Pacemaker Mechanisms

Normal automaticity involves a spontaneous, slow, progressive decline (less negative) in the transmembrane potential during diastole (spontaneous diastolic depolarization or phase 4 depolarization) (see Chap. 1). Once this spontaneous depolarization reaches threshold (approximately −40 mV), a new action potential is generated.²

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., inward depolarizing current; Fig. 3-1).^1–6

FIGURE 3-1 Normal cardiac automaticity. Action potentials from typical sinus nodal and His-Purkinje cells are shown with the voltage scale on the vertical axes; dashed lines are threshold potential, and numbers on the figure refer to phases of the action potential. Note the qualitative differences between the two types of cells, as well as different rates of spontaneous depolarization. Ca²⁺ = calcium; Na⁺ = sodium.

Originally, a major role was attributed to the decay of the delayed K⁺ conductance (an outward current) activated during the preceding action potential, (the I_K-decay theory). This model of pacemaker depolarization lost interest on the discovery of the pacemaker current (I_f). Other ionic currents gated by membrane depolarization (i.e., L-type and T-type calcium [Ca²⁺] currents), nongated and nonspecific background leak currents, and a current generated by the sodium (Na⁺)–Ca²⁺ exchanger, were also proposed to be involved in pacemaking.

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 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 approximately −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 Ca²⁺ current activates to initiate the action potential.⁷ 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, 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.^2,5,8–10

On the other hand, several studies have shown 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 node cells are strongly modulated by Ca²⁺ and phosphorylation, a finding suggesting that intracellular Ca²⁺ 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⁺-Ca²⁺ exchanger current activated by submembrane spontaneous rhythmic local Ca²⁺ releases from the sarcoplasmic reticulum, a major Ca²⁺ store within sinus node cells, via ryanodine receptors (RyR2). Activation of the local oscillatory Ca²⁺ releases is independent of membrane depolarization and is driven by a high level of basal state phosphorylation of Ca²⁺ cycling proteins. Critically timed Ca²⁺ releases occur during the later phase of diastolic depolarization and activate the forward mode of the Na⁺-Ca²⁺ exchanger (one Ca²⁺ for three Na⁺). The result is in an 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 Ca²⁺ channels and leading to generation of the rapid upstroke of the next action potential (see Fig. 1-3).Although regulated by membrane potential and submembrane Ca²⁺, the Na⁺-Ca²⁺ exchanger does not have time-dependent gating, as do ion channels, but generates an inward current almost instantaneously when submembrane Ca²⁺ concentration increases.^8,9,11

Such rhythmic, spontaneous intracellular Ca²⁺ cycling has been referred to as an “intracellular Ca²⁺ clock.” Phosphorylation-dependent gradation of the speed at which Ca²⁺ 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 Ca²⁺ clock and the classic sarcolemmal “ion channel clock” (formed by voltage-dependent membrane ion channels) to form the overall pacemaker clock. The action potential shape and ion fluxes are tuned by membrane clocks to sustain operation of the Ca²⁺ clock, which produces timely and powerful ignition of the membrane clocks to effect action potentials.

There is some degree of uncertainty about the relative role of I_f versus that of intracellular Ca²⁺ 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 Ca²⁺ clock and the cellular mechanisms underlying this internal Ca²⁺ clock are not completely elucidated.^8,9,11

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.¹ 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 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

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 or slope of phase 4 depolarization (Fig. 3-2). 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.¹

FIGURE 3-2 Abnormalities of automaticity. A, Normal His-Purkinje action potential. B, Modulation of rate of depolarization from baseline (1) by slowing rate of phase 4 depolarization (2), increasing threshold potential (3), starting from a more negative resting membrane potential (4), all of which slow discharge rate, or by increasing rate of phase 4 depolarization (5), thus yielding a faster discharge rate. C, Abnormal automaticity with change in action potential contour (resembling sinus nodal cell) when resting membrane potential is less negative, inactivating most sodium channels.

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. 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 beta₁-adrenergic receptors are nonuniformly distributed in the sinus node, and they modulate both the rate of depolarization and impulse propagation.¹

Sympathetic Activity

Increased sympathetic nerve traffic and the adrenomedullary release of catecholamines increase sinus node discharge rate. Stimulation of beta₁-receptors by catecholamines enhances the L-type of inward Ca²⁺ current (I_CaL) by increasing cAMP and activating the protein kinase A system; the increment in inward Ca²⁺ current increases the slope of diastolic depolarization and enhances pacemaker activity (see Fig. 3-2). The redistribution of Ca²⁺ can also increase the completeness and the rate of deactivation of the rapid (I_Kr) and slow (I_Ks) components of the delayed rectifier I_K; 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.¹⁰

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 beta₁-adrenergic stimulation and the parasympathetic nervous system inhibiting pacemaker activity through muscarinic receptor stimulation.¹

Suppression of Normal and Abnormal Automatic Subsidiary Pacemakers

The sinus node likely maintains its dominance over subsidiary pacemakers in the AVN and the Purkinje fibers 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.¹ 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).

FIGURE 3-3 Overdrive suppression of automaticity. A spontaneously firing cell is paced more rapidly, resulting in depression of resting membrane potential; after pacing is stopped, spontaneous depolarization takes longer than usual and gradually resumes baseline rate. Dashed line = threshold potential.

Mechanism of Overdrive Suppression

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, because more Na⁺ enters the cell per unit time.¹ 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. Additionally, 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. 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; 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 can be 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 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 Ca²⁺ loading. Such Ca²⁺ loading can activate Ca²⁺-dependent K⁺ conductance (favoring repolarization) and promote Ca²⁺ extrusion through the Na⁺-Ca²⁺ exchanger and Ca²⁺ channel phosphorylation, thus increasing Na⁺ load and thus Na⁺-K⁺ exchange pump activity. The increase in intracellular Ca²⁺ load can also reduce the depolarizing I_CaL by promoting Ca²⁺-induced inactivation of the Ca²⁺ 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.

Inappropriate Sinus Node Discharge

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. Examples of these arrhythmias include sinus bradycardia, sinus arrest, inappropriate sinus tachycardia, and respiratory sinus arrhythmia. Respiratory sinus arrhythmia is primarily caused by withdrawal of vagal tone during inhalation and reinstitution of vagal tone during exhalation.

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 Ca²⁺, 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. Such block, however, 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 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 are (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.¹⁷

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.¹⁷

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. 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 left 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, 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).

Ionic Basis of Delayed Afterdepolarizations

DADs usually occur under a variety of conditions in which Ca²⁺ overload develops in the cytoplasm and sarcoplasmic reticulum. During the plateau phase of the normal action potential, Ca²⁺ flows through voltage-dependent L-type Ca²⁺ channels (I_CaL). Although the rise in intracellular Ca²⁺ is small and not sufficient to induce contraction, the small amount of Ca²⁺ entering the cell via I_CaL triggers a massive release of Ca²⁺ from the sarcoplasmic reticulum (the major store for Ca²⁺) into the cytosol by opening the RyR2 channels (present in the membrane of the sarcoplasmic reticulum) in a process known as Ca²⁺-induced Ca²⁺ release (CICR).^1,6 During repolarization (i.e., diastole), most of the surplus Ca²⁺ in the cytosol is resequestered into the sarcoplasmic reticulum by the sarcoplasmic reticulum Ca²⁺ adenosine triphosphatase (SERCA), the activity of which is controlled by the phosphoprotein phospholamban. Additionally, some of the Ca²⁺ is extruded from the cell by the Na⁺-Ca²⁺ exchanger to balance the Ca²⁺ that enters with Ca²⁺ current. Recurring Ca²⁺ release-uptake cycles provide the basis for periodic elevations of the cytosolic Ca²⁺ concentration and contractions of myocytes, hence for the orderly beating of the heart (Fig. 3-6).^18–20

FIGURE 3-6 Signal transduction schema for initiation and termination of cyclic adenosine monophosphate (cAMP)-mediated triggered activity. See text for discussion. AC = adenylyl cyclase; ACh = acetylcholine; ADO = adenosine; A₁R = alpha₁-adenosine receptor; ATP = adenosine triphosphate; β-AR = beta-adrenergic receptor; Ca = calcium; CCB = calcium channel blocker; DAD = delayed afterdepolarization; G_αi = inhibitory G protein; G_αs = stimulatory G protein; GDP = guanosine diphosphate; GTP = guanosine triphosphate; I_ti = transient inward current; M₂R = muscarinic receptor; Na = sodium; NCX = sodium (Na⁺)-calcium (Ca²⁺) exchanger; PLB = phospholamban; PKA = protein kinase A; RyR = ryanodine receptor; SR = sarcoplasmic reticulum.

(From Lerman BB: Mechanism of outflow tract tachycardia. Heart Rhythm 4:973, 2007.)

Under various pathological conditions, Ca²⁺ concentration in the sarcoplasmic reticulum can rise to a critical level during repolarization (i.e., Ca²⁺ overload), at which time a secondary spontaneous release of Ca²⁺ from the sarcoplasmic reticulum occurs after the action potential, rather than as a part of excitation-contraction coupling. This secondary release of Ca²⁺ results in inappropriately timed Ca²⁺ transients and contractions. Spontaneous Ca²⁺ waves are arrhythmogenic; they induce Ca²⁺-dependent depolarizing membrane currents (transient inward current), mainly by activation of the Na⁺-Ca²⁺ exchanger, thereby causing oscillations of the membrane potential known as DADs. After one or several DADs, myoplasmic Ca²⁺ can decrease because the Na⁺-Ca²⁺ exchanger extrudes Ca²⁺ from the cell, and the membrane potential stops oscillating.^18–20

When the DADs are of low amplitude, 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 Ca²⁺-mediated oscillations is increased and can reach the stimulation threshold, and an action potential is triggered. If this process continues, sustained tachycardia will develop. 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.

