1) the presence of variable coupling intervals of the manifest ectopic beats; (2) interectopic intervals that are simple multiples of a common denominator; and (3) the presence of fusion beats. Occasionally, the parasystolic focus can exhibit exit block, during which it may fail to depolarize excitable myocardium.
Although the parasystolic focus is protected, it may not be totally immune to the surrounding electrical activity. The effective electrical communication that permits the emergence of the ectopic discharges can also allow the rhythmic activity of the surrounding tissues to electrotonically influence the periodicity of the pacemaker discharge rate (described as modulated parasystole ). Electrotonic influences arriving during the early stage of diastolic depolarization result in a delay in the firing of the parasystolic focus, whereas those arriving late accelerate the discharge of the parasystolic focus. As a consequence, the dominant pacemaker can entrain the partially protected parasystolic focus and force it to discharge at periods that may be faster or slower than its own intrinsic cycle and give rise to premature discharges whose patterns depend on the degree of modulation and the basic heart rate, occasionally mimic reentry, and occur at fixed coupling intervals. Therefore appropriate diagnosis of modulated parasystole relies on the construction of a phase response curve as theoretical evidence of modulation of the ectopic pacemaker cycle length (CL) by the electrotonic activity generated by the sinus discharges across the area of protection.
All these features of abnormal automaticity can be found in the Purkinje fibers that survive in regions of transmural MI and cause ventricular arrhythmias during the subacute phase.
Arrhythmias Caused by Abnormal Automaticity
There appears to be an association between abnormal Purkinje fiber automaticity and the arrhythmias that occur during the acute phase of MI (e.g., an accelerated idioventricular rhythm). However, the role of abnormal automaticity in the development of ventricular arrhythmias associated with chronic ischemic heart disease is less certain. In addition, isolated myocytes obtained from hypertrophied and failing hearts have been shown to manifest spontaneous diastolic depolarization and enhanced I f , findings, suggesting that abnormal automaticity can contribute to the occurrence of some arrhythmias in heart failure and ventricular hypertrophy.
Abnormal automaticity can underlie atrial tachycardia, accelerated idioventricular rhythms, and ventricular tachycardia (VT), particularly that associated with ischemia and reperfusion. It has also been suggested that injury currents at the borders of ischemic zones can depolarize adjacent nonischemic tissue, thus predisposing to automatic VT.
Although automaticity is not responsible for most clinical tachyarrhythmias, which are usually caused by reentry or triggered activity, normal or abnormal automaticity can lead to arrhythmias caused by nonautomatic mechanisms. Premature beats, caused by automaticity, can initiate reentry. Rapid automatic activity in sites such as the cardiac veins can cause fibrillatory conduction, reentry, and atrial fibrillation (AF).
Triggered Activity
Triggered activity is impulse initiation in cardiac fibers caused by afterdepolarizations that occur consequent to a preceding impulse or series of impulses. Afterdepolarizations are depolarizing oscillations in membrane potential that follow the upstroke of a preceding action potential. Afterdepolarizations can occur early during the repolarization phase of the action potential (early afterdepolarization [EAD]) or late, after completion of the repolarization phase (delayed afterdepolarization [DAD]) ( Fig. 3.4 ). When either type of afterdepolarization is large enough to reach the threshold potential for activation of a regenerative inward current, a new action potential is generated, which is referred to as triggered .
Unlike automaticity, triggered activity is not a self-generating rhythm. Instead, triggered activity occurs as a response to a preceding impulse (the trigger). Automatic rhythms, on the other hand, can arise de novo in the absence of any prior electrical activity.
Delayed Afterdepolarizations and Triggered Activity
DADs are oscillations in membrane voltage that occur after completion of repolarization of the action potential (i.e., during phase 4). The transient nature of the DAD distinguishes it from normal spontaneous diastolic (pacemaker) depolarization, during which the membrane potential declines almost monotonically until the next action potential occurs. DADs may or may not reach threshold. Subthreshold DADs do not initiate action potentials or trigger arrhythmias. When a DAD does reach threshold, only one triggered action potential occurs ( Fig. 3.5 ). The triggered action potential can also be followed by a DAD that, again, may or may not reach threshold and may or may not trigger another action potential. The first triggered action potential is often followed by a short or long train of additional triggered action potentials, each arising from the DAD caused by the previous action potential.
