The Cardiac Action Potential

Figure 16-1 illustrates action potentials found in different cardiac cells. Two main types of action potentials occur in the heart and are shown. One type, the fast response, occurs in normal atrial and ventricular myocytes and in the specialized conducting fibers (Purkinje fibers of the heart) and is divided into five phases. The rapid upstroke of the action potential is designated phase 0. The upstroke is followed by a brief period of partial, early repolarization (phase 1) and then by a plateau (phase 2) that persists for about 0.1 to 0.2 second. The membrane then repolarizes (phase 3) until the resting state of polarization (phase 4) is again attained (at point e). Final repolarization (phase 3) develops more slowly than depolarization (phase 0). The other type of action potential, the slow response, occurs in the sinoatrial (SA) node, which is the natural pacemaker region of the heart, and in the atrioventricular (AV) node, which is the specialized tissue that conducts the cardiac impulse from the atria to the ventricles. The slow-response cells lack the early repolarization phase (phase 1). Other differences between the electrical properties of the fast-response and slow-response cells include the following. The resting membrane potential (phase 4) of the fast-response cells is considerably more negative than that of the slow-response cells. Moreover, the slope of the upstroke (phase 0), the amplitude of the action potential, and the overshoot are greater in the fast-response than in the slow-response cells. The action potential amplitude and the steepness of the upstroke are important determinants of propagation velocity along the myocardial fibers. In slow-response cardiac tissue, the action potential is propagated more slowly and conduction is more likely to be blocked than in fast-response cardiac tissue. Slow conduction and a tendency toward conduction block increase the likelihood of some rhythm disturbances (see the section Reentry).

Figure 16-1 Action potentials of fast-response (A) and slow-response (B) cardiac fibers. The phases of the action potentials are labeled (see text for details). The effective refractory period (ERP) and the relative refractory period (RRP) are labeled. Note that when compared with fast-response fibers, the resting potential of slow fibers is less negative, the upstroke (phase 0) of the action potential is less steep, the amplitude of the action potential is smaller, phase 1 is absent, and the RRP extends well into phase 4 after the fibers have fully repolarized.

As noted, the action potential initiates contraction of the myocyte. The relationships between the action potential and contraction of cardiac muscle are shown in Figure 16-2. Rapid depolarization (phase 0) precedes the development of force, and completion of repolarization coincides approximately with peak force. Relaxation of the muscle takes place mainly during phase 4 of the action potential. The duration of contraction usually parallels the duration of the action potential.

Figure 16-2 Time relationships between the force developed and changes in transmembrane potential in a thin strip of ventricular muscle.

(Redrawn from Kavaler F et al: Bull NY Acad Med 41:5925, 1965.)

The various phases of the cardiac action potential are associated with changes in cell membrane permeability, mainly to Na⁺, K⁺, and Ca⁺⁺ ions. Changes in cell membrane permeability alter the rate of movement of these ions across the membrane and thereby change the membrane voltage (V_m). These changes in permeability are accomplished by the opening and closing of ion channels that are specific for individual ions (see Chapters 1 and 2).

As with all other cells in the body, the concentration of K⁺ inside a cardiac muscle cell ([K⁺]_i) exceeds the concentration outside the cell ([K⁺]_o). The reverse concentration gradient exists for Na⁺ and Ca⁺⁺. Estimates of the extracellular and intracellular concentrations of Na⁺, K⁺, and Ca⁺⁺ and the Nernst equilibrium potentials (see Chapter 1) for these ions are compiled in Table 16-1.

Table 16-1 Intracellular and Extracellular Ion Concentrations and Equilibrium Potentials in Cardiac Muscle Cells

Resting Membrane Voltage

The resting cell membrane has relatively high permeability to K⁺; permeability to Na⁺ and Ca⁺⁺ is much less. Given the existing chemical gradient for K⁺ and V_m, K⁺ tends to diffuse from the inside to the outside of the cell. Any flux of K⁺ that occurs at the resting membrane potential (i.e., during phase 4) takes place mainly through specific K⁺ channels. Several types of K⁺ channels exist in cardiac cell membranes. Opening and closing of some of these channels are regulated by V_m, whereas others are controlled by a chemical signal (e.g., the extracellular acetylcholine concentration). The specific K⁺ channel through which K⁺ passes during phase 4 is a voltage-regulated channel that conducts the inwardly rectifying K⁺ current. This current is symbolized i_K1 and is discussed in more detail later. For now, it is necessary only to know how this current is established.