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, consequentially, an enhancement of the Na⁺-Ca²⁺ exchanger in the reverse mode (Na⁺ removal, Ca²⁺ entry) and an accumulation of intracellular Ca²⁺.¹⁶ 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 can cause DADs by increasing intracellular Ca²⁺ overload secondary to different mechanisms. Catecholamines increase the slow, inward I_CaL through stimulation of beta-adrenergic receptors and increasing cAMP, which result in an increase in transsarcolemmal Ca²⁺ influx and intracellular Ca²⁺ overload (see Fig. 3-6). Catecholamines can also enhance the activity of the Na⁺-Ca²⁺ exchanger, thus increasing the likelihood of DAD-mediated triggered activity. Additionally, catecholamines enhance the uptake of Ca²⁺ by the sarcoplasmic reticulum and lead to increased Ca²⁺ stored in the sarcoplasmic reticulum and the subsequent release of an increased amount of Ca²⁺ from the sarcoplasmic reticulum during contraction.¹⁶ Sympathetic stimulation can potentially cause triggered atrial and ventricular arrhythmias, possibly some of the ventricular arrhythmias that accompany exercise and those occurring during ischemia and infarction.

Elevations in intracellular Ca²⁺ in the ischemic myocardium are also associated with DADs and triggered arrhythmias. Accumulation of lysophosphoglycerides in the ischemic myocardium, with consequent Na⁺ and Ca²⁺ 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 Ca²⁺ from sarcoplasmic reticulum, which can generate waves of intracellular Ca²⁺ elevation and arrhythmias.^19,20

Abnormal sarcoplasmic reticulum function caused by genetic defects that impair the ability of the sarcoplasmic reticulum to sequester Ca²⁺ during diastole can lead to DADs and be the cause of certain inherited ventricular tachyarrhythmias. Mutations in the cardiac RyR2, the sarcoplasmic reticulum Ca²⁺ 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 Ca²⁺, and perhaps also DADs, underlie arrhythmias in this syndrome (see Fig. 3-6).^18,21

Several drugs can inhibit DAD-related triggered activity via different mechanisms, including reduction of the inward Ca²⁺ current and intracellular Ca²⁺ overload (Ca²⁺ channel blockers, beta-adrenergic blockers; see Fig. 3-6), reduction of Ca²⁺ release from the sarcoplasmic reticulum (caffeine, ryanodine, thapsigargin, cyclopiazonic acid), and reduction of the inward I_Na (tetrodotoxin, lidocaine, phenytoin).

DAD-related triggered activity is thought to be a mechanism for tachyarrhythmia associated with MI, reperfusion injury, some right ventricular outflow tract tachycardia, and some atrial tachyarrhythmias. DADs are more likely to occur with fast spontaneous or paced rates or with increased premature beats.^15,18,20,22

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 a 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 Ca²⁺ 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; that is, 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 Ca²⁺ in the myoplasm and the sarcoplasmic reticulum, thus increasing the transient inward current responsible for the increased afterdepolarization amplitude, causing the current to reach its maximum amplitude more rapidly, and decreasing the coupling interval of triggered impulses. The repetitive depolarizations can increase intracellular Ca²⁺ because of repeated activation of I_CaL. This characteristic property can help distinguish triggered activity from reentrant activity because the relationship for reentry impulses initiated by rapid stimulation is often the opposite; that is, 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 influenced markedly 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.

Ionic Basis of Early Afterdepolarizations

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 and lead to EADs. Such a shift can arise from blockage of the outward current, carried by Na⁺ or Ca²⁺ at that time, or enhancement of the inward current, mostly carried by K⁺ at that time.¹

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.¹ At the depolarized membrane voltages of phase 2, Na⁺ channels are inactivated; hence, the I_CaL and Na⁺-Ca²⁺ exchanger current are the major currents potentially responsible for EADs. Voltage steady-state activation and inactivation of the L-type Ca²⁺ 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).²³

FIGURE 3-7 A, Normal action potential (left) and an action potential with phase 2 early afterdepolarization (EAD) (solid line) or phase 3 EAD (dashed line) (right)B, Schematic plot of L-type calcium (Ca²⁺) channel conductance (G_Ca,L) versus membrane voltage (mV) showing the window L-type inward Ca²⁺ current (I_Ca,L) region (purple area) where the steady-state activation (SSA) and steady-state inactivation (SSI) curves overlap and a fraction of Ca channels remain continuously open. Dashed lines show a potential therapeutic intervention that shifts the SSA and SSI curves to reduce the overlapping window current region. C, Schematic diagram illustrating the interaction between time-dependent I_Ca,L reactivation (blue dashed lines) and time-dependent deactivation of repolarizing currents (I_K) (dashed red lines) in the window voltage range during action potential repolarization. For the normal action potential (left), the repolarization rate is too fast for I_Ca,L to grow larger than I_K. If the repolarization rate is too slow, however, I_Ca,L can grow larger than I_K, thereby reversing repolarization to cause an EAD (right).

(From Weiss JN, Garfinkel A, Karagueuzian HS, et al: Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm 7:1891-1899, 2010.)

The cardiac Na⁺-Ca²⁺ exchanger exchanges three Na⁺ ions for one Ca²⁺ ion; the direction is dependent on the Na⁺ and Ca²⁺ concentrations on the two sides of the membrane and the transmembrane potential difference. When operating in forward mode, this exchanger generates a net Na⁺ influx, thereby resisting repolarization. The increase in the window I_CaL further increases the Na⁺-Ca²⁺ exchanger, thus possibly facilitating EAD formation and increasing the probability of an EAD-triggered action potential.²³

EADs occurring late in repolarization develop at membrane potentials more negative than −60 mV in atrial, ventricular, or Purkinje cells that have normal resting potentials. Normally, a net outward membrane current shifts the membrane potential progressively in a negative direction during phase 3 repolarization of the action potential. Despite fewer data, it has been suggested that current through the Na⁺-Ca²⁺ exchanger and possibly the I_Na can participate in the activation of phase 3 EADs. Nevertheless, this concept was questioned by a study suggesting that phase 2 EADs appear to be responsible for inducing phase 3 EADs through electrotonic interactions and that a large voltage gradient related to heterogeneous repolarization is essential for phase 3 EADs.^23,24

The upstrokes of the action potentials elicited by phase 2 and phase 3 EADs also differ.¹ Phase 2 EAD-triggered action potential upstrokes are exclusively mediated by Ca²⁺ currents. Even when these triggered action potentials do not propagate, they can substantially exaggerate heterogeneity of the time course of repolarization of the action potential (a key substrate for reentry), because EADs occur more readily in some regions (e.g., Purkinje fibers, mid left ventricular myocardium, right ventricular outflow tract epicardium) than others (e.g., left ventricular epicardium, endocardium). Action potentials triggered by phase 3 EADs arise from more negative membrane voltages. Therefore, the upstrokes can be caused by Na⁺ and Ca²⁺ currents and are more likely to propagate.

Under certain conditions, when an EAD is large enough, the decrease in membrane potential leads to an increase in net inward (depolarizing) current, and a second upstroke or an action potential is triggered before complete repolarization of the first. The triggered action potential also can be followed by other action potentials, all occurring at the low level of membrane potential characteristic of the plateau or at the higher level of membrane potential of later phase 3 (Fig. 3-8). The sustained rhythmic activity can continue for a variable number of impulses and terminates when repolarization of the initiating action potential returns membrane potential to a high level. As repolarization occurs, the rate of the triggered rhythm slows because the rate is dependent on the level of membrane potential. Sometimes repolarization to the high level of membrane potential may not occur, and membrane potential can remain at the plateau level or at a level intermediate between the plateau level and the resting potential. The sustained rhythmic activity then can continue at the reduced level of membrane potential and assumes the characteristics of abnormal automaticity. However, in contrast to automatic rhythms, without the initiating action potential, there can be no triggered action potentials.

FIGURE 3-8 Mixed focal reentrant polymorphic ventricular tachycardia as a result of early afterdepolarization (EAD)-mediated premature ventricular complexes (PVCs) arising from EAD islands in simulated two-dimensional homogeneous tissue. The tissue was paced from the left edge at a slow rate. Four successive voltage snapshots show an EAD (red in upper left quadrant) that generates a PVC (red blob). The PVC then initiates reentry by reentering (white arrow) the receding waveback of the region without EADs (blue blob). The voltage trace below from a representative cell shows multiple EADs followed by rapid tachycardia resulting from a mixture of triggered activity and reentry.

(From Weiss JN, Garfinkel A, Karagueuzian HS, et al: Early afterdepolarizations and cardiac arrhythmias. Heart Rhythm 7:1891-1899, 2010.)

The ability of the triggered action potentials to propagate is related to the level of membrane potential at which the triggered action potential occurs. The more negative the membrane potential is, the more Na⁺ channels are available for activation, the greater the influx of Na⁺ into the cell during phase 0, and the higher the conduction velocity. At more positive membrane potentials of the plateau (phase 2) and early during phase 3, most Na⁺ channels are still inactivated, and the triggered action potentials most likely have upstrokes caused by the inward I_CaL. Therefore, those triggered action potentials have slow upstrokes and are less able to propagate. Increased dispersion of repolarization facilitates the ability of phase 2 EADs to trigger propagating ventricular responses.²⁴

A fundamental condition that underlies the development of EADs is action potential prolongation, which is manifest on the surface ECG by QT prolongation. Hypokalemia, hypomagnesemia, bradycardia, and drugs can predispose to the formation of EADs, invariably in the context of prolonging the action potential duration; drugs are the most common cause. Class IA and III antiarrhythmic agents prolong the action potential duration and the QT interval, effects intended to be therapeutic but frequently causing proarrhythmia. Noncardiac drugs such as some phenothiazines, some nonsedating antihistamines, and some antibiotics can also prolong the action potential duration and predispose to EAD-mediated triggered arrhythmias, particularly when there is associated hypokalemia, bradycardia, or both. Decreased extracellular K⁺ concentration paradoxically decreases some membrane I_K (particularly the I_Kr) in the ventricular myocyte. This finding explains why hypokalemia causes action potential prolongation and EADs. EAD-mediated triggered activity likely underlies initiation of the characteristic polymorphic VT, torsades de pointes, seen in patients with congenital and acquired forms of long QT syndrome (see Chapter 31). Although the genesis of ventricular arrhythmias in these patients is still unclear, marked transmural dispersion of repolarization can create a vulnerable window for development of reentry. EADs arising from these regions can underlie the premature complexes that initiate or perpetuate the tachycardia.¹ Structural heart disease such as cardiac hypertrophy and failure can also delay ventricular repolarization—so-called electrical remodeling—and predispose to arrhythmias related to abnormalities of repolarization. The abnormalities of repolarization in hypertrophy and failure are often magnified by concomitant drug therapy or electrolyte disturbances.