Ionic Basis of Delayed Afterdepolarizations
DADs usually occur under a variety of conditions in which Ca 2+ overload develops in the cytoplasm and sarcoplasmic reticulum. During the plateau phase of the normal action potential, Ca 2+ flows through voltage-dependent L-type Ca 2+ channels (I CaL ). Although the rise in intracellular Ca 2+ is small and not sufficient to induce contraction, the small amount of Ca 2+ entering the cell via I CaL triggers a massive release of Ca 2+ from the sarcoplasmic reticulum (the major store for Ca 2+ ) into the cytosol by opening the RyR2 channels (present in the membrane of the sarcoplasmic reticulum) in a process known as calcium-induced calcium release (CICR). During electrical diastole, most of the surplus Ca 2+ in the cytosol is resequestered into the sarcoplasmic reticulum by the sarcoplasmic/endoplasmic reticulum calcium adenosine triphosphatase (SERCA), the activity of which is controlled by the phosphoprotein phospholamban. In addition, some of the Ca 2+ is extruded from the cell by the Na + -Ca 2+ exchanger to balance the Ca 2+ that enters via I CaL . Recurring Ca 2+ release-uptake cycles provide the basis for periodic elevations of the cytosolic Ca 2+ concentration and contractions of myocytes, hence for the orderly beating of the heart ( Fig. 3.6 ).
Under various pathological conditions, Ca 2+ concentration in the sarcoplasmic reticulum can rise to a critical level during repolarization (i.e., Ca 2+ overload), at which time a secondary spontaneous release of Ca 2+ from the sarcoplasmic reticulum occurs after the action potential, rather than as a part of excitation-contraction coupling. This secondary release of Ca 2+ results in inappropriately timed Ca 2+ transients and contractions. Spontaneous Ca 2+ waves can be arrhythmogenic; they induce Ca 2+ -dependent depolarizing membrane currents (transient inward current [I ti ]), mainly by activation of the Na + -Ca 2+ exchanger. Increases in intracellular Ca 2+ levels can stimulate the Na + -Ca 2+ exchanger (I Na-Ca ), which exchanges three Na + ions for one Ca 2+ ion; the direction depends on the Na + and Ca 2+ concentrations on the two sides of the membrane and the E m difference. At resting E m and during a spontaneous sarcoplasmic reticulum Ca 2+ release event, this exchanger operates in the forward mode (three Na + ions in for one Ca 2+ ion out) and generates a net Na + influx, causing transient oscillations of the membrane potential (DADs). After one or several DADs, myoplasmic Ca 2+ can decrease because the Na + -Ca 2+ exchanger extrudes Ca 2+ from the cell, and the membrane potential stops oscillating.
When the DADs are of low amplitude ( subthreshold DAD), they usually are not apparent or clinically significant. However, during pathological conditions (e.g., myocardial ischemia, acidosis, hypomagnesemia, digitalis toxicity, and increased catecholamines), the amplitude of the Ca 2+ -mediated membrane depolarization is increased and can reach the stimulation threshold ( suprathreshold DAD) and an action potential is triggered (called triggered activity ). If this process continues, sustained tachycardia will develop. Triggered action potentials can also initiate reentry when they encounter a vulnerable tissue substrate.
Probably the most important influence that causes subthreshold DADs to reach threshold is a decrease in the initiating CL because that increases both the amplitude and rate of the DADs. Therefore initiation of arrhythmias triggered by DADs can be facilitated by a spontaneous or pacing-induced increase in the heart rate.
Subthreshold DADs can also play a role in arrhythmogenesis by partially depolarizing the cell membrane and hence inactivating a portion of Na + channels and reducing their availability during the subsequent (triggered or nontriggered) action potential. The resultant regional dispersion of excitability or refractoriness can generate a tissue substrate vulnerable to unidirectional conduction block and reentry.
Role of Delayed Afterdepolarizations in Arrhythmogenesis
A suprathreshold DAD can trigger an action potential and generate triggered activity, which can cause focal, nonreentrant arrhythmias (triggered activity atrial or ventricular ectopic beats or tachycardia) or, when it encounters a vulnerable tissue substrate, the triggered action potential can act as a trigger for initiation of reentrant arrhythmias.
Both suprathreshold and subthreshold DADs can potentially generate a vulnerable substrate and promote reentry by regionally decreasing excitability sufficiently to cause regional conduction block of a subsequent nontriggered action potential. In addition, when both subthreshold and suprathreshold DADs coexist in the same tissue, the combination of triggers and a vulnerable substrate can lead directly to reentry initiation. DADs can potentially generate both a vulnerable substrate that promotes reentry, as well as a trigger for initiation of reentrant arrhythmias. In some regions, suprathreshold DADs can trigger an action potential, whereas in other regions, subthreshold DADs promoting regional conduction block. Once the triggered action potential propagates to the region of conduction block, it may initiate reentry.
