Physiology 5th Ed.

CARDIAC ELECTROPHYSIOLOGY

Cardiac electrophysiology includes all of the processes involved in the electrical activation of the heart: the cardiac action potentials; the conduction of action potentials along specialized conducting tissues; excitability and the refractory periods; the modulating effects of the autonomic nervous system on heart rate, conduction velocity, and excitability; and the electrocardiogram (ECG).

Ultimately, the function of the heart is to pump blood through the vasculature. To serve as a pump, the ventricles must be electrically activated and then contract. In cardiac muscle, electrical activation is the cardiac action potential, which normally originates in the sinoatrial (SA) node. The action potentials initiated in the SA node then are conducted to the entire myocardium in a specific, timed sequence. Contraction follows, also in a specific sequence. “Sequence” is especially critical because the atria must be activated and contract before the ventricles, and the ventricles must contract from apex to base for efficient ejection of blood.

Cardiac Action Potentials

Origin and Spread of Excitation within the Heart

The heart consists of two kinds of muscle cells: contractile cells and conducting cells. Contractile cells constitute the majority of atrial and ventricular tissues and are the working cells of the heart. Action potentials in contractile cells lead to contraction and generation of force or pressure. Conducting cells constitute the tissues of the SA node, the atrial internodal tracts, the AV node, the bundle of His, and the Purkinje system. Conducting cells are specialized muscle cells that do not contribute significantly to generation of force; instead, they function to rapidly spread action potentials over the entire myocardium. Another feature of the specialized conducting tissues is their capacity to generate action potentials spontaneously. Except for the SA node, however, this capacity normally is suppressed.

Figure 4-11 is a schematic drawing showing the relationships of the SA node, atria, ventricles, and specialized conducting tissues. The action potential spreads throughout the myocardium in the following sequence:

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Figure 4–11 Schematic diagram showing the sequence of activation of the myocardium. The cardiac action potential is initiated in the sinoatrial node and spreads throughout the myocardium, as shown by the arrows.

1.     SA node. Normally, the action potential of the heart is initiated in the specialized tissue of the SA node, which serves as the pacemaker. After the action potential is initiated in the SA node, there is a specific sequence and timing for the conduction of action potentials to the rest of the heart.

2.     Atrial internodal tracts and atria. The action potential spreads from the SA node to the right and left atria via the atrial internodal tracts. Simultaneously, the action potential is conducted to the AV node.

3.     AV node. Conduction velocity through the AV node is considerably slower than in the other cardiac tissues. Slow conduction through the AV node ensures that the ventricles have sufficient time to fill with blood before they are activated and contract. Increases in conduction velocity of the AV node can lead to decreased ventricular filling and decreased stroke volume and cardiac output.

4.     Bundle of His, Purkinje system, and ventricles. From the AV node, the action potential enters the specialized conducting system of the ventricles. The action potential is first conducted to the bundle of His through the common bundle. It then invades the left and right bundle branches and then the smaller bundles of the Purkinje system. Conduction through the His-Purkinje system is extremely fast, and it rapidly distributes the action potential to the ventricles. The action potential also spreads from one ventricular muscle cell to the next, via low-resistance pathways between the cells. Rapid conduction of the action potential throughout the ventricles is essential and allows for efficient contraction and ejection of blood.

The term normal sinus rhythm has a specific meaning. It means that the pattern and timing of the electrical activation of the heart are normal. To qualify as normal sinus rhythm, the following three criteria must be met: (1) The action potential must originate in the SA node. (2) The SA nodal impulses must occur regularly at a rate of 60 to 100 impulses per minute. (3) The activation of the myocardium must occur in the correct sequence and with the correct timing and delays.

Concepts Associated with Cardiac Action Potentials

The concepts applied to cardiac action potentials are the same concepts that are applied to action potentials in nerve, skeletal muscle, and smooth muscle. The following section is a summary of those principles, which are discussed in Chapter 1:

1.     The membrane potential of cardiac cells is determined by the relative conductances (or permeabilities) to ions and the concentration gradients for the permeant ions.