EADs are opposed by ATP-dependent K⁺ channel (I_KATP) openers (pinacidil, cromakalim, rimakalim, and nicorandil), magnesium, alpha-adrenergic blockade, tetrodotoxin, nitrendipine, and antiarrhythmic drugs that shorten action potential (e.g., lidocaine and mexiletine). Alpha-adrenergic stimulation can exacerbate EADs.

It was traditionally thought that unlike DADs, EADs do not depend on a rise in intracellular Ca²⁺; instead, action potential prolongation and reactivation of depolarizing currents are fundamental to their production. More recent experimental evidence suggested a previously unappreciated interrelationship between intracellular Ca²⁺ loading and EADs. Cytosolic Ca²⁺ levels can increase when action potentials are prolonged. This situation, in turn, appears to enhance I_CaL (possibly via Ca²⁺-calmodulin kinase activation), thus further prolonging the action potential duration as well as providing the inward current driving EADs. Intracellular Ca²⁺ loading by action potential prolongation can also enhance the likelihood of DADs. The interrelationship among intracellular Ca²⁺, DADs, and EADs can be one explanation for the susceptibility of hearts that are Ca²⁺ loaded (e.g., in ischemia or congestive heart failure) to develop arrhythmias, particularly on exposure to action potential–prolonging drugs.

Properties of Early Afterdepolarizations

EAD-triggered arrhythmias exhibit rate dependence. In general, the amplitude of an EAD is augmented at slow rates when action potentials are longer in duration.⁶ Pacing-induced increases in rate shorten the action potential duration and reduce EAD amplitude. Action potential shortening and suppression of EADs with increased stimulation rate are likely the result of augmentation of delayed rectifier I_K and perhaps hastening of Ca²⁺-induced inactivation of I_CaL. Once EADs have achieved a steady-state magnitude at a constant drive CL, any event that shortens the drive CL tends to reduce their amplitude. Hence, the initiation of a single premature depolarization, which is associated with an acceleration of repolarization, will reduce the magnitude of the EADs that accompany the premature action potential; as a result, triggered activity is not expected to follow premature stimulation. The exception is when a long compensatory pause follows a premature ventricular complex. This situation can predispose to the development of an EAD and can be the mechanism of torsades de pointes in some patients with the long QT syndrome. Thus, EADs are more likely to trigger rhythmic activity when the spontaneous heart rate is slow because bradycardia is associated with prolongation of the QT interval and action potential duration (e.g., bradycardia- or pause-induced torsades de pointes). Similarly, catecholamines increase heart rate and decrease action potential duration and EAD amplitude, despite the effect of beta-adrenergic stimulation to increase I_CaL.

Substrate

The initiation and maintenance of a reentrant arrhythmia require the presence of myocardial tissue with adjacent tissue or pathways having different EP properties, conduction, and refractoriness, and that they be joined proximally and distally, forming a circuit. These circuits can be stationary or can move within the myocardial substrate.

The reentrant circuit can be an anatomical structure, such as a loop of fiber bundles in the Purkinje system or accessory pathways, or a functionally defined pathway, with its existence, size, and shape determined by the EP properties of cardiac tissues in which the reentrant wavefront circulates. The circuit can also be an anatomical-functional combination. The cardiac tissue that constitutes the substrate for reentrant excitation can be located almost anywhere in the heart.¹ The reentrant circuit can be a variety of sizes and shapes and can include different types of myocardial cells (e.g., atrial, ventricular, nodal, Purkinje; Fig. 3-10).

FIGURE 3-10 Reentry in the Wolff-Parkinson-White syndrome. AV = atrioventricular.

Central Area of Block

A core of inexcitable tissue around which the wavefront circulates is required to sustain reentry. Without this central area of block, the excitation wavefront will not necessarily be conducted around the core of excitable tissue; rather, it could take a shortcut, permitting the circulating excitation wavefront to arrive early at the site where it originated. If it arrives sufficiently early, the tissue at the site of origination will still be refractory, and reentrant excitation will not be possible.

As mentioned earlier, the area of block can be anatomical, functional, or a combination of the two.^6,27 Anatomical block is the result of a nonconductive medium in the center of the circuit, such as the tricuspid annulus in typical atrial flutter (AFL). Functional block at the center of a circuit occurs when there is block of impulses in otherwise excitable cardiac muscle. The central area of functional block develops during the initiation of the reentrant circuit by the formation of a line of block that most likely is caused by refractoriness. When the reentrant circuit forms, the line of block then is sustained by centripetal activation from the circulating wavefront that, by repeatedly bombarding the central area of block, maintains the state of refractoriness of this region. A combination of an anatomical and a functional central area of block in the reentrant circuit has been described in some models of AFL such as the orifice of one or both venae cavae and an area of functional block continuous with or adjacent to either or both caval orifice(s). Additionally, it has now been shown that a functional extension of an anatomical line of block can occur such that it plays a role in creating the necessary or critical substrate for reentry. Thus, a surgical incision in the right atrium made to repair a congenital heart lesion can, under certain circumstances, develop a functional extension to one or both of the venae cavae, such that the substrate to create and sustain AFL develops.

Unidirectional Conduction Block

Transient or permanent unidirectional block is usually a result of heterogeneity of EP properties of the myocardium and is essential for the initiation of reentry. The excitation wavefront propagating in the substrate must encounter unidirectional block; otherwise, the excitation wavefronts traveling down both limbs of the reentrant circuit will collide and extinguish each other.²⁷

Area of Slow Conduction

In a successful reentrant circuit, the wavefront of excitation must encounter excitable cells or the tachycardia will terminate. Therefore, a condition necessary for reentry is the maintenance of excitable tissue ahead of the propagating wavefront. In other words, the tissue initially activated by the excitation wavefront should have sufficient time to recover its excitability by the time the reentrant wavefront returns. Thus, conduction of the circulating wavefront must be sufficiently delayed in an alternate pathway to allow for expiration of the refractory period in the tissue proximal to the site of unidirectional block, and there must always be a gap of excitable tissue (fully or partially excitable) ahead of the circulating wavefront (i.e., the length of the reentrant pathway must equal or exceed the reentrant wavelength; see later). This is facilitated by a sufficiently long reentrant pathway (which is especially important when conduction is normal along the reentrant path), sufficiently slow conduction in all or part of the alternative pathway (because sufficiently long pathways are usually not present in the heart), sufficient shortening of the refractory period, or a combination of these factors.¹

Critical Tissue Mass

An additional requisite for random reentry is the necessity of a critical mass of tissue to sustain the one or usually more simultaneously circulating reentrant wavefronts. Thus, it is essentially impossible to achieve sustained fibrillation of ventricles of very small, normal, mammalian hearts and equally difficult to achieve sustained fibrillation of the completely normal atria of humans or smaller mammals.

Initiating Trigger

Another prerequisite for reentrant excitation to occur is often, but not always, the presence of an initiating trigger, which invokes the necessary EP milieu for initiation of reentry.¹ Susceptible patients with appropriate underlying substrates usually do not suffer from incessant tachycardia because the different EP mechanisms required for the initiation and maintenance of a reentrant tachycardia are infrequently present at exactly the same time. However, changes in heart rate or autonomic tone, ischemia, electrolyte or pH abnormalities, or the occurrence of a premature depolarization can be sufficient to initiate reentrant tachycardia.

The trigger frequently is required because it elicits or brings to a critical state one or more of the conditions necessary to achieve reentrant excitation. In fact, premature depolarizations frequently initiate these tachyarrhythmias because they can cause slow conduction and unidirectional block. Thus, a premature impulse initiating reentry can arrive at one site in the potential reentrant circuit sufficiently early that it encounters unidirectional block, because that tissue has had insufficient time to recover excitability after excitation by the prior impulse. Furthermore, in the other limb of the potential reentrant circuit, the premature arrival of the excitation wavefront causes slow conduction or results in further slowing of conduction of the excitation wavefront through an area of already slow conduction. The resulting increase in conduction time around this limb of the potential reentrant circuit allows the region of unidirectional block in the tissue in the other limb activated initially by the premature beat to recover excitability. It should be noted that the mechanism causing the premature impulse can be different from the reentrant mechanism causing the tachycardia. Thus, the premature impulse can be caused by automaticity or triggered activity.

Anatomical Reentry

In anatomically determined circuits, a discrete inexcitable anatomical obstacle creates a surrounding circular pathway, resulting in a fixed length and location of the reentrant circuit. Because the length and location of the reentrant pathway are relatively fixed, the characteristics of the reentrant circuit are determined by the characteristics of the anatomical components of that circuit.

A reentrant tachycardia is initiated when an excitation wavefront splits into two limbs after going around the anatomical obstacle and travels down one pathway and not the other, thus creating a circus movement. Tachycardia rates are determined by the wavelength and by the length of the reentrant pathway (the path length). The initiation and maintenance of anatomical reentry depend on conduction velocity and refractory period. Thus, as long as the extension of the refractory zone behind the excitation wave, the so-called wavelength of excitation, is smaller than the entire length of the anatomically defined reentrant pathway, a zone of excitable tissue, the so-called excitable gap, exists between the tail of the preceding wave and the head of the following wave.²⁷ In essence, circus movements containing an excitable gap are stable with respect to their frequency of rotation and can persist at a constant rate for hours. In the setting where the wavelength of excitation exceeds the path length, the excitation wavefront becomes extinct when it encounters the not yet recovered inexcitable tissue. A special case is present in the intermediate situation, when the head of the following wavefront meets the partially refractory tail of the preceding wavefront (i.e., the wavelength approximates the path length). This situation is characterized by unstable reentrant CLs and complex dynamics of the reentrant wavefront. There is often a long excitable gap associated with anatomical reentry.

