Automaticity: Natural Excitation of the Heart

Sinoatrial Node

The SA node is the phylogenetic remnant of the sinus venosus of lower vertebrate hearts. In humans it is about 8 mm long and 2 mm thick. It lies in the groove where the superior vena cava joins the right atrium ( Fig. 3.1 ). The sinus node artery runs lengthwise through the center of the node.

The SA node contains two principal cell types: (1) small, round cells, that have few organelles and myofibrils; and (2) slender, spindle-shaped cells that are intermediate in appearance between the round cells and the ordinary atrial myocardial cells. The round cells are probably the pacemaker cells, whereas the transitional cells serve a subsidiary pacemaker role and conduct the impulses within the node and to the nodal margins.

A typical transmembrane action potential recorded from a cell in the SA node is depicted in Fig. 2.16 B. Compared with the transmembrane potential recorded from a ventricular myocardial cell ( Fig. 2.16 A), the maximum diastolic potential of the SA node cell is usually less, the upstroke of the action potential (phase 0) is less steep, a plateau is not sustained, and repolarization (phase 3) is more gradual. These are all characteristic of the slow response described in Chapter 2 .

The transmembrane potential (V _m ) during phase 4 is much less negative in SA (and AV) nodal automatic cells than in atrial or ventricular myocytes, because nodal cells lack the i _KI (inward-rectifying) type of K ⁺ channel. Therefore the ratio of conductances of K ⁺ (g _K ) and Na ⁺ (g _Na ), or g _K /g _Na , during phase 4 is much less in the nodal cells than in the myocytes. During phase 4 therefore V _m deviates much more from the K ⁺ equilibrium potential (E _K ) in nodal cells than it does in myocytes.

Although primary SA node pacemaker cells have fast Na ⁺ channels, their function is suppressed because they are inactivated at the maximum diastolic potential of these cells. Thus tetrodotoxin has no influence on the action potential ( Fig. 3.2A ) at the primary SA nodal pacemaker site. This fact indicates that the action potential upstroke is not produced by an inward current of Na ⁺ through the fast channels. However, blockade of Ca ⁺⁺ channels by nifedipine suppresses action potential generation in primary SA node cells (see Fig. 3.2B ). Subsidiary or latent pacemaker cells within the SA node have a more negative maximum diastolic potential that allows some Na ⁺ channels to recover from inactivation. Tetrodotoxin or local anesthetic drugs can block such channels and impede conduction from primary pacemaker cells to the atrium.

The principal feature that distinguishes a pacemaker fiber from other cardiac fibers resides in phase 4. In nonautomatic cells the potential remains constant during this phase, whereas in a pacemaker fiber there is a slow depolarization, called the pacemaker potential , throughout phase 4. Depolarization proceeds at a steady rate until a threshold is attained, and then an action potential is triggered.

The discharge frequency of pacemaker cells may be varied by a change in either the rate of depolarization during phase 4 or the maximal diastolic potential ( Fig. 3.3 ). A change of the threshold potential, the voltage at which the action potential is initiated, is another variable that affects pacemaker cell frequency.

Changes in autonomic neural activity often also induce a pacemaker shift , in which the site of initiation of the cardiac impulse may shift to a different locus within the SA node or to a different component of the atrial pacemaker complex.

Ionic Basis of Automaticity

Several ionic currents contribute to the slow depolarization that occurs during phase 4 in automatic cells in the heart. In SA node pacemaker cells the diastolic depolarization is affected by the interaction of at least three ionic currents: (1) an inward current, I _f, induced by hyperpolarization; (2) a calcium current, I _Ca ; and (3) an outward K ⁺ current, I _K ( Fig. 3.4 ).

The hyperpolarization-induced inward current, I _f , is carried mainly by Na ⁺ through specific channels that differ from the fast Na ⁺ channels. The I _f current becomes activated during repolarization of the membrane, as the membrane potential becomes more negative than about −60 mV. The more negative the membrane potential becomes at the end of repolarization, the greater the activation of the I _f current.