2.     If the cell membrane has a high conductance or permeability to an ion, that ion will flow down its electrochemical gradient and attempt to drive the membrane potential toward its equilibrium potential(calculated by the Nernst equation). If the cell membrane is impermeable to an ion, that ion will make little or no contribution to the membrane potential.

3.     By convention, membrane potential is expressed in millivolts (mV), and intracellular potential is expressed relative to extracellular potential; for example, a membrane potential of −85 mV means 85 mV, cell interior negative.

4.     The resting membrane potential of cardiac cells is determined primarily by potassium ions (K+). The conductance to K+ at rest is high, and the resting membrane potential is close to the K+ equilibrium potential. Since the conductance to sodium (Na+) at rest is low, Na+ contributes little to the resting membrane potential.

5.     The role of Na+-K+ ATPase is primarily to maintain Na+ and K+ concentration gradients across the cell membrane, although it makes a small direct electrogenic contribution to the membrane potential.

6.     Changes in membrane potential are caused by the flow of ions into or out of the cell. For ion flow to occur, the cell membrane must be permeable to that ion. Depolarization means the membrane potential has become less negative. Depolarization occurs when there is net movement of positive charge into the cell, which is called an inward current. Hyperpolarization means the membrane potential has become more negative, and it occurs when there is net movement of positive charge out of the cell, which is called an outward current.

7.     Two basic mechanisms can produce a change in membrane potential. In one mechanism, there is a change in the electrochemical gradient for a permeant ion, which changes the equilibrium potential for that ion. The permeant ion then will flow into or out of the cell in an attempt to reestablish electrochemical equilibrium, and this current flow will alter the membrane potential. For example, consider the effect of decreasing the extracellular K+ concentration on the resting membrane potential of a myocardial cell. The K+ equilibrium potential, calculated by the Nernst equation, will become more negative. K+ions will then flow out of the cell and down the now larger electrochemical gradient, driving the resting membrane potential toward the new, more negative K+ equilibrium potential.

  In the other mechanism, there is a change in conductance to an ion. For example, the resting permeability of ventricular cells to Na+ is quite low, and Na+ contributes minimally to the resting membrane potential. However, during the upstroke of the ventricular action potential, Na+ conductance dramatically increases, Na+ flows into the cell down its electrochemical gradient, and the membrane potential is briefly driven toward the Na+equilibrium potential (i.e., is depolarized).

8.     Threshold potential is the potential difference at which there is a net inward current (i.e., inward current becomes greater than outward current). At threshold potential, the depolarization becomes self-sustained and gives rise to the upstroke of the action potential.

Action Potentials of Ventricles, Atria, and the Purkinje System

The ionic basis for the action potentials in the ventricles, atria, and Purkinje system is identical. The action potential in these tissues shares the following characteristics (Table 4-2):

Table 4–2 Comparison of Action Potentials in Cardiac Tissues

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image Long duration. In each of these tissues, the action potential is of long duration. Action potential duration varies from 150 msec in atria, to 250 msec in ventricles, to 300 msec in Purkinje fibers. These durations can be compared with the brief duration of the action potential in nerve and skeletal muscle (1 to 2 msec). Recall that the duration of the action potential also determines the duration of the refractory periods: The longer the action potential, the longer the cell is refractory to firing another action potential. Thus, atrial, ventricular, and Purkinje cells have long refractory periods compared with other excitable tissues.

image Stable resting membrane potential. The cells of the atria, ventricles, and Purkinje system exhibit a stable, or constant, resting membrane potential. (AV nodal and Purkinje fibers can develop unstable resting membrane potentials, and under special conditions, they can become the heart’s pacemaker, as discussed in the section on latent pacemakers.)

image Plateau. The action potential in cells of the atria, ventricles, and Purkinje system is characterized by a plateau. The plateau is a sustained period of depolarization, which accounts for the long duration of the action potential and, consequently, the long refractory periods.

Figure 4-12A and B illustrate the action potential in a ventricular muscle fiber and an atrial muscle fiber. An action potential in a Purkinje fiber (not shown) would look similar to that in the ventricular fiber, but its duration would be slightly longer. The phases of the action potential are described subsequently and correspond to the numbered phases shown in Figure 4-12A and B. The ventricular action potential has also been redrawn in Figure 4-13 to show the ionic currents responsible for each phase. Some of this information also is summarized in Table 4-2.