Anatomical circuits therefore are associated with ordered reentry. Examples of this type of reentry are AV reentrant tachycardia associated with an AV bypass tract, AVN reentrant tachycardia, AFL, VT originating within the HPS (bundle branch reentrant VT), and post-MIVT.

Functional Reentry

In functionally determined circuits, the reentrant pathway depends on the intrinsic heterogeneity of the EP properties of the myocardium, not by a predetermined anatomical circuit (i.e., without involvement of an anatomical obstacle or anatomically defined conducting pathway). Such heterogeneity involves dispersion of excitability or refractoriness and conduction velocity, as well as anisotropic conduction properties of the myocardium.²⁸

Functional circuits typically tend to be small and unstable; the reentrant excitation wavefront can fragment, generating other areas of reentry. The location and size of these tachycardias can vary. The circumference of the leading circle around a functional obstacle can be as small as 6 to 8 mm and represents a pathway in which the efficacy of stimulation of the circulating wavefront is just sufficient to excite the tissue ahead, which is still in its relative refractory phase. Therefore, conduction through the functional reentrant circuit is slowed because impulses are propagating in partially refractory tissue. Consequently, this form of functional reentry has a partially excitable gap. The reentry CLs are therefore significantly dependent on the refractory period of the involved tissue.²⁸

The mechanisms for functionally determined reentrant circuits include the leading circle type of reentry, anisotropic reentry, and spiral wave reentry. Functional circuits can be associated with ordered reentry (the reentrant circuit remains in the same place) or random reentry (the reentrant circuit changes size and location). Random reentry can occur when leading circle reentry causes fibrillation.

Anisotropic Reentry

Isotropic conduction is uniform in all directions; anisotropic conduction is not. Anisotropy is a normal feature of heart muscle and is related to the differences in longitudinal and transverse conduction velocities, which are attributable to the lower resistivity of myocardium in the longitudinal (parallel to the long axis of the myocardial fiber bundles) versus the transverse direction (Fig. 3-11). Anisotropy in myocardium composed of tissue with structural features different from those of adjacent tissue results in heterogeneity in conduction velocities and repolarization properties (see later discussion), which can lead to blocked impulses and slowed conduction, thereby setting the stage for reentry (referred to as anisotropic reentry).

FIGURE 3-11 Anisotropic conduction. Progression of activation wavefronts in blocks of ventricular myocardium with longitudinal fiber orientation are shown. A wavefront stimulated (asterisk) at the left edge progresses more rapidly (wider isochrone spacing, A) than one starting perpendicularly (B) because of more favorable conduction parameters in the former direction.

Unlike the functional characteristic that leads to the leading circle type of reentry (differences in refractoriness in adjacent areas caused by local differences in membrane properties), the functional characteristic that is important in functional reentry caused by anisotropy is the difference in effective axial resistance to impulse propagation dependent on fiber direction. In its pure form, the unidirectional conduction block and slow conduction in the reentrant circuit result from anisotropic, discontinuous propagation, and there is no need for variations in membrane properties, such as regional differences in refractoriness or depression of the resting and action potentials.²⁹

Anisotropic circuits are elliptical or rectangular because of the directional differences in conduction velocities, with the long axis of the ellipse in the fast longitudinal direction and a central line of functional block parallel to the long axis of fibers. Circuits with this shape can have a smaller dimension than circular circuits, such as the leading circle. Reentrant circuits caused by anisotropy also can occur without well-defined anatomical pathways and may be classified as functional.

Anisotropic reentrant circuits usually remain in a fixed position and cause ordered reentry. The degree of anisotropy (i.e., the ratio of longitudinal to transverse conduction velocity) varies in different regions of the heart, and the circuit can reside only in a region in which the conduction transverse to the longitudinal axis is sufficiently slow to allow reentry. Stability of anisotropic reentrant circuits is also assisted by the presence of an excitable gap, which does not occur in the leading circle functional circuit. The excitable gap is caused by the sudden slowing of conduction velocity and a decrease in the wavelength of excitation as the reentrant impulse turns the corner from the fast longitudinal direction to the slow transverse direction and from the slow transverse direction to the fast longitudinal direction. Anisotropic reentry is typically initiated by a premature stimulus that blocks in the direction of propagation parallel to the long axis of the cells and then propagates slowly in the transverse direction of fiber orientation because of high axial resistance (see later).²⁹

Anisotropic reentry can potentially provide the substrate for sustained VT that occurs in the epicardial border zone region of healed infarcts, where viable normal myocytes are intermingled with islands of fibrous connective tissue that separate muscle-fiber bundles preferentially in the longitudinal direction and decrease the density of side-to-side junctional connections, therefore creating nonuniform anisotropy.

Figure-of-8 Reentry

The model of figure-of-8 or double-loop reentry involves two concomitant excitation wavefronts circulating in opposite directions, clockwise and counterclockwise, around a long line of functional conduction block rejoining on the distal side of the block. The wavefront then breaks through the arc of block to reexcite the tissue proximal to the block. The single arc of block is thus divided into two, and reentrant activation continues as two circulating wavefronts that travel clockwise and counterclockwise around the two arcs in a pretzel-like configuration.³⁰ This form of reentry has been shown in atrial and ventricular myocardia (Fig. 3-12, Video 1).

FIGURE 3-12 Figure-of-8 reentry. A, ECG and intracardiac recordings from a left ventricular mapping catheter (Map) and the right ventricle (RV) are shown during scar-based ventricular tachycardia. B, A stylized tachycardia circuit is shown in which propagation proceeds through a central common pathway (small arrows and asterisk) constrained by scar or other barriers and then around the outside of these same barriers. Activation in the circuit during electrical diastole is shaded (also in A).

Reflection

Reflection is a special subclass of reentry in which the excitation wavefront does not require a circuit but appears to travel back and forth in a linear segment of tissue (e.g., trabecula or Purkinje fiber) containing an area of conduction block (see Fig. 3-9). In such a situation, an action potential propagates toward, but not through, the inexcitable zone. Subsequently, an electrotonic current conducts passively (i.e., without eliciting an action potential) through the inexcitable zone toward the distal portion of the pathway. If the inexcitable zone is sufficiently small and the magnitude of the electrotonic current is sufficiently large, the segment of tissue distal to the blocked area will be excited (i.e., an action potential is elicited) but with a significant delay. The action potential generated in the distal portion of the pathway will then cause electrotonic current to flow back through the inexcitable zone toward the proximal region. Provided the proximal portion of the conduction pathway recovers quickly enough, this current may be sufficient to elicit a second action potential on the proximal side of the inexcitable zone, which propagates in the opposite direction to the first action potential, thus giving the appearance that the inexcitable zone has reflected the initial action potential. Because reflection can occur within areas of tissue as small as 1 to 2 mm², it is likely to appear of focal origin. Its identification as a mechanism of arrhythmia may be difficult even with very high spatial resolution mapping of the electrical activity of discrete sites.

Wavelength Concept

The wavelength is defined as the product of the conduction velocity of the circulating excitation wavefront and the effective refractory period of the tissue in which the excitation wavefront is propagating.⁶ The wavelength quantifies how far the impulse travels relative to the duration of the refractory period. The wavelength of the reentrant excitation wavefront must be shorter than the length of the pathway of the potential reentrant circuit for reentrant excitation to occur; that is, the impulse must travel a distance during the refractory period that is less than the complete reentrant path length to give myocardium ahead of it sufficient time to recover excitability. Slowing of impulse conduction or shortening of refractoriness shortens the wavelength and increases the excitable gap.

For almost all clinically important reentrant arrhythmias resulting from ordered reentry and in the presence of uniform, normal conduction velocity along the potential reentrant pathway, the wavelength would be too long to permit reentrant excitation. Thus, almost all these arrhythmias must have, and do have, one or more areas of slow conduction as a part of the reentrant circuit. The associated changes in conduction velocity, as well as associated changes in refractory periods, actually cause the wavelength to change in different parts of the circuit. However, the presence of one or more areas of slow conduction permits the average wavelength of reentrant activation to be shorter than the path length.

The wavelength concept is a good predictive parameter of arrhythmia inducibility. A decrease in conduction velocity or shortening of refractoriness results in a decrease in the wavelength or lessening of the amount of tissue needed to sustain reentry. This situation favors initiation and maintenance of reentry. In contrast, an increase in conduction velocity or prolongation of refractoriness prolongs the wavelength of excitation and, in this situation, a larger anatomical circuit is necessary to sustain reentry. If a larger circuit is not possible, initiation or maintenance of tachycardia cannot occur.

Excitable Gaps

The excitable gap in a reentrant circuit is the region of excitable myocardium that exists between the head of the reentrant wavefront and the tail of the preceding wavefront and, at any given time, is no longer refractory (i.e., is capable of being excited) if the excitation wavelength is shorter than the length of the reentrant circuit (Fig. 3-13).

FIGURE 3-13 Excitable gap of recovered tissue in anatomically determined reentry.

The occurrence of an excitable gap is dependent on the recovery of excitability of the myocardium from its previous excitation by the reentrant wavefront. A fully excitable gap is defined as the segment of the reentrant circuit in which the tail of the preceding wavefront does not affect the head and velocity of the following wavefront (absence of head-tail interaction). A partially excitable gap is defined as the zone where the rotating wave can be captured by local stimulation in the presence of head-tail interaction. Whereas the excitable gap denotes a length of a segment within the reentrant circuit, the fully or partially excitable period denotes the time period during which a segment within the reentrant circuit is fully or partially excitable, respectively (see Fig. 3-13).