The second current responsible for diastolic depolarization is the L-type calcium current, I _Ca . This current becomes activated toward the end of phase 4, as the transmembrane potential reaches a value of about −55 mV (see Fig. 3.4 ). Once the Ca ⁺⁺ channels become activated, the influx of Ca ⁺⁺ into the cell increases. The influx of Ca ⁺⁺ accelerates the rate of diastolic depolarization, which then leads to the upstroke of the action potential. A decrease in the external Ca ⁺⁺ concentration or the addition of a calcium channel antagonist (see Fig. 3.2B ) reduces the amplitude of the action potential and the slope of the pacemaker potential in SA node cells.

The progressive diastolic depolarization mediated by the two inward currents, I _f and I _Ca , is opposed by a third current, an outward K ⁺ current, I _K . This K ⁺ efflux tends to repolarize the cell after the upstroke of the action potential. The outward K ⁺ current continues well beyond the time of maximal repolarization, but it diminishes throughout phase 4 (see Fig. 3.4 ). Hence the opposition of I _K to the depolarizing effects of the two inward currents I _Ca and I _f , gradually decreases.

The understanding of membranes and currents in pacemaking has greatly evolved. Other ionic currents (T-type Ca channels, Na ⁺ /Ca ⁺⁺ antiporter, sustained inward Na ⁺ current) are present in SA node cells along with transient receptor potential (TRP) channels. The generation of membrane current by the Na ⁺ /Ca ⁺⁺ exchanger suggested a possible function of the rather sparse sarcoplasmic reticulum of SA node cells in automaticity. A timing mechanism comprised of ionic channels in the plasma membrane (“membrane clock”) and the sarcoplasmic reticulum (SR) membrane (“Ca ⁺⁺ clock”) has been proposed. That is, local Ca ⁺⁺ spontaneously released (termed Ca ⁺⁺ “sparks”) from the SR during the diastolic depolarization leaves the cell via the Na ⁺ /Ca ⁺⁺ antiporter, generating an inward current. As the membrane depolarizes, L-type Ca ⁺⁺ channels (Ca _v 1.3 clone) open to participate in the slow diastolic depolarization and to produce the action potential upstroke when the membrane reaches the threshold potential in the SA node cell. Calcium released from the SR may participate in diastolic depolarization not only via the Na ⁺ /Ca ⁺⁺ antiporter but also through depletion of SR Ca ⁺⁺ . Store-operated Ca ⁺⁺ channels (SOCCs) are activated by Ca ⁺⁺ depletion from the SR; entry of Ca ⁺⁺ through TRP channels can also assist diastolic depolarization and the regulation of SA node frequency. Several TRP channel isoforms have been detected in the SA node as well as in other cardiac tissues. Thus knockout of TRPM7 (Ca ⁺⁺ permeant channel having kinase activity) was accompanied by reduced automaticity in mouse SA node cells. The effect was attributed to reduced rise of intracellular Ca ⁺⁺ during diastolic depolarization and reduced expression of the gene ( HCN4 ) that encodes the I _f channel. Attempts to suppress the expression or activity of various ion channels and the components of the Ca ⁺ clock usually result in the reduction but not abolition of pacemaker frequency. For example, knockout of the Na ⁺ /Ca ⁺⁺ exchange current had no effect on basal frequency but reduced the positive chronotropic effect of a sympathetic stimulant.

The number of cells within the SA node and the extent of their interaction via gap junctions influence the effect of membrane current alterations on impulse initiation within the SA node. Overall, the structural complexity of the node, together with the many ionic currents that contribute to pacemaking, allow the SA node to sustain this vital function under a variety of physiological and pathological conditions.

The ionic basis for automaticity in the AV node pacemaker cells appears similar to that in the SA node cells. In cardiac Purkinje fibers, automaticity can be detected at two voltage ranges, from −60 to −100 mV and from −50 to 0 mV. The slow diastolic depolarization in the voltage range from −60 to −100 mV is attributed to a voltage- and time-dependent K ⁺ current. The action potential arises from the fast Na ⁺ current. Whether the hyperpolarization-induced inward current, I _f , functions physiologically in this voltage range remains to be clarified. Automaticity at −50 to 0 mV depends on I _K and I _Ca , but the precise mechanism is not known.