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Figure 4–12 Cardiac action potentials in the ventricle, atrium, and sinoatrial node. A–C, The numbers correspond to the phases of the action potentials.

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Figure 4–13 Currents responsible for ventricular action potential. The length of the arrows shows the relative size of each ionic current. E, Equilibrium potential; ECF, extracellular fluid; ICF, intracellular fluid.

1.     Phase 0, upstroke. In ventricular, atrial, and Purkinje fibers, the action potential begins with a phase of rapid depolarization, called the upstroke. As in nerve and skeletal muscle, the upstroke is caused by a transient increase in Na+ conductance (gNa), produced by depolarization-induced opening of activation gates on the Na+ channels. When gNa increases, there is an inward Na+ current (influx of Na+ into the cell), or INa, which drives the membrane potential toward the Na+ equilibrium potential of approximately +65 mV. The membrane potential does not quite reach the Na+ equilibrium potential because, as in nerve, the inactivation gates on the Na+ channels close in response to depolarization (albeit more slowly than the activation gates open). Thus, the Na+ channels open briefly and then close. At the peak of the upstroke, the membrane potential is depolarized to a value of about +20 mV.

  The rate of rise of the upstroke is called dV/dT. dV/dT is the rate of change of the membrane potential as a function of time, and its units are volts per second (V/sec). dV/dT varies, depending on the value of the resting membrane potential. This dependence is called the responsiveness relationship. Thus, dV/dT is greatest (the rate of rise of the upstroke is fastest) when the resting membrane potential is most negative, or hyperpolarized (e.g., −90 mV), and dV/dT is lowest (the rate of rise of the upstroke is slowest) when the resting membrane potential is less negative, or depolarized (e.g., −60 mV). This correlation is based on the relationship between membrane potential and the position of the inactivation gates on the Na+ channel (see Chapter 1). When the resting membrane potential is relatively hyperpolarized (e.g., −90 mV), the voltage-dependent inactivation gates are open and many Na+ channels are available for the upstroke. When the resting membrane potential is relatively depolarized (e.g., −60 mV), the inactivation gates on the Na+ channels tend to be closed and fewer Na+ channels are available to open during the upstroke. dV/dT also correlates with the size of the inward current (i.e., in ventricular, atrial, and Purkinje fibers, the size of the inward Na+ current).

2.     Phase 1, initial repolarization. Phase 1 in ventricular, atrial, and Purkinje fibers is a brief period of repolarization, which immediately follows the upstroke. Recall that, for repolarization to occur, there must be a net outward current. There are two explanations for the occurrence of the net outward current during phase 1. First, the inactivation gates on the Na+ channels close in response to depolarization. When these gates close, gNa decreases and the inward Na+ current (which caused the upstroke) ceases. Second, there is an outward K+ current, caused by the large driving force on K+ ions: At the peak of the upstroke, both the chemical and the electrical driving forces favor K+ movement out of the cell (the intracellular K+ concentration is higher than extracellular K+ concentration, and the cell interior is electrically positive). Because the K+ conductance (gK) is high, K+ flows out of the cell, down this steep electrochemical gradient.

3.     Phase 2, plateau. During the plateau, there is a long period (150 to 200 msec) of relatively stable, depolarized membrane potential, particularly in ventricular and Purkinje fibers. (In atrial fibers, the plateau is shorter than in ventricular fibers.) Recall that for the membrane potential to be stable, inward and outward currents must be equal such that there is no net current flow across the membrane.

  How is such a balance of inward and outward currents achieved during the plateau? There is an increase in Ca2+ conductance (gCa), which results in an inward Ca2+ current. Inward Ca2+ current is also called slow inward current, reflecting the slower kinetics of these channels (compared with the fast Na+ channels of the upstroke). The Ca2+ channels that open during the plateau are L-type channels and are inhibited by the Ca2+ channel blockers nifedipine, diltiazem, and verapamil. To balance the inward Ca2+ current, there is an outward K+ current, driven by the electrochemical driving force on K+ ions (as described for phase 1). Thus, during the plateau, the inward Ca2+ current is balanced by the outward K+ current, the net current is zero, and the membrane potential remains at a stable depolarized value. (See Fig. 4-13, where during phase 2, the inward Ca2+ current is shown as equal in magnitude to the outward K+ current.)

