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)

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