The dependence of V_m on conductance and the intracellular and extracellular concentrations of K⁺, Na⁺, and other ions is described by the chord conductance equation (see Chapter 2). In a resting cardiac cell, conductance to K⁺ (g_K) is about 100 times greater than conductance to Na⁺ (g_Na). Therefore, V_m is similar to the Nernst equilibrium potential for K⁺. As a result, alterations in extracellular [K⁺] can significantly change V_m, with hypokalemia causing hyperpolarization and hyperkalemia causing depolarization. In contrast, because g_Na is so small in the resting cell, changes in [Na⁺]_o do not significantly affect V_m.

IN THE CLINIC

Fast responses may change to slow responses under certain pathological conditions. For example, in coronary artery disease, a region of cardiac muscle may be deprived of its normal blood supply. As a result, [K⁺] in the interstitial fluid that surrounds the affected muscle cells rises because K⁺ is lost from the inadequately perfused (or ischemic) cells. The action potentials in some of these cells may then be converted from fast to slow responses. Conversion from a fast to a slow response as a result of increasing interstitial [K⁺] is illustrated later in Figure 16-13.

Figure 16-13 Effect of changes in [K⁺]_o on the transmembrane action potentials recorded from a Purkinje fiber. The stimulus artifact (St) appears as a biphasic spike to the left of the upstroke of the action potential. The horizontal lines near the peaks of the action potentials denote 0 mV. When [K⁺]_o is 3 mM (A and F), the resting V_m is −82 mV and the slope of phase 0 is steep. At the end of phase 0, the overshoot attains a value of 30 mV. Hence, the action potential amplitude is 112 mV. The distance from the stimulus artifact to the beginning of phase 0 is inversely proportional to the conduction velocity. When [K⁺]_o is increased gradually to 16 mM (B to E), the resting V_m becomes progressively less negative. At the same time, the amplitudes and durations of the action potentials and the steepness of the upstrokes all diminish. As a consequence, conduction velocity decreases progressively. At [K⁺]_o levels of 14 and 16 mM (D and E), the resting V_m attains levels sufficient to inactivate all the fast Na⁺ channels and leave the characteristic slow-response action potentials.

(From Myerburg RJ, Lazzara R: In Fisch E [ed]: Complex Electrocardiography. Philadelphia, FA Davis, 1973.)

Fast-Response Action Potentials

Genesis of the Upstroke (Phase 0)

Any stimulus that abruptly depolarizes V_m to a critical value (called the threshold) elicits an action potential. The characteristics of fast-response action potentials are shown in Figure 16-1, A. The rapid depolarization (phase 0) is related almost exclusively to the influx of Na⁺ into the myocyte as a result of a sudden increase in g_Na. The action potential amplitude (the potential change during phase 0) is dependent on [Na⁺]_o. When [Na⁺]_o is decreased, the amplitude of the action potential decreases, and when [Na⁺]_o is reduced from its normal value of about 140 mEq/L to about 20 mEq/L, the cell is no longer excitable.

When the resting membrane potential, V_m, is suddenly depolarized from −90 mV to the threshold level of about −65 mV, the cell membrane properties change dramatically. Na⁺ enters the myocyte through specific fast voltage-activated Na⁺ channels that exist in the membrane. These channels can be blocked by the puffer fish toxin tetrodotoxin. In addition, many drugs used to treat certain cardiac rhythm disturbances (cardiac arrhythmias) act by blocking these fast Na⁺ channels.

The Na⁺ channels open very rapidly or activate (in about 0.1 msec), thereby resulting in an abrupt increase in g_Na. However, once open, the Na⁺ channels inactivate (time course ≈ 1 to 2 msec), and g_Na rapidly decreases (Fig. 16-3). The Na⁺ channels remain in the inactivated state until the membrane begins to repolarize. With repolarization, the channel transitions to the closed state, from which it can then be reopened by another depolarization of V_m to the threshold. These properties of the Na⁺ channel underlie the basis of the action potential refractory period. When the Na⁺ channels are in the inactivated state, they cannot be reopened, and another action potential cannot be generated. During this period the cell is said to be in the effective refractory period. This prevents a sustained, tetanic contraction of cardiac muscle, which would retard ventricular relaxation and therefore interfere with the normal intermittent pumping action of the heart. As the cell repolarizes (phase 3), the inactivated channels begin to transition to the closed state. During this period, called the relative refractory period, another action potential can be generated, but it requires a larger than normal depolarization of V_m. Only when V_m has returned to the resting level (phase 4) are all the Na⁺ channels closed and thus able to be reactivated by the normal depolarization of V_m.