  The significance of the inward Ca2+ current extends beyond its effect on membrane potential. This Ca2+ entry during the plateau of the action potential initiates the release of more Ca2+ from intracellular stores for excitation-contraction coupling. This process of so-called Ca2+-induced Ca2+release is discussed in the section on cardiac muscle contraction.

4.     Phase 3, repolarization. Repolarization begins gradually at the end of phase 2, and then there is rapid repolarization to the resting membrane potential during phase 3. Recall that repolarization is produced when outward currents are greater than inward currents. During phase 3, repolarization results from a combination of a decrease in gCa (previously increased during the plateau) and an increase in gK (to even higher levels than at rest). The reduction in gCa results in a decrease in the inward Ca2+ current, and the increase in gK results in an increase in the outward K+ current (IK), with K+ moving down a steep electrochemical gradient (as described for phase 1). At the end of phase 3, the outward K+ current is reduced because repolarization brings the membrane potential closer to the K+ equilibrium potential, thus decreasing the driving force on K+.

5.     Phase 4, resting membrane potential, or electrical diastole. The membrane potential fully repolarizes during phase 3 and returns to the resting level of approximately −85 mV. During phase 4, the membrane potential is stable again, and inward and outward currents are equal. The resting membrane potential approaches, but does not fully reach, the K+ equilibrium potential, reflecting the high resting conductance to K+. The K+ channels, and the resulting K+ current, responsible for phase 4 are different from those responsible for repolarization in phase 3. In phase 4, the K+ conductance is called gK1 and the K+ current is called, accordingly, IK1.

  The stable membrane potential in phase 4 means that inward and outward currents are equal. The high conductance to K+ produces an outward K+ current (IK1), which has already been described. The inward current that balances this outward current is carried by Na+ and Ca2+ (see Fig. 4-13), even though the conductances to Na+ and Ca2+ are low at rest. The question may arise: How can the sum of inward Na+ and Ca2+ currents be the same magnitude as the outward K+ current, given that gNa and gCa are very low, and gK1 is very high? The answer lies in the fact that, for each ion, current = conductance × driving force. Although gK1 is high, the driving force on K+ is low because the resting membrane potential is close to the K+ equilibrium potential; thus, the outward K+ current is relatively small. On the other hand, gNa and gCa are both low, but the driving forces on Na+ and Ca2+ are high because the resting membrane potential is far from the Na+ and Ca2+ equilibrium potentials; thus, the sum of the inward currents carried by Na+ and Ca2+ is equal to the outward current carried by K+.

Action Potentials in the Sinoatrial Node

The SA node is the normal pacemaker of the heart. The configuration and ionic basis for its action potential differ in several important aspects from those in atrial, ventricular, and Purkinje fibers (see Fig. 4-12C). The following features of the action potential of the SA node are different from those in atria, ventricles, and Purkinje fibers: (1) The SA node exhibits automaticity; that is, it can spontaneously generate action potentials without neural input. (2) It has an unstable resting membrane potential, in direct contrast to cells in atrial, ventricular, and Purkinje fibers. (3) It has no sustained plateau.

The phases of the SA node action potential are described here and correspond to the numbered phases shown in Figure 4-12C.

1.     Phase 0, upstroke. Phase 0 (as in the other cardiac cells) is the upstroke of the action potential. Note that the upstroke is not as rapid or as steep as in the other types of cardiac tissues. The ionic basis for the upstroke in the SA node differs as well. In the other myocardial cells, the upstroke is the result of an increase in gNa and an inward Na+ current. In the SA nodal cells, the upstroke is the result of an increase in gCa and an inward Ca2+ currentcarried primarily by L-type Ca2+ channels. There are also T-type Ca2+ channels in SA node, which carry part of the inward Ca2+ current of the upstroke.

