Electrophysiological mechanisms of cardiac arrhythmias

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 the 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 then 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 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 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. 4.1 ) (see Chapter 2 ).

The ionic mechanisms responsible for normal pacemaker activity in the sinus node are still being investigated. 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. 4.2 ).

FIG. 4.2, Ionic Currents Involved in Producing the Sinus Node Pacemaker Potential.

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 the 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 (NCX, I _NCX ) 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. The hyperpolarization-activated cyclic nucleotide-gated (HCN) channels, which mediate I _f , 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 (HCN) 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 I _NCX 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 releases of Ca ² ⁺ 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 NCX operating in the forward mode (one Ca ² ⁺ out for three Na ⁺ in). This generates a net inward membrane current (I _NCX ) 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 the generation of the rapid upstroke of the next action potential (see Fig. 2.8 ). Although regulated by membrane potential and submembrane Ca ² ⁺ , the NCX does not have time-dependent gating, as do ion channels, but generates an inward current almost instantaneously when submembrane Ca ² ⁺ concentration increases. As a result, the rate and size of local Ca ² ⁺ releases, and the balance between Ca ² ⁺ reuptake into the sarcoplasmic reticulum (through sarcoplasmic reticulum calcium adenosine triphosphatase [SERCA] pump) and extrusion through the NCX are key determinants of the rate of diastolic depolarization.

FIG. 4.8, Mechanisms Underlying Early Afterdepolarizations (EADs).

Such rhythmic, spontaneous intracellular Ca ² ⁺ cycling has been referred to as an intracellular calcium clock . Phosphorylation-dependent gradation of the speed at which the calcium clock cycles is the essential regulatory mechanism of normal pacemaker rate and rhythm.

Coupled clocks

Regulation of sinus node automaticity is ensured by the tight integration of the calcium clock and the membrane clock. Together, the coupled clocks form the overall pacemaker clock . Coupling of the two clocks occurs via effects of one on the other and through the mutual entrainment of membrane ion channel activity and Ca ² ⁺ cycling by intracellular regulatory mechanisms. While I _f is an important activator of the membrane clock at the beginning of diastolic depolarization, I _CaL and I _NCX cooperate in the last part of diastolic depolarization to drive the membrane voltage to the action potential threshold. During the action potential phase, Ca ² ⁺ entry via the voltage-gated L-type Ca ² ⁺ channels restores sarcoplasmic reticulum Ca ² ⁺ load, allowing new diastolic local Ca ² ⁺ releases to occur in the following cycle. Spontaneous local Ca ² ⁺ releases are generated by early diastolic openings of ryanodine receptors that activate the NCX, which generates an inward current (I _NCX ) that contributes to diastolic depolarization. Additionally, high basal intracellular cyclic adenosine monophosphate (cAMP) concentrations and elevated activity of protein kinases contribute to mutual entrainment between diastolic RyR-dependent Ca ² ⁺ release underlying the calcium clock and the membrane clock. ^,

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. ^,

Of note, 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 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 pacemaking 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. 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., secondary to 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 and inferior vena cava, near or on the eustachian ridge, near the ostium of the coronary sinus, 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) atrial 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 atrioventricular 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, whereby Purkinje fibers exhibit 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 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 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 ( Fig. 4.3 ). 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.

FIG. 4.3, Abnormalities of Automaticity.

The sinus node is densely innervated with postganglionic adrenergic and cholinergic nerve terminals (threefold greater density of β ₁ -adrenergic and muscarinic cholinergic receptors than on adjacent atrial tissue). The balance between the two divisions of the autonomic nervous system importantly controls the pacemaker rate. The classic concept has been that of a reciprocal relationship between sympathetic and parasympathetic inputs. More recent investigations, however, stress dynamic, demand-oriented interactions, and the anatomical distribution of fibers that allows both autonomic systems to act quite selectively. Muscarinic cholinergic and β ₁ -adrenergic receptors are nonuniformly distributed in the sinus node, and they modulate both the rate of depolarization and impulse propagation.

In healthy, resting individuals, parasympathetic influences usually predominate over sympathetic effects at the sinus node. When both divisions of the autonomic nervous system are completely blocked (e.g., by the muscarinic receptor antagonist atropine and the β-adrenergic receptor antagonist propranolol), the sinus rate increases as compared to baseline. The rate that prevails after complete autonomic blockade is known as the intrinsic heart rate .