Figure 16-3 Principal ionic currents and channels that generate the various phases of the action potential in a cardiac cell. Phase 0: The chemical and electrostatic forces both favor the entry of Na⁺ into the cell through fast Na⁺ channels to generate the upstroke. Phase 1: The chemical and electrostatic forces both favor the efflux of K⁺ through i_to channels to generate early, partial repolarization. Phase 2: During the plateau, the net influx of Ca⁺⁺ through Ca⁺⁺ channels is balanced by the efflux of K⁺ through i_K, i_K1, and i_to channels. Phase 3: The chemical forces that favor the efflux of K⁺ through i_K and i_K1 channels predominate over the electrostatic forces that favor the influx of K⁺ through these same channels. Phase 4: The chemical forces that favor the efflux of K⁺ through i_K and i_K1 channels very slightly exceed the electrostatic forces that favor the influx of K⁺ through these same channels.

AT THE CELLULAR LEVEL

Ionic currents through single membrane channels can be measured with the patch clamp technique. The individual channels open and close repeatedly in a random manner. This process is illustrated in Figure 16-4, which shows the current flow through single Na⁺ channels in a myocardial cell. To the left of the arrow, the membrane potential was clamped at −85 mV. At the arrow, the potential was suddenly changed to −45 mV, at which value it was held for the remainder of the record. Figure 16-4 indicates that immediately after the membrane potential was made less negative, one Na⁺ channel opened three times in sequence. It remained open for about 2 or 3 msec each time and closed for about 4 or 5 msec between openings. In the open state it allowed 1.5 pA of current to pass. During the first and second openings of this channel, a second channel also opened, but for periods of only 1 msec. During the brief times that both channels were open simultaneously, the total current was 3 pA. After the first channel closed for the third time, both channels remained closed for the rest of the recording, even though the membrane was held constant at −45 mV.

Figure 16-4 Current (in picoamperes) through two individual Na⁺ channels in a cultured heart cell recorded with the patch clamp technique. Membrane voltage was held at −85 mV and then abruptly changed to −45 mV at the arrow and held at this potential for the remainder of the record.

(Redrawn from Cachelin AB et al: J Physiol 340:389, 1983.)

The overall change in ionic conductance of the entire cell membrane at any given time reflects the number of channels that are open at that time. Because the individual channels open and close randomly, the overall membrane conductance represents the statistical probability of the open or closed state of the individual channels. The temporal characteristics of the activation process then represent the time course of the increasing probability that the specific channels will be open rather than the kinetic characteristics of the activation gates in the individual channels. Similarly, the temporal characteristics of inactivation reflect the time course of the decreasing probability that the channels will be open and not the kinetic characteristics of the inactivation gates in the individual channels.

Genesis of Early Repolarization (Phase 1)

In many cardiac cells that have a prominent plateau, phase 1 is an early, brief period of limited repolarization. This brief repolarization results in the notch between the end of the upstroke and the beginning of the plateau (Figs. 16-1 and 16-3). Repolarization is brief because of activation of a transient outward current (i_to) carried mainly by K⁺. Activation of K⁺ channels during phase 1 causes a brief efflux of K⁺ from the cell because the cell interior is positively charged and [K⁺]_i greatly exceeds [K⁺]_o (Fig. 16-3). The cell is briefly and partially repolarized as a result of this transient efflux of K⁺.

The size of the phase 1 notch varies among cardiac cells. It is prominent in myocytes in the epicardial and midmyocardial regions of the left ventricular wall (Fig. 16-5) and in ventricular Purkinje fibers. However, the notch is negligible in myocytes from the endocardial region of the left ventricle (Fig. 16-5) because the density of i_to channels is less in these cells. The notch is also less prominent in the presence of 4-aminopyridine, which blocks the K⁺ channels that carry i_to.

Figure 16-5 Action potentials recorded from the epicardial (A), midmyocardial (B), and endocardial (C) regions of the free wall of the canine left ventricle. The preparations were driven at a basic cycle length (BCL) of 300 and 8000 msec.

(From Liu D-W et al: Circ Res 72:671, 1993.)

Genesis of the Plateau (Phase 2)

During the action potential plateau, Ca⁺⁺ enters myocardial cells through calcium channels (see later) that activate and inactivate much more slowly than the fast Na⁺ channels do. During the flat portion of phase 2 (Figs. 16-1 and 16-3), this influx of Ca⁺⁺ is counterbalanced by the efflux of K⁺. K⁺ exits through channels that conduct mainly the i_to, i_K, and i_K1 currents. The i_to current is responsible for phase 1, as described previously, but it is not completely inactivated until after phase 2 has expired. The i_K and i_K1 currents are described later in this chapter.

Ca⁺⁺ enters the cell via voltage-regulated Ca⁺⁺ channels, which are activated as V_m becomes progressively less negative during the action potential upstroke. Two types of Ca⁺⁺ channels (L type and T type) have been identified in cardiac tissue. Some of their important characteristics are illustrated in Figure 16-6. L-type channels are so designated because once open they inactivate slowly (Fig. 16-6, lower panel) and provide a “long-lasting” Ca⁺⁺ current. They are the predominant type of Ca⁺⁺ channel in the heart, and they are activated during the action potential upstroke when V_m reaches about −20 mV. L-type channels are blocked by Ca⁺⁺ channel antagonists such as verapamil, amlodipine, and diltiazem (Fig. 16-7).