Autonomic neurotransmitters affect automaticity by altering the ionic currents across the cell membranes. The β-adrenergic transmitters increase all three currents involved in SA nodal automaticity. The adrenergically mediated increase in the slope of diastolic depolarization indicates that the augmentations of I _f and I _Ca must exceed the enhancement of I _K . Adrenergic transmitters also increase automaticity in Purkinje fibers; this is evident at both voltage ranges.

The hyperpolarization ( Fig. 3.5 ) induced by acetylcholine released at the vagus endings in the heart is achieved by an increased conductance mediated by activation of specific K ⁺ channels that are controlled by the cholinergic receptors (I _K,ACh ). Acetylcholine also depresses the I _f and I _Ca currents.

Overdrive Suppression

A period of excitation at a high frequency depresses automaticity of pacemaker cells. This phenomenon is known as overdrive suppression . The firing of the SA node tends to suppress the automaticity in the other loci because the SA node has a greater intrinsic rhythmicity than the other latent pacemaking sites in the heart.

The mechanism responsible for overdrive suppression appears to be based on the activity of the membrane pump (Na ⁺ ,K ⁺ -ATPase) that actively extrudes three Na ⁺ from the cell, in exchange for two K ⁺ . During each depolarization, a certain quantity of Na ⁺ enters the cell; therefore the more frequently it is depolarized, the greater the amount of Na ⁺ that enters the cell per minute. At high excitation frequencies the Na ⁺ pump becomes more active in extruding this larger quantity of Na ⁺ from the cell interior. This enhanced pump activity hyperpolarizes the cell through the net loss of cations from the cell interior. Because of the hyperpolarization, the slow diastolic depolarization requires more time to reach the threshold, as shown in Fig. 3.3B . Furthermore, when the overdrive suddenly ceases, the Na ⁺ pump does not decelerate instantaneously but continues to operate at an accelerated rate for some time. This excessive extrusion of Na ⁺ opposes the gradual depolarization of the pacemaker cell during phase 4 and thereby suppresses its intrinsic automaticity temporarily.

Atrial Conduction

From the SA node, the cardiac impulse spreads radially throughout the right atrium ( Fig. 3.6 ) along ordinary atrial myocardial fibers, at a conduction velocity of approximately 1 m/s. A special pathway, the anterior interatrial myocardial band (or Bachmann’s bundle ), conducts the impulse from the SA node directly to the left atrium. Three tracts, the anterior , middle , and posterior internodal pathways , have been described. These tracts consist of a mixture of ordinary myocardial cells and specialized conducting fibers. Some investigators assert that these pathways constitute the principal routes for conduction of the cardiac impulse from the SA node to the AV node.

The configuration of the atrial action potential is depicted in Fig. 2.16 C. Compared with the potential recorded from a typical ventricular fiber (see Fig. 2.16 A), the plateau (phase 2) is not as well developed, repolarization (phase 3) occurs as a slower rate, and the action potential duration is briefer.

Atrioventricular Conduction

The cardiac action potential proceeds along the internodal pathways in the atrium and ultimately reaches the AV node (see Fig. 3.6 ). This node is approximately 22 mm long, 10 mm wide, and 3 mm thick in adult humans. The node is situated posteriorly on the right side of the interatrial septum and is circumscribed by the ostium of the coronary sinus, the tendon of Todaro, and the tricuspid valve. The AV node contains the same two cell types as the SA node, but the round cells are more sparse and the spindle-shaped cells preponderate. Conduction of the impulse from the atrium to the AV node has been described as consisting of fast and slow pathways. There is some anatomical evidence for this well-known observation. The existence of fast and slow conduction paths allows a substrate for reentrant circuits within the AV node. Cells in the inferior portion of the AV node serve as a subsidiary pacemaker.