2.     Phases 1 and 2 are absent.

3.     Phase 3, repolarization. As in the other myocardial tissues, repolarization in the SA node is due to an increase in gK. Because the electrochemical driving forces on K+ are large (both chemical and electrical driving forces favor K+ leaving the cell), there is an outward K+ current, which repolarizes the membrane potential.

4.     Phase 4, spontaneous depolarization or pacemaker potential. Phase 4 is the longest portion of the SA node action potential. This phase accounts for the automaticity of SA nodal cells (the ability to spontaneously generate action potentials without neural input). During phase 4, the most negative value of the membrane potential (called the maximum diastolic potential) is approximately −65 mV, but the membrane potential does not remain at this value. Rather, there is a slow depolarization, produced by the opening of Na+ channels and an inward Na+ current called If. The “f,” which stands for funny,denotes that this Na+ current differs from the fast Na+ current responsible for the upstroke in ventricular cells. Ifis turned on by repolarization from the preceding action potential, thus ensuring that each action potential in the SA node will be followed by another action potential. Once Ifand slow depolarization bring the membrane potential to threshold, the T-type Ca2+ channels are opened for the upstroke.

  The rate of phase 4 depolarization sets the heart rate. If the rate of phase 4 depolarization increases, threshold is reached more quickly, the SA node will fire more action potentials per time, and heart rate will increase. Conversely, if the rate of phase 4 depolarization decreases, threshold is reached more slowly, the SA node will fire fewer action potentials per time, and heart rate will decrease. The effects of the autonomic nervous system on heart rate are based on such changes in the rate of phase 4 depolarization and are discussed later in the chapter.

Latent Pacemakers

The cells in the SA node are not the only myocardial cells with intrinsic automaticity; other cells, called latent pacemakers, also have the capacity for spontaneous phase 4 depolarization. Latent pacemakers include the cells of the AV nodebundle of Hisand Purkinje fibers. Although each of these cells has the potential for automaticity, it normally is not expressed.

The rule is that the pacemaker with the fastest rate of phase 4 depolarization controls the heart rate. Normally, the SA node has the fastest rate of phase 4 depolarization, and therefore, it sets the heart rate (Table 4-3). Recall also that, of all myocardial cells, the SA nodal cells have the shortest action potential duration (i.e., the shortest refractory periods). Therefore, SA nodal cells recover faster and are ready to fire another action potential before the other cell types are ready.

Table 4–3 Firing Rate of Sinoatrial Node and Latent Pacemakers in the Heart

Location

Intrinsic Firing Rate (impulses/min)

Sinoatrial node

70–80

Atrioventricular node

40–60

Bundle of His

40

Purkinje fibers

15–20

When the SA node drives the heart rate, the latent pacemakers are suppressed, a phenomenon called overdrive suppression, which is explained as follows: The SA node has the fastest firing rate of all the potential pacemakers, and impulses spread from the SA node to the other myocardial tissues in the sequence illustrated in Figure 4-11. Although some of these tissues are potential pacemakers themselves (AV node, bundle of His, Purkinje fibers), as long as their firing rate is driven by the SA node, their own capacity to spontaneously depolarize is suppressed.

The latent pacemakers have an opportunity to drive the heart rate only if the SA node is suppressed or if the intrinsic firing rate of a latent pacemaker becomes faster than that of the SA node. Since the intrinsic rate of the latent pacemakers is slower than that of the SA node, the heart will beat at the slower rate if it is driven by a latent pacemaker (see Table 4-3).

Under the following conditions a latent pacemaker takes over and becomes the pacemaker of the heart, in which case it is called an ectopic pacemaker, or ectopic focus. (1) If the SA node firing rate decreases (e.g., due to vagal stimulation) or stops completely (e.g., because the SA node is destroyed, removed, or suppressed by drugs), then one of the latent sites will assume the role of pacemaker in the heart. (2) Or, if the intrinsic rate of firing of one of the latent pacemakers should become faster than that of the SA node, then it will assume the pacemaker role. (3) Or, if the conduction of action potentials from the SA node to the rest of the heart is blocked because of disease in the conducting pathways, then a latent pacemaker can appear in addition to the SA node.