Figure 16-6 Effects of isoproterenol on the Ca⁺⁺ currents conducted by T-type (upper panel) and L-type (lower panel) Ca⁺⁺ channels in atrial myocytes. Upper panel, potential changed from −80 to −20 mV; lower panel, potential changed from −30 to +30 mV.

(Redrawn from Bean BP: J Gen Physiol 86:1, 1985.)

Figure 16-7 Effects of diltiazem, a Ca⁺⁺ channel antagonist, on the action potentials (in millivolts) and isometric contractile forces (in millinewtons) recorded from an isolated papillary muscle. The tracings were recorded under control conditions (C) and in the presence of diltiazem in concentrations of 3, 10, and 30 μmol/L.

(Redrawn from Hirth C et al: J Mol Cell Cardiol 15:799, 1983.)

T-type (or “transient”) Ca⁺⁺ channels are much less abundant in the heart. They are activated at more negative potentials (about −70 mV) than L-type channels are. They also inactivate more quickly than L-type channels do (Fig. 16-6, upper panel).

Because L-type channels are the most abundant, the following is focused on their function and properties. Opening of Ca⁺⁺ channels results in an increase in Ca⁺⁺ conductance (g_Ca) and current (i_Ca) soon after the action potential upstroke (Fig. 16-3). Because [Ca⁺⁺]_i is much less than [Ca⁺⁺]_o (Table 16-1), the increase in g_Ca promotes the influx of Ca⁺⁺ into the cell throughout the plateau. This Ca⁺⁺ influx during the plateau is involved in excitation-contraction coupling, as described later (see also Chapter 13).

Various neurotransmitters and drugs may substantially influence g_Ca. The adrenergic neurotransmitter norepinephrine, the β-adrenergic receptor agonist isoproterenol, and various other catecholamines enhance g_Ca, whereas the parasympathetic neurotransmitter acetylcholine decreases g_Ca. Enhancement of g_Ca by catecholamines is the principal mechanism by which they enhance cardiac muscle contractility.

During the plateau (phase 2) of the action potential, the concentration gradient for K⁺ across the cell membrane is virtually the same as it is during phase 4. However, V_m is now positive. Therefore, there is a large gradient that favors efflux of K⁺ from the cell (Fig. 16-3). If g_K were the same during the plateau as it is during phase 4, efflux of K⁺ during phase 2 would greatly exceed the influx of Ca⁺⁺, and a sustained plateau could not be achieved. However, as V_m approaches and then attains positive values near the peak of the action potential upstroke, g_K suddenly decreases (Fig. 16-8). The diminished K⁺ current associated with the reduction in g_K prevents excessive loss of K⁺ from the cell during the plateau.

Figure 16-8 Changes in depolarizing (upper panels) and repolarizing (lower panels) ion currents during the various phases of the action potential in a fast-response cardiac ventricular cell. The inward currents include the fast Na⁺ and L-type Ca⁺⁺ currents. Outward currents are i_K1, i_to, and the rapid (i_Kr) and slow (i_Ks) delayed rectifier K⁺ currents.

(Redrawn from Tomaselli G, Marbán E: Cardiovasc Res 42:270, 1999.)

AT THE CELLULAR LEVEL

To enhance g_Ca, catecholamines first bind to βadrenergic receptors in the cardiac cell membrane. This interaction stimulates the membrane-bound enzyme adenylyl cyclase, which raises the intracellular concentration of cAMP (see also Chapter 3). The rise in the level of cAMP activates cAMP-dependent protein kinase, which in turn promotes phosphorylation of the L-type Ca⁺⁺ channels in the cell membrane and thus augments the influx of Ca⁺⁺ into the cells (Fig. 16-6). Conversely, acetylcholine interacts with muscarinic receptors in the cell membrane to inhibit adenylyl cyclase. In this way, acetylcholine antagonizes the activation of Ca⁺⁺ channels and thereby diminishes g_Ca.

IN THE CLINIC

Ca⁺⁺ channel antagonists are substances that block Ca⁺⁺ channels. Examples include the drugs verapamil, amlodipine, and diltiazem. These drugs decrease g_Ca and thereby impede the influx of Ca⁺⁺ into myocardial cells. Ca⁺⁺ channel antagonists decrease the duration of the action potential plateau and diminish the strength of the cardiac contraction (Fig. 16-7). Ca⁺⁺ channel antagonists also depress the contraction of vascular smooth muscle and thereby induce generalized vasodilation. This diminished vascular resistance reduces the counterforce (afterload) that opposes the propulsion of blood from the ventricles into the arterial system, as explained in Chapter 17. Hence, vasodilator drugs such as the Ca⁺⁺ channel antagonists are often referred to as afterload-reducing drugs.