There are two different measurements of the excitable gap. The spatial excitable gap is the distance (in millimeters) of excitability occupied at any moment of time in the circuit ahead of the reentrant wavefront. On the other hand, the temporal excitable gap is the time interval (in milliseconds) of excitability between the head of activation of one impulse and the tail of refractoriness of the prior impulse. Both the spatial and temporal gaps can be composed of partially excitable or fully excitable myocardium, depending on the time interval between successive excitations of the circuit. The size of the spatial gap and the duration of the temporal gap vary in different parts of the circuit as the wavelength of the reentrant impulse changes because of changes in conduction velocity, refractory periods, or both.

The characteristics of the excitable gap can be different in different types of reentrant circuits. Many anatomically determined reentrant circuits have large excitable gaps with a fully excitable component, although, even in anatomically determined circuits, the gap can sometimes be only partially excitable. On the other hand, functional reentrant circuits caused by the leading circle mechanism have very small gaps that are only partially excitable, although parts of some functionally determined reentrant circuits (anisotropic reentrant circuits) can have fully excitable gaps. An excitable gap has been shown to occur during AF, VF, and AFL; these are examples of arrhythmias caused by functional reentrant mechanisms, possibly including spiral waves. The relationship between the excitable gap and the excitable period can be complex if the velocity of propagation changes within the reentry circuit.²⁷

The existence and the extent of an excitable gap in a reentrant circuit have important implications.²⁷ The presence of an excitable gap enables modulation of the frequency of a reentrant tachycardia by a locally applied stimulus or by field stimulation; the longer the excitable gap is, the more likely it will be for an extrastimulus to be able to enter the reentrant circuit and initiate or terminate a reentrant arrhythmia. In addition, resetting and entrainment are more likely to occur when the excitable gap is longer. The excitable gap can be exploited to terminate a reentrant tachycardia. The presence of a significant temporal and spatial excitable gap in some reentrant circuits enables reentry to be terminated by a single premature stimulus or by overdrive stimulation. Termination of arrhythmias by stimulation would be expected to be much more difficult when the reentrant circuit has only a small partially excitable gap. Additionally, the excitable gap can influence the effects of drugs on the reentrant circuit, so that reentry with a partially excitable gap and mainly functional components may respond more readily to drugs that prolong repolarization, without slowing conduction, whereas fixed anatomical reentry with a large excitable gap responds to drugs that decrease conduction velocity, preferentially at pivot points.

The properties of the excitable gap influence the characteristics of arrhythmias caused by reentry. Arrhythmias caused by leading circle reentry, in which the wavefront propagates in the just-recovered myocardium of the refractory tail and in which there is only a small partially excitable gap, are inherently unstable and often terminate after a short period or go on to fibrillation. On the other hand, the reentrant wavefront in anatomical and nonuniform anisotropic reentrant circuits, in general, is not propagating in myocardium that has just recovered excitability, and the excitable gap can be large. This property can contribute to the stability of these reentrant circuits.²⁷

The shape of the anatomical obstacle determines the path of a reentrant wave in fixed anatomical reentry. Therefore, instability of anatomical reentry is confined to variations of the rotating interval and wavelength of excitation. This instability is characterized by the wavefront’s invading the repolarizing phase of the preceding wave, with resulting oscillations of the rotation period.²⁷

Definition

Resetting is the advancement (acceleration) of a tachycardia impulse by timed premature electrical stimuli. The extrastimulus is followed by a pause that is less than fully compensatory before resumption of the original rhythm. The tachycardia complexes that return first should have the same morphology and CL as the tachycardia before the extrastimulus, regardless of whether single or multiple extrastimuli are used.^36–38

The introduction of a single extrastimulus (S₂) during a tachycardia yields a return cycle (S₂X₃) if the tachycardia is not terminated (Fig. 3-14). If S₂ does not affect the arrhythmogenic focus, the coupling interval (X₁S₂) plus the return cycle (S₂X₃) will be equal to twice the tachycardia cycle (2 × [X₁X₁]); that is, a fully compensatory pause will occur. Resetting of the tachycardia occurs when a less than fully compensatory pause occurs. In this situation, X₁S₂ + S₂X₃ will be less than 2 × (X₁X₁), as measured from the surface ECG. Tachycardia CL stability should be taken into account when the return cycle is measured. To account for any tachycardia CL instability, at least a 20-millisecond shortening of the return cycle is required to demonstrate resetting.³⁹

FIGURE 3-14 Response of tachycardia to a single extrastimulus (S₂). The tachycardia cycle length (CL) is [X₁X₁]. The coupling interval of the extrastimulus is [X₁S₂]. The return CL of the first complex of tachycardia after the extrastimulus is [S₂X₃]. In the top portion of the figure, the extrastimulus does not affect the tachycardia circuit, and a compensatory pause occurs. Resetting (i.e., advancement) of the tachycardia is shown at the bottom of the figure.

(From Frazier DW, Stanton MS: Resetting and transient entrainment of ventricular tachycardia. Pacing Clin Electrophysiol 18:1919, 1995.)

When more than a single extrastimulus is used, the relative prematurity should be corrected by subtracting the coupling interval or intervals from the spontaneous tachycardia cycles when the extrastimuli are delivered.⁴⁰

Reentrant Tachycardia Resetting

To reset reentrant tachycardia, the stimulated wavefront must reach the reentrant circuit, encounter excitable tissue within the circuit (i.e., enter the excitable gap of the reentrant circuit), collide in the antidromic (retrograde) direction with the previous tachycardia impulse, and continue in the orthodromic (anterograde) direction to exit at an earlier than expected time and perpetuate the tachycardia (Fig. 3-15).^36–38 If the extrastimulus encounters fully excitable tissue, which commonly occurs in reentrant tachycardias with large excitable gaps, the tachycardia will be advanced by the extent that the stimulated wavefront arrives at the entrance site prematurely. If the tissue is partially excitable, which can occur in reentrant tachycardias with small or partially excitable gaps or even in circuits with large excitable gaps when the extrastimulus is very premature, the stimulated wavefront will encounter some conduction delay in the orthodromic direction within the circuit (see Fig. 3-15). Therefore, the degree of advancement of the next tachycardia beat depends on both the degree of prematurity of the extrastimulus and the degree of slowing of its conduction within the circuit. The reset tachycardia beat consequently can be early, on time, or delayed.

FIGURE 3-15 A, Schematic representation of the reentrant circuit is illustrated with separate entrance and exit sites. During tachycardia, a wavefront is shown propagating through the tissue of the reentrant circuit (arrow). The dark portion of the arrow represents fully refractory tissue, and the fading portion represents partially refractory tissue. B, A premature stimulus (Stim) introduced during the tachycardia results in a wavefront of depolarization (red arrow), which enters the reentrant circuit and conducts antegradely over fully excitable tissue while it collides retrogradely with the already propagating wavefront (blue arrow). The premature wavefront (red arrow) then propagates around the circuit to the exit site, thus leading to the less than compensatory pause and resetting of the tachycardia. C, A more premature extrastimulus (Stim) results in a wavefront of depolarization (red arrow), which enters the circuit at a time when it collides retrogradely with the previously propagating wavefront (blue arrow) and encounters antegrade tissue incapable of sustaining further propagation. As a result, circus movement in the circuit is extinguished, and tachycardia terminates.

(From Rosenthal ME, Stamato NJ, Almendral JM, et al: Coupling intervals of ventricular extrastimuli causing resetting of sustained ventricular tachycardia secondary to coronary artery disease: relation to subsequent termination. Am J Cardiol 61:770, 1988.)

Termination of the tachycardia occurs when the extrastimulus collides with the preceding tachycardia impulse antidromically and blocks in the reentrant circuit orthodromically (see Fig. 3-15). This occurs when the premature impulse enters the reentrant circuit early in the relative refractory period; it fails to propagate in the anterograde direction because it encounters absolutely refractory tissue. In the retrograde direction, it encounters increasingly recovered tissue and can propagate until it encroaches on the circulating wavefront and terminates the arrhythmia.^39,40

Resetting does not require that the pacing site be located in the reentrant circuit. The closer the pacing site is to the circuit, however, the less premature a single stimulus can be and reach the circuit without being extinguished by collision with a wave emerging from the circuit. The longest coupling interval for an extrastimulus to be able to reset a reentrant tachycardia depends on the tachycardia CL, the duration of the excitable gap of the tachycardia, refractoriness at the pacing site, and the conduction time from the pacing site to the reentrant circuit.³⁹

Resetting Response Curves

Response patterns during resetting are characterized by plotting the coupling interval of the extrastimulus producing resetting versus the return cycle measured at the pacing site. Alternatively, the return cycle is measured to the onset of the first tachycardia complex following stimulation on the surface ECG; then, qualitatively similar but quantitatively different response curves are obtained.³⁹ Demonstration of a noncompensatory pause following the extrastimulus is required, and the interval encompassing the extrastimulus should be 20 or more milliseconds earlier than the expected compensatory pause following a single extrastimulus and 20 or more milliseconds less than three tachycardia CLs when double extrastimuli are used.³⁹ As always, it is important to establish the stability of tachycardia CL before assessing any perturbation in tachycardia presumed to be caused by resetting.

Four resetting response patterns are possible (Fig. 3-16)³⁹:

FIGURE 3-16 Mechanisms of various resetting response patterns. A, Schemas of three types of resetting response curves. B, A theoretical mechanism of resetting patterns in response to extrastimuli at coupling intervals of X and X-50 milliseconds. The reentrant circuit is depicted as having a separate entrance and exit in each pattern. Each tachycardia wavefront is followed by a period of absolute refractoriness (blue arrow), which is then followed by a period of relative refractoriness (fading tail of the arrow) of variable duration. On the left side, a flat curve results when the stimulated wavefront reaches the tachycardia circuit and finds a fully excitable gap between the head and tail of the tachycardia wavefront. The gap is still fully excitable at a coupling interval of X-50. Therefore, the conduction time from the entrance to exit is the same. An increasing curve is shown in the middle; this results when the initial stimulated wavefront enters the reentrant circuit when the excitable gap is partially refractory. The curve continues to increase at a coupling interval of X-50 because the tissue is still in a relative refractory state. A mixed curve (right side) results when the less premature extrastimuli find the reentrant circuit fully excitable, whereas the more premature one (at coupling intervals of X-50) finds it in the relative refractory period.