DAD-related triggered activity is thought to be a mechanism for tachyarrhythmia associated with MI, reperfusion injury, digitalis toxicity, and some idiopathic VTs, as well as some arrhythmias associated with inherited channelopathies. DADs are more likely to occur with fast spontaneous or paced rates or with increased premature beats.
Digitalis.
Digitalis causes DAD-dependent triggered arrhythmias by inhibiting the Na + -K + exchange pump. In toxic amounts, this effect results in the accumulation of intracellular Na + and consequently an enhancement of the Na + -Ca 2+ exchanger in the reverse mode (three Na + ions out for one Ca 2+ ion in) and an accumulation of intracellular Ca 2+ . Spontaneously occurring accelerated ventricular arrhythmias that occur during digitalis toxicity are likely to be caused by DADs. Triggered ventricular arrhythmias caused by digitalis also can be initiated by pacing at rapid rates. As toxicity progresses, the duration of the trains of repetitive responses induced by pacing increases.
Catecholamines.
Catecholamines can facilitate the development of DADs by increasing intracellular Ca 2+ overload via several mechanisms, including (1) increasing the I CaL through stimulation of beta-adrenergic receptors and increasing cAMP, which results in an increase in transsarcolemmal Ca 2+ influx and intracellular Ca 2+ overload (see Fig. 3.6 ); (2) enhancing the activity of the Na + -Ca 2+ exchanger, thus increasing the likelihood of DAD-mediated triggered activity; (3) enhancing the uptake of Ca 2+ by the sarcoplasmic reticulum, leading to increased Ca 2+ stored in the sarcoplasmic reticulum and the subsequent release of an increased amount of Ca 2+ from the sarcoplasmic reticulum during contraction; and (4) increasing the heart rate.
Sympathetic stimulation can potentially cause triggered atrial and ventricular arrhythmias and possibly underlies some of the ventricular arrhythmias that accompany exercise and those occurring during ischemia and infarction.
Myocardial ischemia.
Elevations in intracellular Ca 2+ in the ischemic myocardium are also associated with DADs and triggered arrhythmias. Accumulation of lysophosphoglycerides in the ischemic myocardium, with consequent Na + and Ca 2+ overload, has been suggested as a mechanism for DADs and triggered activity. Cells from damaged areas or surviving the infarction can display spontaneous release of Ca 2+ from sarcoplasmic reticulum, which can generate waves of intracellular Ca 2+ elevation and arrhythmias.
Genetic mutations.
DADs can be caused by genetic defects that impair the ability of the sarcoplasmic reticulum to sequester Ca 2+ during diastole. Mutations in the cardiac RyR2, the sarcoplasmic reticulum Ca 2+ release channel in the heart, have been identified in kindreds with the syndrome of catecholaminergic polymorphic VT and ventricular fibrillation (VF) with short QT intervals. It seems likely that perturbed intracellular Ca 2+ and perhaps also DADs underlie arrhythmias in this syndrome (see Fig. 3.6 ).
Drugs.
Several drugs can inhibit DAD-related triggered activity via different mechanisms, including reduction of the inward Ca 2+ current and intracellular Ca 2+ overload (Ca 2+ channel blockers, beta-adrenergic blockers), reduction of Ca 2+ release from the sarcoplasmic reticulum (caffeine, ryanodine, thapsigargin, cyclopiazonic acid), and reduction of the inward I Na (tetrodotoxin, lidocaine, phenytoin).
Properties of Delayed Afterdepolarizations
The amplitude of DADs and the possibility of triggered activity are influenced by the level of membrane potential at which the action potential occurs. The reduction of the membrane potential during DADs may also result in Na + channel inactivation and hence slowing of conduction.
The duration of the action potential is a critical determinant of the presence of DADs. Longer action potentials, which are associated with more transsarcolemmal Ca 2+ influx, are more likely to be associated with DADs. Drugs that prolong action potential duration (e.g., class IA antiarrhythmic agents) can increase DAD amplitude, whereas drugs that shorten action potential duration (e.g., class IB antiarrhythmic agents) can decrease DAD amplitude.
The number of the action potentials preceding the DAD affects the amplitude of the DAD (i.e., after a period of quiescence, the initiation of a single action potential can be followed by either no DAD or only a small one). With continued stimulation, the DADs increase in amplitude, and triggered activity can eventually occur.