This reduction in g_K at both positive and low negative values of V_m is called inward rectification. Inward rectification is a characteristic of several K⁺ currents, including the i_K1 current (Fig. 16-9). For these channels, large K⁺ currents flow at negative values of V_m (i.e., g_K is large). However, when V_m is near 0 mV, or positive, as occurs during the plateau (phase 2), little or no K⁺ current flows (i.e., g_K is low). Thus, the substantial g_K that prevails during phase 4 of the cardiac action potential (Fig. 16-8) is largely due to the i_K1 channels, but current through these channels is greatly diminished during the plateau (Fig. 16-9).

Figure 16-9 Inwardly rectified K⁺ currents recorded from a ventricular myocyte when the potential was changed from a holding potential of −80 mV to various test potentials. Positive values along the vertical axis represent outward currents; negative values represent inward currents. The V_m coordinate of the point (open circle) at which the curve intersects the x axis is the reversal potential; it denotes the Nernst equilibrium potential (E_K), at which point the chemical and electrostatic forces are equal.

(Redrawn from Giles WR, Imaizumi Y: J Physiol [Lond] 405:123, 1988.)

Other K⁺ channels play a role in phase 2 of the action potential. These are characterized as delayed rectifier (i_K) channels. These K⁺ channels are closed during phase 4 and are activated very slowly by the potentials that prevail toward the end of phase 0. Hence, activation of these channels tends to increase g_K very gradually during phase 2. These channels play only a minor role during phase 2, but they contribute to the process of final repolarization (phase 3), as described later. Two types of i_K channels exist, depending on their rates of activation. The more slowly activating channel is designated the i_Ks channel, whereas the more rapidly activating channel is designated the i_Kr channel (Fig. 16-8). The duration of the action potential in myocytes in various regions of the ventricular myocardium is determined in part by the relative distributions of these i_Kr and i_Ks channels.

The action potential plateau persists as long as the efflux of charge carried mainly by K⁺ is balanced by the influx of charge carried mainly by Ca⁺⁺. The effects of altering this balance are demonstrated by the action of the Ca⁺⁺ channel antagonist diltiazem in an isolated papillary muscle preparation (Fig. 16-7). With increasing concentrations of diltiazem, the plateau voltage becomes progressively less positive and the plateau duration diminishes. Conversely, administration of certain K⁺ channel antagonists prolongs the plateau substantially.

Genesis of Final Repolarization (Phase 3)

The process of final repolarization (phase 3) starts at the end of phase 2, when efflux of K⁺ from the cardiac cell begins to exceed influx of Ca⁺⁺. As noted, at least three outward K⁺ currents (i_to, i_K, and i_K1) contribute to the final repolarization (phase 3) of the cardiac cell (Figs. 16-3 and 16-8).

The transient outward (i_to) and the delayed rectifier (i_Kr, i_Ks) currents help initiate repolarization. These currents are therefore important determinants of the duration of the plateau. For example, the duration of the plateau is substantially less in atrial than in ventricular myocytes (Fig. 16-10) because the magnitude of i_to during the plateau is greater in atrial than in ventricular myocytes. As already noted, the duration of the action potential in ventricular myocytes varies considerably with the location of these myocytes in the ventricular walls (Fig. 16-5). The i_to and delayed rectifier (i_K) currents mainly account for these differences. In endocardial myocytes, in which the duration of the action potential is least, the magnitude of i_K is greatest. The converse applies to the midmyocardial myocytes. The magnitude of i_K and the duration of the action potential are intermediate for epicardial myocytes.

Figure 16-10 Typical action potentials (in millivolts) recorded from cells in the ventricle (A), SA node (B), and atrium (C). Note that the time calibration in B differs from that in A and C.

(From Hoffman BF, Cranefield PF: Electrophysiology of the Heart. New York, McGraw-Hill, 1960.)

The inwardly rectified K⁺ current i_K1 does not participate in the initiation of repolarization because the conductance of these channels is very small over the range of V_m values that prevail during the plateau. However, the i_K1 channels contribute substantially to the rate of repolarization once phase 3 has been initiated. As V_m becomes increasingly negative during phase 3, the conductance of the channels that carry the i_K1 current progressively increases and thereby accelerates repolarization (Fig. 16-3).

Slow-Response Action Potentials

As described earlier, fast-response action potentials (Fig. 16-1, A) consist of four principal components: an upstroke (phase 0), an early partial repolarization (phase 1), a plateau (phase 2), and a final repolarization (phase 3). However, in the slow-response action potential (Fig. 16-1, B), the upstroke is much less steep, early repolarization (phase 1) is absent, the plateau is less prolonged and not as flat, and the transition from the plateau to the final repolarization is less distinct.