(From Josephson ME: Recurrent ventricular tachycardia. In Josephson ME, editor: Clinical cardiac electrophysiology, ed 3, Philadelphia, 2004, Lippincott Williams & Wilkins, pp 425-610.)

Occasionally, a response pattern to a single extrastimulus cannot be characterized because resetting occurs over too narrow a range of coupling intervals as a result of significant variability of the baseline tachycardia CL or of variability in the return cycle. Triggered rhythms secondary to DADs usually have a flat or decreasing response. A flat response can be observed in automatic, triggered, or reentrant rhythms.

In all cases in which a single extrastimulus resets the tachycardia, double extrastimuli from the same pacing site produce an identical or expected resetting curve. Thus, if a single extrastimulus produces a flat curve, double extrastimuli will produce a flat or mixed curve. If a single extrastimulus produces an increasing or mixed curve, double extrastimuli will produce the same curve.

The types of resetting curves can vary depending on the site of stimulation. Extrastimuli from different pacing sites likely engage different sites in the reentrant circuit that are in different states of excitability or refractoriness and therefore result in different conduction velocities and resetting patterns.³⁹

Resetting with Fusion

Fusion of the stimulated impulse can be observed on surface ECG or intracardiac recordings if the stimulated impulse is intermediate in morphology between a fully paced complex and the tachycardia complex. The ability to recognize ECG fusion requires a significant mass of myocardium to be depolarized by both the extrastimulus and the tachycardia.^37,39,41 With early extrastimuli, the paced antidromic wavefront captures all or most of the myocardium prior to the orthodromic wavefront of the tachycardia impulse exiting from the reentrant circuit. Thus, no ECG fusion is present, although resetting can occur. With later coupled extrastimuli, the orthodromic wavefront exits from the reentrant circuit, thus capturing a certain portion of myocardium before colliding with the paced antidromic wavefront. In this situation, ECG fusion occurs. Resetting with ECG fusion requires wide separation of the entrance and exit of the reentrant circuit, with the stimulus wavefront preferentially engaging the entrance.

If presystolic activity in the reentrant circuit is recorded before delivery of the extrastimulus that resets the tachycardia, one must consider this to represent local fusion (Fig. 3-17).³⁹ Thus, an extrastimulus that is delivered after the onset of the tachycardia complex and enters and resets the circuit always demonstrates local fusion. Resetting with local fusion and a totally paced complex morphology provides evidence that the reentrant circuit is electrocardiographically small.

FIGURE 3-17 Resetting with fusion. An atrial tachycardia is shown with a stable cycle length (450 msec). A single extrastimulus (S) is delivered from the high right atrium (HRA) that resets or advances the timing of the next cycle (420 msec); however, the coronary sinus (CS) electrogram occurs on time when the extrastimulus is given. Thus, intracardiac fusion is evident when resetting occurs, signifying macroreentry. dist = distal; mid = middle; prox = proximal.

The farther the pacing site is from the reentrant circuit, the less likely resetting with ECG fusion will occur because the extrastimulus should be delivered at a shorter coupling interval to reach the circuit with adequate prematurity. Consequently, the stimulated impulse is more likely to capture both the exit and entrance sites and therefore have a purely paced ECG complex morphology without fusion.

Reentrant circuits reset with fusion have a higher incidence of flat resetting curves, longer resetting zones, and significantly shorter return cycles measured from the stimulus to the onset of the tachycardia complex. Resetting with fusion is a potential indication that the pacing site is located proximal to the zone of slow conduction (i.e., prior to the entrance site) within the reentrant circuit, whereas resetting without fusion potentially suggests pacing distal to the zone of slow conduction, because pacing closer to the exit is more likely to capture both the exit and entrance sites and produce resetting without fusion.

Resetting of Tachycardias with Diverse Mechanisms

Resetting can be demonstrated for tachycardias based on different mechanisms, including reentry, normal or abnormal automaticity, and triggered activity. Although the ability to reset an arrhythmia is not helpful in distinguishing the underlying mechanism, certain features of the resetting response can be useful for the differential diagnosis.³⁹

Basic Principles of Entrainment

Entrainment of reentrant tachycardias by external stimuli was originally defined in the clinical setting as “an increase in the rate of a tachycardia to a faster pacing rate, with resumption of the intrinsic rate of the tachycardia upon either abrupt cessation of pacing or slowing of pacing beyond the intrinsic rate of the tachycardia” and taken to indicate an underlying reentrant mechanism. The ability to entrain a tachycardia also establishes that the reentrant circuit contains an excitable gap.^27,39,42,43

Orthodromic resetting and transient entrainment are manifestations of the same phenomenon (i.e., premature penetration of a tachycardia circuit by a paced wavefront), and the ability to demonstrate resetting is a strong indication that entrainment can occur from that specific pacing site. Entrainment is the continuous resetting of a reentrant circuit by a train of capturing stimuli. However, following the first stimulus of the pacing train that penetrates and resets the reentrant circuit, the subsequent stimuli interact with the reset circuit, which has an abbreviated excitable gap.²⁷

During entrainment, each pacing stimulus creates two activation wavefronts, one in the orthodromic direction and the other in the antidromic direction. The wavefront in the antidromic direction collides with the existing tachycardia wavefront. The wavefront that enters the reentrant circuit in the orthodromic direction (i.e., the same direction as the spontaneous tachycardia wavefront) conducts through the reentrant pathway, resets the tachycardia, and emerges through the exit site to activate the myocardium and collide with the antidromically paced wavefront from the next paced stimulus. This sequence continues until cessation of pacing or block somewhere within the reentrant circuit develops.³⁷ The first entrained stimulus results in retrograde collision between the stimulated and tachycardia wavefronts, whereas for all subsequent stimuli, the collision occurs between the currently stimulated wavefront and the one stimulated previously. Depending on the degree to which the excitable gap is preexcited (and abbreviated) by the first resetting stimulus, subsequent stimuli fall on fully or partially excitable tissue. Entrainment is said to be present when two consecutive extrastimuli conduct orthodromically through the circuit with the same conduction time while colliding antidromically with the preceding paced wavefront. Because all pacing impulses enter the tachycardia circuit during the excitable gap, each paced wavefront advances and resets the tachycardia. Thus, when pacing is terminated, the last paced impulse will continue to activate the entire tachycardia reentrant circuit orthodromically at the pacing CL and also will activate the entire myocardium orthodromically on exiting the reentrant circuit.^42,43

Overdrive pacing at long CLs (approximately 10 to 20 milliseconds shorter than the tachycardia CL) can almost always entrain reentrant circuits with large flat resetting curves and a post-pacing interval (PPI) equal to the return cycle observed during the flat part of the resetting curve.³⁹ During overdrive pacing, once the n^th pacing stimulus resets the circuit, the following pacing stimulus (n + 1)^th will reach the circuit more prematurely. Depending on how premature it is, this (n + 1)^th extrastimulus may produce no change in the return cycle (compared with that in response to the n^th extrastimulus), encounter progressive conduction delay (until a fixed, longer return cycle is reached), or terminate the tachycardia. The larger the flat curve observed during resetting or the longer the pacing CL, or both, the more likely the return cycle of the n^th and (n + 1)^th extrastimuli will be the same. In this case, no matter how many subsequent extrastimuli are delivered, the return cycle will be the same and equal to that observed during the flat portion of the resetting curve. However, if the flat portion of the resetting curve is small, the pacing CL is short, or both, the (n + 1)^th extrastimulus will fall on partially refractory tissue and the return cycle will increase. Continued pacing at the same CL will result in a stable but longer return cycle than the n^th extrastimulus or termination of the tachycardia. Consequently, circuits with large fully excitable gaps (i.e., large flat resetting curves) can demonstrate prolonged return cycles or even termination at pacing CLs equal to coupling intervals of a single extrastimulus demonstrating a fully excitable gap.

Entrainment Response Curves

During entrainment, the orthodromic wavefront of the last extrastimulus propagates around the circuit to become the first complex of the resumed tachycardia. The conduction time of this impulse to the exit site of the circuit is termed the last entrained interval, and it characterizes the properties of the reset circuit during entrainment.^37,39 Measurement of the interval between the last paced extrastimulus to the first nonpaced tachycardia complex (on the surface ECG or presystolic electrogram) during entrainment at progressively shorter pacing CLs characterizes an entrainment response curve, analogous but not identical to resetting response curves with single extrastimuli. In this case, the return cycle depends critically on the number of extrastimuli delivered that reset the circuit before the return cycle is measured, because following the first extrastimulus producing resetting (the n^th extrastimulus), subsequent extrastimuli are relatively more premature and can lead to a different return cycle.^42,43

During entrainment, the return cycle measured at an orthodromically captured presystolic electrogram should equal the pacing CL regardless of the site of pacing, as long as the presystolic electrogram is orthodromically activated at a fixed stimulus-to-electrogram interval (i.e., fixed orthodromic conduction time). This would not be observed if the electrogram were captured antidromically. If the time from the orthodromically activated electrogram to the onset of the return cycle on the surface ECG remains constant, which is a requirement to prove that the electrogram is within or attached to the reentrant circuit proximal to the exit site, then the interval from the stimulus to the surface ECG complex will remain constant. The same is true for the electrogram measured at the stimulation site. In the absence of recording of a presystolic electrogram, other measurements may be used to characterize the last entrained interval at any pacing CL. Therefore, during entrainment, curves relating the pacing CL to the last entrained interval can be measured from the stimulus to the orthodromic presystolic electrogram, to the onset of the surface ECG of the first tachycardia (nonpaced) complex, or to the local activation time at the pacing site of the first tachycardia (nonpaced) complex. These measurements will be qualitatively identical but have different absolute values. As always, it is important to establish the stability of tachycardia CL and document the presence of entrainment before assessing the return cycle and PPI.^42,43

Termination is the usual response to overdrive pacing of circuits that demonstrate an increasing curve in response to resetting by a single extrastimulus. However, if the number of extrastimuli following the n^th extrastimulus is limited to one or two (especially at long pacing CLs), termination may not occur, although the return cycle will be progressively longer following each extrastimulus. Entrainment is not present until two consecutive PPIs are identical. In such cases, when termination does not occur, the return cycle will be longer than that observed if pacing were discontinued following the n^th extrastimulus at that pacing CL.^37,39 Thus, if only the return cycle following entrainment is used to analyze the excitable gap, an increasing curve suggesting decremental conduction can result, even though a flat curve is observed with single or double extrastimuli, or both. Therefore, only resetting phenomena describe the characteristics of the reentrant circuit. Entrainment analyzes a reset circuit that has a shorter excitable gap. Flat, mixed (flat and increasing), and increasing curves can be seen during entrainment of macroreentrant circuits. Increasing curves are almost always observed during entrainment of small or microreentrant circuits.