The AV node is divided into three functional regions: (1) the AN region, the transitional zone between the atrium and the remainder of the node; (2) the N region, the midportion of the AV node; and (3) the NH region, the zone in which nodal fibers gradually merge with the bundle of His , which is the upper portion of the specialized ventricular conducting system. Normally, the AV node and bundle of His constitute the only pathways for conduction from atria to ventricles.

Several features of AV conduction are of physiological and clinical significance. The principal delay in the passage of the impulse from the atria to the ventricles occurs in the AN and N regions of the AV node. The conduction velocity is actually less in the N region than in the AN region. However, the path length is substantially greater in the AN region than in the N region. The conduction times through the AN and N regions largely account for the delay between the onsets of the P wave (the electrical manifestation of the spread of atrial excitation) and the QRS complex (spread of ventricular excitation) in the electrocardiogram ( Fig. 3.7 ). Functionally, this delay between atrial excitation and ventricular excitation permits optimal ventricular filling during atrial contraction.

In the N region, slow response action potentials prevail. The resting potential is about −60 mV, the upstroke velocity is very low (about 5 V/s), and the conduction velocity is about 0.05 m/s. Tetrodotoxin, which blocks the fast Na ⁺ channels, does not affect the action potentials in this region. Conversely, the Ca ⁺⁺ channel antagonists decrease the amplitude and duration of the action potentials ( Fig. 3.8 ) and slow AV conduction. The shapes of the action potentials in the AN region are intermediate between those in the N region and the atria. Similarly, the action potentials in the NH region are transitional between those in the N region and the bundle of His. The relative refractory period of the cells in the N region extends well beyond the period of complete repolarization; that is, these cells display post-repolarization refractoriness (see Fig. 2.19 ).

As the repetition rate of atrial depolarizations is increased, conduction through the AV junctions slows. An abnormal prolongation of AV conduction time is called first-degree AV block ( Fig. 3.9A ). Most of the prolongation of AV conduction caused by an increase in repetition rate takes place in the N region.

Impulses tend to be blocked in the AV node at stimulus frequencies that are easily conducted in other regions of the heart. If the atria are depolarized at a high frequency, only a fraction (e.g., one-half) of the atrial impulses might be conducted through the AV junction to the ventricles. The conduction pattern in which only a fraction of the atrial impulses are conducted to the ventricles is called second-degree AV block (see Fig. 3.9B ). This type of block may protect the ventricles from excessive contraction frequencies, wherein the filling time between successive ventricular contractions might be inadequate, and therefore the ventricles would be unable to deliver an adequate cardiac output.

Retrograde conduction can occur through the AV node. However, the propagation time is significantly longer, and the impulse tends to be blocked at lower repetition rates during retrograde conduction than during antegrade conduction. Finally, the AV node is a common site for reentry, a phenomenon explained later in this chapter.

The autonomic nervous system regulates AV conduction. Weak vagal activity may simply prolong the AV conduction time. Stronger vagal activity may cause some or all of the impulses arriving from the atria to be blocked in the node. The conduction pattern in which none of the atrial impulses reach the ventricles over a substantial number of atrial depolarizations is called third-degree , or complete AV block (see Fig. 3.9C ). The delayed conduction or block induced by vagal stimulation occurs largely in the N region of the node.

Acetylcholine released by vagus nerve fibers hyperpolarizes the conducting fibers in the N region ( Fig. 3.10 ). The greater the hyperpolarization at the time of arrival of the atrial impulse, the more impaired the AV conduction will be. In the experiment shown in Fig. 3.10 , vagus nerve fibers were stimulated intensely (at St) shortly before the second atrial depolarization (A ₂ ). This atrial impulse arrived at the AV node cell when its cell membrane was maximally hyperpolarized. The absence of a corresponding depolarization of the bundle of His (H) shows that the second atrial impulse was not conducted through the AV node. Only a small, nonpropagated response to the second atrial impulse is evident in the recording from the conducting fiber.