Blocking fast Na⁺ channels with tetrodotoxin in a fast-response fiber can generate slow responses under appropriate conditions. The Purkinje fiber action potential shown in Figure 16-11 clearly exhibits the two response types. In the control tracing (A), the typical fast-response action potential displays a prominent notch as a result of i_to that separates the upstroke from the plateau. In action potentials B to E, progressively larger quantities of tetrodotoxin produce a graded blockade of the fast Na⁺ channels. The upstroke and notch become progressively less prominent in action potentials B to D. In action potential E, the notch has disappeared and the upstroke is very gradual; this action potential resembles a typical slow response.

Figure 16-11 Effect of tetrodotoxin, which blocks the fast Na⁺ channels, on the action potentials recorded in a Purkinje fiber. The concentration of tetrodotoxin was 0 M in A, 3 × 10⁻⁸ M in B, 3 × 10⁻⁷ M in C, and 3 × 10⁻⁶ M in D and E; E was recorded later than D.

(Redrawn from Carmeliet E, Vereecke J: Pflügers Arch 313:300, 1969.)

Certain cells in the heart, notably those in the SA and AV nodes, exhibit slow-response action potentials. In these cells, depolarization is achieved mainly by influx of Ca⁺⁺ through L-type Ca⁺⁺ channels instead of influx of Na⁺ through fast Na⁺ channels. Repolarization is accomplished in these fibers by inactivation of the Ca⁺⁺ channels and by the increased K⁺ conductance through the i_K1 and i_K channels (Fig. 16-3).

Conduction of the Fast Response

The characteristics of conduction differ in fast- and slow-response fibers. In fast-response fibers, fast Na⁺ channels are activated when the transmembrane potential of one region of the fiber suddenly changes from a resting value of about −90 mV to the threshold value of about −65 mV. The inward Na⁺ current then rapidly depolarizes the cell at that site. This portion of the fiber subsequently becomes part of the depolarized zone, and the border is displaced accordingly. The same process then begins at the new border. This process is repeated again and again, and the border moves continuously down the fiber as a wave of depolarization (Fig. 16-12).

Figure 16-12 The role of local currents in the propagation of a wave of excitation down a cardiac fiber.

The conduction velocity along the fiber varies directly with the amplitude of the action potential and the rate of change of the potential (dV_m/dt) during phase 0. The amplitude of the action potential equals the potential difference between the fully depolarized and the fully polarized regions of the cell interior. The magnitude of the local current is proportional to this potential difference (see Chapter 5). Because these local currents shift the potential of the resting zone toward the threshold value, they are local stimuli that depolarize the adjacent resting portion of the fiber to its threshold potential. The greater the potential difference between the depolarized and polarized regions (i.e., the greater the action potential amplitude), the more effective are local stimuli in depolarizing adjacent parts of the membrane and the more rapidly is the wave of depolarization propagated down the fiber.

The rate of change in potential during phase 0 is also an important determinant of conduction velocity. If the active portion of the fiber depolarizes gradually, the local currents between the resting region and the neighboring depolarizing region are small. The resting region adjacent to the active zone is depolarized gradually, and consequently more time is required for each new section of the fiber to reach threshold. This allows some Na⁺ channels to inactivate.

The resting membrane potential is also an important determinant of conduction velocity. Changes in the resting membrane potential influence both the amplitude of the action potential and the slope of the upstroke, which in turn alter the conduction velocity (Fig. 16-13). Depolarization of V_m leads to inactivation of the fast Na⁺ channels, which in turn decreases the amplitude of the action potential and the slope of the upstroke, and as a consequence conduction velocity is slowed. In addition to changes in [K⁺]_o, premature excitation of a cell that has not completely repolarized will also result in a decrease in conduction velocity. This too reflects the fact that when V_m is depolarized, more fast Na⁺ channels are inactivated, and thus only a fraction of the Na⁺ channels are available to conduct the inward Na⁺ current during phase 0.

Conduction of the Slow Response

Local circuits (Fig. 16-12) also propagate the slow response, the conduction characteristics of which differ quantitatively from those of the fast response. The threshold potential is about −40 mV for the slow response, and conduction is much slower than for the fast response. The conduction velocities of the slow response in the SA and AV nodes are about 0.02 to 0.1 m/sec. The fast-response conduction velocities are about 0.3 to 1 m/sec for myocardial cells and 1 to 4 m/sec for the specialized conducting (Purkinje) fibers in the ventricles. Slow responses are more readily blocked than fast responses; that is, conduction ceases before the impulse reaches the end of the myocardial fiber. In addition, fast-response fibers can respond at repetition rates that are much greater than those of slow-response fibers.