Sympathetic activity

Increased sympathetic nerve traffic and the adrenomedullary release of catecholamines (norepinephrine and epinephrine) increase the sinus node discharge rate. Catecholamines act through β ₁ -adrenergic receptors to activate stimulatory G proteins (G _s ), which bind and activate the membrane-bound adenylate cyclase. Adenylate cyclase, in turn, enhances the production of cAMP, which activates protein kinase A, with the consequent phosphorylation of multiple target proteins including L-type Ca ² ⁺ channels and the sarcoplasmic reticulum Ca ² ⁺ handling protein phospholamban. As a result, β ₁ -receptor stimulation enhances I _CaL , which increases the slope of diastolic depolarization and enhances pacemaker activity ( Fig. 4.3 ). 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 K ⁺ current results in a further net increase in inward current.

Catecholamines also enhance the inward I _f current, thus augmenting the slope of phase 4 and increasing the rate of sinus node firing. These effects are mediated by cAMP, which directly binds to HCN channels and shifts the I _f activation curve to more positive voltages. In addition to effects on membrane currents, there is also evidence of a role of alterations in calcium clock components in the response to β ₁ -receptor activation. ^,

In addition to altering components of membrane and calcium clocks, changes in autonomic tone can produce changes in the rate of sinus node discharge 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 (and change in P wave morphology). 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 β ₁ -adrenergic stimulation and the parasympathetic nervous system inhibiting pacemaker activity through muscarinic receptor stimulation.

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 inhibitory G proteins (G _i ), which subsequently results in the 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 ( Fig. 4.3 ).

In addition, activation of the G _i protein results in the inhibition of β-receptor-stimulated adenylate cyclase activity, thus reducing cAMP and inhibiting protein kinase A, with consequent inhibition of the inward current I _CaL . This results in the reduction of the rate of diastolic depolarization because of less Ca ² ⁺ entry and subsequent slowing of the pacemaker activity. Inhibition of β-receptor-stimulated adenylate cyclase activity can also inhibit the inward I _f current.

It is important to note that vagal effects on sinus and AV nodal function have a very brief latency (≈50–100 milliseconds) and they decay very quickly when vagal stimulation is discontinued. The fast response to vagal stimulation is related to the fact that acetylcholine acts through M ₂ muscarinic receptors to activate I _KACh channels. These channels open quickly because the muscarinic receptor is coupled directly to the channel by a guanine nucleotide–binding protein, and no cytosolic components are required for current activation. On the other hand, the rapid decay of the response is related to the abundance of acetylcholinesterase in the sinus and AV nodes, an enzyme that rapidly hydrolyzes the neurotransmitter acetylcholine.

In contrast, the onset of the cardiac response to sympathetic stimulation is slower than that in response to vagal stimulation. This is related to the fact that norepinephrine is released slowly from the sympathetic nerve terminals, and its effects are mediated mainly by a relatively slow second messenger system involving cAMP. Further, the effects of sympathetic stimulation dissipate gradually after stimulation is stopped due to the slower process of elimination of the released norepinephrine (via reuptake by nerve terminals or by the bloodstream). Therefore, while the parasympathetic system is able to exert beat-by-beat modulation of sinus and AV nodal function, sympathetic activity alters the heart rate and AV conduction relatively slowly.

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, 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. Also, 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. Additionally, 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. A greater increase in extracellular K ⁺ , however, 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 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 resting membrane potentials (−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 ( Fig. 4.3 ). 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. It can, however, 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 normal and abnormal automaticity is that the membrane potentials of fibers showing the abnormal type of activity are reduced from their own normal levels. 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 Na ⁺ current (through the NCX), 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 less negative the membrane potential, the faster the automatic rate ( Fig. 4.3 ). 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. The circumstance under which membrane depolarization occurs, however, 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 AV junction and Purkinje fibers by several mechanisms. During sinus rhythm in the normal heart, the intrinsic automatic rate of the sinus node is faster than that of the other potentially automatic cells. As a result, 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. Phase 4 diastolic depolarization of 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. 4.4 ).

FIG. 4.4, Overdrive Suppression of Automaticity.

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, 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 faster the overdrive rate and the longer the duration of overdrive, the greater the enhancement of pump activity, and the longer the period of quiescence after the cessation of overdrive.

The sinus node itself also is vulnerable to overdrive suppression. When overdrive suppression of the normal sinus node occurs, however, 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; hence 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. The diseased sinus node, however, 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 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 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 NCX and Ca ² ⁺ channel phosphorylation, thus increasing Na ⁺ load and, as a result, enhancing 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 ⁺ 1current.

In addition to overdrive suppression being of paramount importance for the maintenance of normal sinus rhythm, 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 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 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 the 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 sinus rhythm) 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. Such block, however, must be unidirectional so that activity from the ectopic pacemaker can exit and produce depolarization whenever the surrounding myocardium is excitable. In this setting, 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

Abnormal automaticity is the underlying mechanism for some atrial tachycardias, accelerated idioventricular rhythms, and some ventricular tachycardias (VTs), 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.

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. Additionally, 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.

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.

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