Conduction Velocity

Conduction of the Cardiac Action Potential

In the heart, conduction velocity has the same meaning that it has in nerve and skeletal muscle fibers: It is the speed at which action potentials are propagated within the tissue. The units for conduction velocity are meters per second (m/sec). Conduction velocity is not the same in all myocardial tissues: It is slowest in the AV node (0.01 to 0.05 m/sec) and fastest in the Purkinje fibers (2 to 4 m/sec), as shown in Figure 4-14.

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Figure 4–14 Timing of activation of the myocardium. The numbers superimposed on the myocardium indicate the cumulative time, in msec, from the initiation of the action potential in the sinoatrial node.

Conduction velocity determines how long it takes the action potential to spread to various locations in the myocardium. These times, in milliseconds, are superimposed on the diagram in Figure 4-14. The action potential originates in the SA node at what is called time zero. It then takes a total of 220 msec for the action potential to spread through the atria, AV node, and His-Purkinje system to the farthest points in the ventricles. Conduction through the AV node (called AV delay) requires almost one half of the total conduction time through the myocardium. The reason for the AV delay is that, of all the myocardial tissues, conduction velocity in the AV node is slowest (0.01 to 0.05 m/sec), making conduction time the longest (100 msec).

Differences in conduction velocity among the cardiac tissues have implications for their physiologic functions. For example, the slow conduction velocity of the AV node ensures that the ventricles do not activate too early (i.e., before they have time to fill with blood from the atria). On the other hand, the rapid conduction velocity of the Purkinje fibers ensures that the ventricles can be activated quickly and in a smooth sequence for efficient ejection of blood.

Mechanism of Propagation of Cardiac Action Potential

As in nerve and skeletal muscle fibers, the physiologic basis for conduction of cardiac action potentials is the spread of local currents (see Chapter 1). Action potentials at one site generate local currents at adjacent sites; the adjacent sites are depolarized to threshold as a result of this local current flow and fire action potentials themselves. This local current flow is the result of the inward current of the upstroke of the action potential. Recall that, in atrial, ventricular, and Purkinje fibers, this inward current of the upstroke is carried by Na+, and in the SA node, the inward current of the upstroke is carried by Ca2+.

Conduction velocity depends on the size of the inward current during the upstroke of the action potential. The larger the inward current, the more rapidly local currents will spread to adjacent sites and depolarize them to threshold. Conduction velocity also correlates with dV/dT, the rate of rise of the upstroke of the action potential, because dV/dT also correlates with the size of the inward current, as discussed previously.

Propagation of the action potential depends not only upon the inward current of the upstroke to establish local currents, but also on the cable properties of the myocardial fibers. Recall that these cable properties are determined by cell membrane resistance (Rm) and internal resistance (Ri). For example, in myocardial tissue, Ri is particularly low because of low-resistance connections between the cells called gap junctions. Thus, myocardial tissue is especially well suited to fast conduction.

Conduction velocity does not depend on action potential duration, a point that can be confusing. Recall, however, that action potential duration is simply the time it takes a given site to go from depolarization to complete repolarization (e.g., action potential duration in a ventricular cell is 250 msec). Action potential duration implies nothing about how long it takes for that action potential to spread to neighboring sites.

Excitability and Refractory Periods

Excitability is the capacity of myocardial cells to generate action potentials in response to inward, depolarizing current. Strictly speaking, excitability is the amount of inward current required to bring a myocardial cell to the threshold potential. The excitability of a myocardial cell varies over the course of the action potential, and these changes in excitability are reflected in the refractory periods.