Fast Response

Once the fast response has been initiated, the depolarized cell is no longer excitable until the cell has partially repolarized (Fig. 16-1, A). The interval from the beginning of the action potential until the fiber is able to conduct another action potential is called the effective refractory period. In the fast response, this period extends from the beginning of phase 0 to a point in phase 3 at which repolarization has reached about −50 mV (phase 3 in Fig. 16-1, A). At about this value of V_m, many of the fast Na⁺ channels have transitioned from the inactivated to the closed state. However, the cardiac fiber is not fully excitable until it has been completely repolarized. Before complete repolarization (i.e., during the relative refractory period), an action potential may be evoked only when the stimulus is stronger than a stimulus that could elicit a response during phase 4.

When a fast response is evoked during the relative refractory period of a previous excitation, its characteristics vary with the membrane potential that exists at the time of stimulation (Fig. 16-14). The later in the relative refractory period that the fiber is stimulated, the greater the increase in the amplitude of the response and the slope of the upstroke because the number of fast Na⁺ channels that have recovered from inactivation increases as repolarization proceeds. As a consequence, propagation velocity also increases the later in the relative refractory period that the fiber is stimulated. Once the fiber is fully repolarized, the response is constant no matter what time in phase 4 the stimulus is applied.

Figure 16-14 Changes in action potential amplitude and upstroke slope as action potentials are initiated at different stages of the relative refractory period of the preceding excitation.

(Redrawn from Rosen MR et al: Am Heart J 88:380, 1974.)

Slow Response

In slow-response fibers, the relative refractory period frequently extends well beyond phase 3 (Fig. 16-1, B). Even after the cell has completely repolarized, it may be difficult to evoke a propagated response for some time. This characteristic of slow-response fibers is called postrepolarization refractoriness.

IN THE CLINIC

In a patient who has occasional premature depolarizations (Fig. 16-32), the timing of these early beats may determine their clinical consequence. If they occur late in the relative refractory period of the preceding depolarization, or after full repolarization, the premature depolarization is probably inconsequential. However, if the premature depolarizations originate early in the relative refractory period of the ventricles, conduction of the premature impulse from the site of origin will be slow, and hence reentry is more likely to occur. If that reentry is irregular (i.e., if ventricular fibrillation ensues), the heart cannot pump effectively and death may result.

Figure 16-32 Premature atrial depolarization (A) and premature ventricular depolarization (B). The premature atrial depolarization (the second beat in A) is characterized by an inverted P wave and normal QRS complexes and T waves. The interval after the premature depolarization is not much longer than the usual interval between beats. The brief rectangular deflection just before the last depolarization is a standardization signal. The premature ventricular depolarization is characterized by bizarre QRS complexes and T waves and is followed by a compensatory pause.

Action potentials evoked early in the relative refractory period are small and the upstrokes are not very steep (Fig. 16-15). The amplitudes and upstroke slopes progressively improve as action potentials are elicited later in the relative refractory period. Recovery of full excitability is much slower than recovery of the fast response. Impulses that arrive early in the relative refractory period are conducted much more slowly than those that arrive late in that period. The long refractory periods also lead to conduction blocks. Even when slow responses recur at low frequency, the fiber may be able to conduct only a fraction of these impulses; for example, in certain conditions only alternate impulses may be propagated (see later).

Figure 16-15 Effects of excitation at various times after the initiation of an action potential in a slow-response fiber. In this fiber, excitation very late in phase 3 (or early in phase 4) induces a small, nonpropagated (local) response (a). Later in phase 4, a propagated response (b) can be elicited, but its amplitude is small and the upstroke is not very steep; this response is conducted very slowly. Still later in phase 4, full excitability is regained, and the response (c) displays normal characteristics.

(Modified from Singer DH et al: Prog Cardiovasc Dis 24:97, 1981.)

Sinoatrial Node

As noted, the region of the mammalian heart that ordinarily generates impulses at the greatest frequency is the SA node; it is the main cardiac pacemaker. Detailed mapping of the electrical potentials on the surface of the right atrium reveals that two or three sites of automaticity, located 1 or 2 cm from the SA node itself, serve along with the SA node as an atrial pacemaker complex. At times, all these loci initiate impulses simultaneously. At other times, the site of earliest excitation shifts from locus to locus, depending on certain conditions, such as the level of autonomic neural activity.

In humans, the SA node is about 8 mm long and 2 mm thick, and it lies posteriorly in the groove at the junction between the superior vena cava and the right atrium. 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, elongated cells that are intermediate in appearance between the round and “ordinary” atrial myocardial cells. The round cells are probably the pacemaker cells; the slender, elongated cells probably conduct the impulses within the node and to the nodal margins.