Relationship of Pacing Site and Cycle Length to Entrainment

As with resetting, entrainment does not require the pacing site be located in the reentrant circuit. The closer the pacing site is to the circuit, however, the less premature a single stimulus can be and reach the circuit and, with pacing trains, the fewer the number of stimuli required before a stimulated wavefront reaches the reentrant circuit without being extinguished by collision with a wave emerging from the circuit.

Overdrive pacing at long CLs (approximately 10 to 20 milliseconds shorter than the tachycardia CL) can almost always entrain reentrant tachycardias. However, the number of pacing stimuli required to entrain the reentrant circuit depends on the tachycardia CL, the duration of the excitable gap of the tachycardia, refractoriness at the pacing site, and the conduction time from the stimulation site to the reentrant circuit.^39,42–45

Diagnostic Criteria of Entrainment

Entrainment is the continuous resetting of a tachycardia circuit. Therefore, during constant rate pacing, entrainment of tachycardia results in the activation of all myocardial tissue responsible for maintaining the tachycardia at the pacing CL, with the resumption of the intrinsic tachycardia morphology and rate after cessation of pacing. Unfortunately, it is almost impossible to document the acceleration of all tissues responsible for maintaining the reentrant circuit to the pacing CL. Therefore, certain surface ECG criteria have been proposed for establishing the presence of entrainment: (1) fixed fusion of the paced complexes at a constant pacing rate; (2) progressive fusion or different degrees of fusion at different pacing rates (i.e., the surface ECG and intracardiac morphology progressively look more like the purely paced configuration and less like the pure tachycardia complex in the course of pacing at progressively shorter pacing CLs); and (3) resumption of the same tachycardia morphology following cessation of pacing, with the first PPI displaying no fusion but occurring at a return cycle equal to the pacing CL.⁴⁶ These criteria are discussed in more detail in Chapter 5.^42,43,47

Reduced Membrane Excitability

Excitability of a cardiac cell describes the ease with which the cell responds to a stimulus with a regenerative action potential, and it depends on the passive and active properties of the cell membrane.⁷ The passive properties include the membrane resistance and capacitance and the intercellular resistance. The more negative the membrane potential is, the more Na⁺ channels are available for activation, the greater the influx of Na⁺ into the cell during phase 0, and the greater the conduction velocity.

In contrast, membrane depolarization to levels of −60 to −70 mV can inactivate half the Na⁺ channels, and depolarization to −50 mV or less can inactivate all the Na⁺ channels. Therefore, when stimulation occurs during phase 3 (e.g., during premature stimulation during the relative refractory period), before full recovery and at less negative potentials of the cell membrane, a portion of Na⁺ channels will still be refractory and unavailable for activation. As a result, I_Na and phase 0 of the next action potential are reduced, and conduction of the premature stimulus is slowed, facilitating reentry.^6,27

Reduced membrane excitability occurs in numerous physiological and pathophysiological conditions. Genetic mutations that result in loss of Na⁺ channel function, as occurs in the Brugada syndrome, can cause reduced membrane excitability. Reduced membrane excitability is also present in cardiac cells with persistently low levels of resting potential caused by disease (e.g., during acute ischemia, tachycardia, certain electrical remodeling processes, and treatment with class I antiarrhythmic agents).^27,50 At low resting potentials, the availability of excitable Na⁺ channels is reduced because of inactivation of a significant proportion of the Na⁺ channels and prolonged recovery of Na⁺ channels from inactivation. With progressive reduction of excitability, less Na⁺ source current is generated, and conduction velocity and the safety factor decrease monotonically. When the safety factor falls to less than 1, conduction can no longer be sustained, and failure (conduction block) occurs. Action potentials with reduced upstroke velocity resulting from partial inactivation of Na⁺ channels are called depressed fast responses. These action potential changes are likely to be heterogeneous, with unequal degrees of Na⁺ inactivation that create areas with minimally reduced velocity, more severely depressed zones, and areas of complete block. In addition, refractoriness in cells with reduced membrane potentials can outlast voltage recovery of the action potential; that is, the cell can still be refractory or partially refractory after the resting membrane potential returns to its most negative value.⁵⁰

Thus, in a diseased region with partially depolarized fibers, there can be some areas of slow conduction and some areas of conduction block, depending on the level of resting potential and the number of Na⁺ channels that are inactivated. This combination can be the substrate for reentry. The chance for reentry in such fibers is even greater during premature activation or during rhythms at a rapid rate, because slow conduction or the possibility of block is increased even further.

Reduced Cellular Coupling

Intercellular communication is maintained by gap junctional channels that connect neighboring cells and allow biochemical and low-resistance electrical coupling.⁵² Although the resistivity of the gap junctional membrane for the passage of ions and small molecules and for electrical propagation is several orders of magnitude higher than the cytoplasmic intracellular resistivity, gap junction coupling provides a resistance pathway that is several orders of magnitude lower compared with uncoupled cell membranes.⁵³

In normal adult working myocardium, a given cardiomyocyte is electrically coupled to an average of approximately 11 adjacent cells, with gap junctions being predominantly localized at the intercalated discs at the ends of the rod-shaped cells. Lateral (side-to-side) gap junctions in nondisc lateral membranes of cardiomyocytes are much less abundant and occur more often in atrial than ventricular tissues.^27,53–55 This particular subcellular distribution of gap junctions is a main determinant of anisotropic conduction in the heart; a wavefront must traverse more cells in the transverse direction than over an equivalent distance in the longitudinal direction, because cell diameter is much smaller than cell length. Additionally, less intercellular gap junctional coupling occurs and, hence, greater resistance and slower conduction transversely than longitudinally.^27,52,55

Modification of intercellular coupling occurs in numerous physiological and pathophysiological conditions.²⁷ Physiologically, cell-to-cell coupling is reduced in atrial and ventricular myocardium in the transverse direction to the main fiber axis relative to the longitudinal direction. Reduced intercellular coupling also likely contributes to slow impulse conduction in the AVN. In pathophysiological settings (e.g., myocardial ischemia, ventricular hypertrophy, cardiomyopathy),⁵⁶ modification of intercellular coupling can occur as a consequence of acute changes in the average conductance of gap junctions secondary to ischemia, hypoxia, acidification, or increase in intracellular Ca²⁺, or it can be produced by changes in expression or cellular distribution patterns of gap junctions.^57,58 Changes in the distribution and number of gap junctions (gap junction remodeling) have been reported in almost all cardiac diseases predisposing to arrhythmias. Remodeling includes a decrease in some gap junction channels resulting from the interruption of communication between cells by fibrosis and downregulation of connexin-43 (Cx43) formation or trafficking to the intercalated disc. Additionally, gap junctions can become more prominent along lateral membranes of myocytes (so-called structural remodeling).^54,59

A reduction in the gap junctional conductance increases the intercellular resistance, thus leading to conduction delay or block. Similar to its behavior during reduced membrane excitability, conduction velocity decreases monotonically with reduction in intercellular coupling.⁵² However, the resulting reduction of conduction velocities is more than an order of magnitude larger than that observed during a reduction of excitability.²⁷ Importantly, the changes in the safety factor with uncoupling are opposite to those observed with a reduction in membrane excitability. As cells become less coupled, there is greater confinement of depolarizing current to the depolarizing cell, with less electrotonic load and axial flow of charge to the downstream cells. As a result, individual cells depolarize with a high margin of safety, but conduction proceeds with long intercellular delays. At such low levels of coupling, conduction is very slow but, paradoxically, very robust.^27,57,58

Importantly, there is a high redundancy in connexin expression in the heart with regard to conduction of electrical impulse, and a large reduction of intercellular coupling is required to cause major slowing of conduction velocity. It has been shown that a 50% reduction in Cx43 does not alter ventricular impulse conduction. Cx43 expression must decrease by 90% to affect conduction, but even then conduction velocity is reduced only by 20%.

Tissue Structure and Geometry

Tissue geometry can influence action potential propagation and conduction velocity. In contrast to an uncoupled cell strand, in which the high resistance junctions alternate with the low cytoplasmic resistance of the cells, a high degree of discontinuity can be produced by large tissue segments (consisting of a segment with side branches) alternating with small tissue segments having a small tissue mass (connecting segments without branches).²⁷

When a small mass of cells has to excite the large mass (e.g., an impulse passing abruptly from a fiber of small diameter to one of large diameter or propagating into a region where there is an abrupt increase in branching of the myocardium), transient slowing of the conduction velocity can be observed at the junction. This occurs because of sink-source mismatch, during which the current provided by the excitation wavefront (source) is insufficient to charge the capacity and thus excite the much larger volume of tissue ahead (sink).^27,49,60,61

In a normal heart, abrupt changes in geometric properties are not of sufficient magnitude to provide sufficient sink-source mismatch and cause conduction block of the normal action potential because the safety factor for conduction is large; that is, there is a large excess of activating current over the amount required for propagation. However, when the action potential is abnormal, the unexcited area has decreased excitability (e.g., in the setting of acute ischemia), or both, anatomical impediments can result in conduction block.