The amplitude of DADs and the coupling interval between the first triggered impulse and the last stimulated impulse that induced them are directly related to the drive CL at which triggered impulses are initiated. A decrease in the basic drive CL (even a single drive cycle; i.e., premature impulse), in addition to increasing the DAD amplitude, results in a decrease in the coupling interval between the last drive cycle and the first DAD-triggered impulse, with respect to the last driven action potential, and an increase of the rate of DADs. Triggered activity tends to be induced by a critical decrease in the drive CL, either spontaneous, such as in sinus tachycardia, or pacing induced. The increased time during which the membrane is in the depolarized state at shorter stimulation CLs or after premature impulses increases Ca 2+ in the myoplasm and the sarcoplasmic reticulum (because of repeated activation of I CaL ), thus increasing the I ti responsible for the increased DAD amplitude, causing the current to reach its maximum amplitude more rapidly, and decreasing the coupling interval of triggered impulses. This characteristic property can help to distinguish triggered activity from reentrant activity because the relationship for reentry impulses initiated by rapid stimulation is often the opposite (i.e., as the drive CL is reduced, the first reentrant impulse occurs later with respect to the last driven action potential because of rate-dependent conduction slowing in the reentrant pathway).
In general, triggered activity is markedly influenced by overdrive pacing. These effects are dependent on both the rate and the duration of overdrive pacing. When overdrive pacing is performed for a critical duration of time and at a critical rate during a catecholamine-dependent triggered rhythm, the rate of triggered activity slows until the triggered rhythm stops, because of enhanced activity of the electrogenic Na + -K + exchange pump induced by the increase in intracellular Na + caused by the increased number of action potentials. When overdrive pacing is not rapid enough to terminate the triggered rhythm, it can cause overdrive acceleration (in contrast to overdrive suppression observed with automatic rhythms). Single premature stimuli also can terminate triggered rhythms, although termination is much less common than it is by overdrive pacing.
EADs and triggered activity.
EADs are oscillations in membrane potential that occur during the action potential and interrupt the orderly repolarization of the cardiomyocyte. EADs manifest as an abrupt change in the time course of repolarization of an action potential such that the membrane voltage suddenly shifts in a depolarizing direction.
Ionic Basis of Early Afterdepolarizations
Normal cardiac repolarization relies on a critical balance between depolarizing inward currents and repolarizing outward currents during the action potential plateau. Repolarization has built-in redundancy (“repolarization reserve”) to protect against excessive prolongation of the action potential duration. The plateau of the action potential is a time of high membrane resistance (i.e., membrane conductance to all ions falls to rather low values), when there is little current flow. Consequently, small changes in repolarizing or depolarizing currents can have profound effects on the action potential duration and profile. Normally, during phases 2 and 3, the net membrane current is outward. Any factor that transiently shifts the net current in the inward direction can potentially overcome and reverse repolarization (a condition termed “reduced repolarization reserve”) and lead to EADs and EAD-related arrhythmias. Such a shift can arise from decreased outward (repolarizing) currents (mostly carried by K + at that time), increased inward (depolarizing) currents (carried by Na + or Ca 2+ at that time), or both. However, although reduced repolarization reserve is sufficient to prolong action potential duration, it is not sufficient to produce EADs. Other conditions are required to generate the voltage oscillations pathognomonic of EADs, which arise from different causes. The most critical to the dynamics of EAD oscillations include window I CaL , late I Na , and I Ks . In addition, EADs can also be promoted by intracellular Ca 2+ oscillations or by prolonged Ca 2+ transients via Na + -Ca 2+ exchanger current (I Na-Ca ).
EADs have been classified as phase 2 (occurring at the plateau level of membrane potential) and phase 3 (occurring during phase 3 of repolarization) (see Fig. 3.4 ). The ionic mechanisms of phase 2 and phase 3 EADs and the upstrokes of the action potentials they elicit can differ. At the depolarized membrane voltages of phase 2, Na + channels are inactivated; hence the I CaL and I Na-Ca are the major currents potentially responsible for EADs. Voltage steady-state activation and inactivation of the L-type Ca 2+ channels are sigmoidal, with an activation range over −40 to +10 mV (with a half-activation potential near −15 mV) and a half-inactivation potential near −35 mV. However, a relief of inactivation for voltages positive to 0 mV leads to a U -shaped voltage curve for steady-state inactivation. Overlap of the steady-state voltage-dependent inactivation and activation relations defines a “window” current near the action potential plateau, within which transitions from closed and open states can occur. As the action potential repolarizes into the window region, I CaL increases and can potentially be sufficient to reverse repolarization, thus generating the EAD upstroke ( Fig. 3.7 ).