A typical transmembrane action potential recorded from an SA node cell is depicted in Figure 16-10, B. When compared with the transmembrane potential recorded from a ventricular myocardial cell (Fig. 16-10, A), the resting potential of the SA node cell is usually less negative, the upstroke of the action potential (phase 0) is less steep, the plateau is not sustained, and repolarization (phase 3) is more gradual. These are characteristic attributes of the slow response. As in cells that exhibit the slow response, tetrodotoxin (which blocks the fast Na⁺ current) has no influence on the SA nodal action potential because the action potential upstroke is not produced by an inward Na⁺ current through fast channels.

The transmembrane potential 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_K1 (inward rectifying) type of K⁺ channel. Thus, the ratio of g_K to g_Na during phase 4 is much less in nodal cells than in myocytes. Hence, during phase 4, V_m deviates much more from the K⁺ equilibrium potential (E_K) in nodal cells than it does in myocytes.

The principal feature of a pacemaker cell that distinguishes it from the other cells that we have discussed resides in phase 4. In nonautomatic cells, the potential remains constant during this phase, whereas a pacemaker fiber is characterized by slow diastolic depolarization throughout phase 4. Depolarization proceeds at a steady rate until a threshold is attained, and an action potential is then triggered.

Pacemaker cell frequency may be varied by a change in (1) the rate of depolarization during phase 4, (2) the maximal negativity during phase 4, or (3) the threshold potential (Fig. 16-18). When the rate of slow diastolic depolarization is increased, the threshold potential is attained earlier, and the heart rate increases. A rise in the threshold potential delays the onset of phase 0, and the heart rate is reduced. Similarly, when the maximal negative potential is increased, more time is required to reach the threshold potential, when the slope of phase 4 remains unchanged, and the heart rate therefore diminishes.

Figure 16-18 Mechanisms involved in the changes in frequency of pacemaker firing. In A, a reduction in the slope (from a to b) of slow diastolic depolarization diminishes the firing frequency. In B, an increase in the threshold potential (from TP-1 to TP-2) or an increase in the magnitude of the maximum diastolic potential (from a to d) also diminishes the firing frequency.

(From Hoffman BF, Cranefield PF: Electrophysiology of the Heart. New York, McGraw-Hill, 1960.)

Ionic Basis of Automaticity

Several ionic currents contribute to the slow diastolic depolarization that characteristically occurs in the automatic cells in the heart. In the pacemaker cells of the SA node, at least three ionic currents mediate the slow diastolic depolarization: (1) an outward K⁺ current, i_K; (2) an inward current, i_f, induced by hyperpolarization; and (3) an inward Ca⁺⁺ current, I_Ca (Fig. 16-19).

Figure 16-19 The transmembrane potential changes (top half) that occur in SA node cells are produced by three principal currents (bottom half): (1) the current i_Ca; (2) a hyperpolarization-induced inward current, i_f; and (3) an outward K⁺ current, i_K. The thin noisy green trace shows net membrane current and the approximate time course of (1) the repolarizing outward K⁺ current i_K, (2) the hyperpolarization-induced inward current i_f, and (3) the L-type Ca⁺⁺ current i_Ca. The thick bold red line in the current trace indicates the magnitude and direction of estimated I_f.

(Redrawn from van Ginneken ACG, Giles W: J Physiol 434:57, 1991.)

The repetitive firing of the pacemaker cell begins with the delayed rectifier K⁺ current i_K. Efflux of K⁺ tends to repolarize the cell after the upstroke of the action potential. K⁺ continues to move out well beyond the time of maximal repolarization, but its efflux diminishes throughout phase 4 (Fig. 16-19). As the current diminishes, its opposition to the depolarizing effects of the two inward currents (i_f and i_Ca) also gradually decreases. The progressive diastolic depolarization is mediated by the two inward currents i_f and i_Ca, which oppose the repolarizing effect of the outward current i_K.

AT THE CELLULAR LEVEL

The “f”-current (I_f) in cardiac SA node cells is activated by hyperpolarization and gated by cyclic nucleotides and is designated HCN. There are four members of the HCN gene family, and such channels are found in central nervous system neurons that generate action potentials repetitively. Transmembrane segment 4 (S₄) has many positively charged amino acids that act as voltage sensors, as also found in voltage-gated Na⁺, K⁺, and Ca⁺⁺ channels. The dominant channel expressed in heart is derived from the HCN4 gene. Mutations in amino acids in S₄ and in the S₄-to-S₅ linker cause marked changes in the voltage dependence of activation such that greater hyperpolarization is needed to open the channel. This effect is like that of acetylcholine, and it has been predicted that the occurrence of such mutations in the human heart could underlie sinus bradycardia and sick sinus syndrome.

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