Cellular Coupling: Gap Junctional Organization

The anisotropic conductive properties of ventricular myocardium are dependent on the geometry of the interconnected cells and the number, size, and location of the gap junction channels between them. Additionally, gap junctions vary in their molecular composition, degree of expression, and distribution pattern, whereby each of these variations can contribute to the specific propagation properties of a given tissue in a given species. Tissue-specific connexin expression and gap junction spatial distribution, as well as the variation in the structural composition of gap junction channels, allow for a greater versatility of gap junction physiological features and enable disparate conduction properties in cardiac tissue. The myocytes of the sinus node and AVN are equipped with small, sparse, dispersed gap junctions containing Cx45, a connexin that forms low conductance channels, thus underlying the relatively poor intercellular coupling in nodal tissues, a property that is linked to slowing of conduction. In contrast, ventricular muscle expresses predominantly Cx43 and Cx45, which have larger conductance. Atrial muscle and Purkinje fibers express all three cardiac connexins.

Alterations in distribution and function of cardiac gap junctions are associated with conduction delay or block. Inactivation of gap junctions decreases transverse conduction velocity to a greater degree than longitudinal conduction, thereby resulting in exaggeration of anisotropy and providing a substrate for reentrant activity and increased susceptibility to arrhythmias.^54,59

Myocyte Packing and Tissue Geometry

Discontinuities in myocardial architecture exist at several levels. In addition to discontinuities imposed by cell borders, microvessels and connective tissue sheets separating bundles of excitable myocytes can act as resistive barriers. A propagating impulse is expected to collide with such barriers and travels around them wherever it encounters excitable tissue.⁴⁸

In some regions of the myocardium (e.g., the papillary muscles), connective tissue septa subdivide the myocardium into unit bundles composed of 2 to 30 cells surrounded by a connective tissue sheath.⁶ Within a unit bundle, cells are tightly connected or coupled to each other longitudinally and transversely through intercalated discs that contain the gap junctions and are activated uniformly and synchronously as an impulse propagates along the bundle. Adjacent unit bundles also are connected to each other. Unit bundles are coupled better in the direction of the long axis of its cells and bundles, because of the high frequency of the gap junctions within a unit bundle, than in the direction transverse to the long axis, because of the low frequency of interconnections between the unit bundles. This is reflected as a lower axial resistivity in the longitudinal direction than in the transverse direction in cardiac tissues composed of many unit bundles. Additionally, anisotropy on a macroscopic scale can influence conduction at sites at which a bundle of cardiac fibers branches or separate bundles will coalesce. Marked slowing can occur when there is a sudden change in the fiber direction, causing an abrupt increase in the effective axial resistivity. Conduction block, which sometimes can be unidirectional, can occur at such junction sites, particularly when membrane excitability is reduced.

Uniform Versus Nonuniform Anisotropy

Uniform anisotropy is characterized by smooth wavefront propagation in all directions and measured conduction velocity changes monotonically on moving from fast (longitudinal) to slow (transverse) axes, thus indicating relatively tight coupling between groups of fibers in all directions. However, this definition is based on the characteristics of activation at a macroscopic level, where the spatial resolution encompasses numerous myocardial cells and bundles, and therefore it describes the behavior of the myocardial syncytium. In contrast, when the three-dimensional network of cells is broken down into linear single-cell chains, gap junctions can be shown to limit axial current flow and induce saltatory conduction because of the recurrent increases in axial resistance at the sites of gap junctional coupling; that is, conduction is composed of rapid excitation of individual cells followed by a transjunctional conduction delay. In two- and three-dimensional tissue, these discontinuities disappear because of lateral gap junctional coupling, which serves to average local small differences in activation times of individual cardiomyocytes at the excitation wavefront.^49,55

In multicellular tissue, saltatory conduction reappears only under conditions of critical gap junctional uncoupling, in which it leads to a functional unmasking of the cellular structure and induces ultraslow and meandering conduction, well known to be a key ingredient in arrhythmogenesis.⁴⁹ Change in the characteristics of anisotropic propagation at the macroscopic scale from uniform to nonuniform strongly predisposes to reentrant arrhythmias. Nonuniform anisotropy has been defined as tight electrical coupling between cells in the longitudinal direction but uncoupling to the lateral gap junctional connections. Therefore, there is disruption of the smooth transverse pattern of conduction characteristic of uniform anisotropy that results in a markedly irregular sequence or zigzag conduction, producing the fractionated extracellular electrograms characteristic of nonuniform anisotropic conduction (Fig. 3-18). In nonuniformly anisotropic muscle, there also can be an abrupt transition in conduction velocity from the fast longitudinal direction to the slow transverse direction, unlike the case with uniform anisotropic muscle, in which intermediate velocities occur between the two directions.

FIGURE 3-18 Effect of scar on electrical propagation. A, A homogeneous sheet of myocardium conducts an electrical wavefront rapidly, with synchronous activation of a large number of cells that leads to a sharp electrogram. B, Myocardial scarring produces disordered propagation, resulting in a low-amplitude electrogram, with multiple fragmented peaks.

Nonuniform anisotropic properties can exist in normal cardiac tissues secondary to separation of the fascicles of muscle bundles in the transverse direction by fibrous tissue that proliferates with aging to form longitudinally oriented insulating boundaries (e.g., crista terminalis, interatrial band in adult atria, or ventricular papillary muscle). Similar connective tissue septa cause nonuniform anisotropy in pathological situations such as chronic ischemia or a healing MI, in which fibrosis in the myocardium occurs (see Fig. 3-18).^6,55

Inhomogeneity of Membrane Excitability and Refractoriness

Unidirectional block develops when the activation wavefront interacts with the repolarization phase (tail) of a preceding excitation wave. There is a critical or vulnerable window during the relative refractory period of a propagating action potential within which unidirectional block occurs. When a premature stimulus is delivered outside this window, the induced action potential propagates or blocks in both directions; specifically, a stimulus delivered too early fails to induce a propagating action potential in either direction (bidirectional block), whereas a late stimulus results in bidirectional conduction (no block). In contrast, when a stimulus is applied within the vulnerable window, the induced action potential propagates incrementally in the retrograde direction because the tissue is progressively more recovered as the distance from the window increases in this direction, but it blocks in the anterograde direction following a short distance of decremental conduction because the tissue is progressively less excitable as the distance from the window increases in this direction.²⁷

The size of the vulnerable window provides an index of the vulnerability to the development of reentrant arrhythmias. Therefore, the probability that a premature stimulus will fall inside the window and induce reentry is high when the vulnerable window is large. In contrast, precise timing of a premature stimulus is required to induce reentry in a small window, and the probability of such an event is low. In normal tissue, the vulnerable window is very small, and inducibility of unidirectional block and reentry is negligible. The width of the vulnerable window can be affected by changes in the availability of Na⁺ channels for depolarization, cell-to-cell coupling, and repolarizing I_K. Additionally, the size of the vulnerable window can be widened (and reentry facilitated) by factors that increase the spatial inhomogeneity of refractoriness or decrease cellular coupling via gap junctions.

Unidirectional conduction block in a reentrant circuit also can be persistent and independent of premature activation, in which case it often occurs in a region of depressed and heterogeneous excitability (as occurs in acute ischemia); this leads to a widening of the vulnerable window. Asymmetry in excitability, which can occur because of asymmetrical distribution of a pathological event, can lead to an abrupt rise in the threshold for excitation in one direction and to a more gradual rise in the other. Conduction fails when the wavefront encounters the least depressed site first and is successful in the direction in which it encounters the most depressed site first. Additionally, impulses are conducted more easily from a rapidly conducting tissue to a slowly conducting tissue than in the opposite direction.²⁹

Local dispersion of refractory periods is a normal feature of ventricular myocardium. Critical increases in the dispersion of refractoriness, the difference between the shortest and longest refractory periods, can result in the local widening of the vulnerability window and an increased probability for the generation of unidirectional block and reentry.^6,27 Increased heterogeneity of repolarization and dispersion of refractoriness can be caused by acute or prolonged ischemia, the long QT syndrome, or electrical remodeling in the setting of ventricular hypertrophy and failure and in the setting of MI. When differences in the duration of the refractory periods occur in adjacent areas, conduction of an appropriately timed premature impulse can be blocked in the region with the longest refractory period, which then becomes a site of unidirectional block, whereas conduction continues through regions with a shorter refractory period.⁶

Anisotropy and Unidirectional Block

The anisotropic properties of cardiac muscle can contribute to the occurrence of unidirectional block.⁶ As mentioned earlier, in the anisotropic muscle, the safety factor for conduction is lower in the longitudinal direction of rapid than in the transverse direction of slow conduction. The low safety factor longitudinally is a result of a large current load on the membrane associated with the low axial resistivity and a large membrane capacitance in the longitudinal direction. This low safety factor can result in a preferential conduction block of premature impulses in the longitudinal direction while conduction in the transverse direction continues. The site of block in the longitudinal direction can become a site of unidirectional block that leads to reentry.⁶ In contrast to the propensity of premature impulses to block in the longitudinal direction in nonuniformly anisotropic myocardium because of the decreased depolarizing current and low safety factor, when coupling resistance between cells is increased, conduction of all impulses will block first in the transverse direction. Preferential block in this direction occurs because an increase in coupling resistance will reduce the safety factor below the critical level needed to maintain transverse conduction before the safety factor for longitudinal conduction is reduced to this critical level.^6,55

Discontinuities in Tissue Structure and Geometry

Geometric factors related to tissue architecture also can influence impulse conduction and, under certain conditions, lead to unidirectional block.²⁷ Structural discontinuities exist in the normal heart in the form of trabeculations of the atrial and ventricular walls, sheets interconnected by small trabeculae, or myocardial fibers with different diameters packed in a connective tissue matrix. Structural discontinuities can also be secondary to pathophysiological settings, such as the connective tissue septa characteristic of aging, infarcted, hypertrophic, and failing myocardium. The propagating excitation wave is expected to interact with these normal and abnormal structural discontinuities. These structural features influence conduction by affecting the axial currents that flow ahead of the propagating wavefront.²⁷ Therefore, an impulse conducting in one direction can encounter a different sequence of changes in fiber diameter, branching, and frequency and distribution of gap junctions than it does when traveling in the opposite direction. The configuration of pathways in each direction is not the same.