Cardiac sympathetic nerves, on the other hand, facilitate AV conduction. They decrease AV conduction time and enhance the rhythmicity of the latent pacemakers in the AV junction. The norepinephrine released at the sympathetic nerve terminals increases the amplitude and slope of the upstroke of the AV nodal action potentials, principally in the AN and N regions of the node.

Ventricular Conduction

The bundle of His passes subendocardially down the right side of the interventricular septum for about 1 cm and then divides into the right and left bundle branches ( Figs. 3.6 and 3.11 ). The right bundle branch is a direct continuation of the bundle of His and proceeds down the right side of the interventricular septum. The left bundle branch, which is considerably thicker than the right one, arises almost perpendicularly from the bundle of His and perforates the interventricular septum. On the subendocardial surface of the left side of the interventricular septum, the main left bundle branch splits into a thin anterior division and a thick posterior division .

The right bundle branch and the two divisions of the left bundle branch ultimately subdivide into a complex network of conducting fibers called Purkinje fibers, which ramify over the subendocardial surfaces of both ventricles. In certain mammalian species, such as cattle, the Purkinje fiber network is arranged in discrete, encapsulated bundles (see Fig. 3.11 ).

Purkinje fibers are the broadest cells in the heart, at 70 to 80 μm in diameter, compared with 10 to 15 μm for ventricular myocytes. The large diameter accounts in part for the greater conduction velocity in Purkinje than in myocardial fibers. Conduction of the action potential over the Purkinje fiber system is faster than in any other tissue within the heart; estimates of conduction velocity vary from 1 to 4 m/s. This permits a rapid activation of the entire endocardial surface of the ventricles. Purkinje cells have abundant, linearly arranged sarcomeres, just like myocardial cells. However, the T-tubular system is absent in the Purkinje cells of many species but is well developed in the myocardial cells (see Chapter 4 ).

The action potentials recorded from Purkinje fibers resemble those of ordinary ventricular myocardial fibers (see Fig. 2.16 A). In general, phase 1 is more prominent in Purkinje fiber action potentials (see Fig. 2.3 ) than in action potentials recorded from ventricular fibers (especially endocardial fibers), and the duration of the plateau (phase 2) is longer.

Many premature activations of the atria that are conducted through the AV junction are blocked by the long refractory period of the Purkinje fibers . Therefore they fail to evoke a premature contraction of the ventricles. This function of protecting the ventricles against the effects of premature atrial depolarizations is especially pronounced at slow heart rates, because the action potential duration, and hence the effective refractory period of the Purkinje fibers, varies inversely with the heart rate (see Fig. 2.20 ). At slow heart rates, the effective refractory period of the Purkinje fibers is especially prolonged; as the heart rate increases, the refractory period diminishes. Similar rate-dependent changes in the refractory period also occur in most of the other cells in the heart. However, in the AV node, the effective refractory period does not change appreciably over the normal range of heart rates, and it actually increases at very rapid heart rates. Therefore at high heart rates, it is the AV node that protects the ventricles when atrial impulses arrive at excessive repetition rates .

The first portions of the ventricles to be excited are the interventricular septum (except its basal portion) and the papillary muscles. The wave of activation spreads into the septum from both its left and its right endocardial surfaces. Early contraction of the septum tends to make it more rigid and allows it to serve as an anchor point for the contraction of the remaining ventricular myocardium. Also, early contraction of the papillary muscles prevents eversion of the AV valves during ventricular systole.

The endocardial surfaces of both ventricles are activated rapidly, but the wave of excitation spreads from endocardium to epicardium at a slower velocity (about 0.3–0.4 m/s). Because the right ventricular wall is appreciably thinner than the left, the epicardial surface of the right ventricle is activated earlier than the epicardial surface of the left ventricle. Also, apical and central epicardial regions of both ventricles are activated somewhat earlier than are their respective basal regions. The last portions of the ventricles to be excited are the posterior basal epicardial regions and a small zone in the basal portion of the interventricular septum.