The physiologic basis for the refractory periods in myocardial cells is similar to that in nerve cells. Recall from Chapter 1 that activation gates on Na+ channels open when the membrane potential is depolarized to threshold, permitting a rapid influx of Na+ into the cell, which causes further depolarization toward the Na+ equilibrium potential. This rapid depolarization is the upstroke of the action potential. However, inactivation gates on the Na+ channels also close with depolarization (although they close more slowly than the activation gates open). Therefore, during those phases of the action potential when the membrane potential is depolarized, a portion of the Na+ channels will be closed because the inactivation gates are closed. When the Na+ channels are closed, inward depolarizing current cannot flow through them, and there can be no upstroke. Without an upstroke, a normal action potential cannot occur and the cell is refractory. Once repolarization occurs, the inactivation gates on the Na+ channels open, and the cell is once again excitable.

Figure 4-15 is a familiar diagram showing an action potential in ventricular muscle, with the refractory periods now superimposed on it. The following refractory periods reflect differences in excitability over the duration of the action potential:

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Figure 4–15 Refractory periods of the ventricular action potential. The effective refractory period (ERP) includes the absolute refractory period (ARP) and the first half of the relative refractory period (RRP). The RRP begins when the absolute refractory period ends and includes the last portion of the effective refractory period. The supranormal period (SNP) begins when the relative refractory period ends.

image Absolute refractory period. For most of the duration of the action potential, the ventricular cell is completely refractory to fire another action potential. No matter how large a stimulus (i.e., inward current) might be applied, the cell is incapable of generating a second action potential during the absolute refractory period (ARP), because most of the Na+ channels are closed. The absolute refractory period includes the upstroke, the entire plateau, and a portion of the repolarization. This period concludes when the cell has repolarized to approximately −50 mV.

image Effective refractory period. The effective refractory period (ERP) includes, and is slightly longer than, the absolute refractory period. At the end of the effective refractory period, the Na+ channels start to recover (i.e., become available to carry inward current). The distinction between the absolute and effective refractory periods is that absolute means absolutely no stimulus is large enough to generate another action potential; effective means that a conducted action potential cannot be generated (i.e., there is not enough inward current to conduct to the next site).

image Relative refractory period. The relative refractory period (RRP) begins at the end of the absolute refractory period and continues until the cell membrane has almost fully repolarized. During the relative refractory period, even more Na+ channels have recovered and it is possible to generate a second action potential, although a greater-than-normal stimulus is required. If a second action potential is generated during the relative refractory period, it will have an abnormal configuration and a shortened plateau phase.

image Supranormal period. The supranormal period (SNP) follows the relative refractory period. It begins when the membrane potential is −70 mV and continues until the membrane is fully repolarized back to −85 mV. As the name suggests, the cell is more excitable than normal during this period. In other words, less inward current is required to depolarize the cell to the threshold potential. The physiologic explanation for this increased excitability is that the Na+ channels are recovered (i.e., the inactivation gates are open again), and because the membrane potential is closer to threshold than it is at rest, it is easier to fire an action potential than when the cell membrane is at the resting membrane potential.

Autonomic Effects on the Heart and Blood Vessels

Table 4-4 summarizes the effects of the autonomic nervous system on the heart and blood vessels. For convenience, the autonomic effects on heart rate, conduction velocity, myocardial contractility, and vascular smooth muscle are combined into one table. The effects on cardiac electrophysiology (i.e., heart rate and conduction velocity) are discussed in this section, and the other autonomic effects are discussed in later sections.

Table 4–4 Effects of Autonomic Nervous System on the Heart and Blood Vessels

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AV, Atrioventricular; EDRF, endothelial-derived relaxing factor; M, muscarinic.

Autonomic Effects on Heart Rate

The effects of the autonomic nervous system on heart rate are called chronotropic effects. The effects of the sympathetic and parasympathetic nervous systems on heart rate are summarized in Table 4-4 and are illustrated in Figure 4-16. Briefly, sympathetic stimulation increases heart rate and parasympathetic stimulation decreases heart rate.

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Figure 4–16 Effect of sympathetic and parasympathetic stimulation on the SA node action potential. A, The normal firing pattern of the SA node is shown. B, Sympathetic stimulation increases the rate of phase 4 depolarization and increases the frequency of action potentials. C, Parasympathetic stimulation decreases the rate of phase 4 depolarization and hyperpolarizes the maximum diastolic potential to decrease the frequency of action potentials.

Figure 4-16A shows the normal firing pattern of the SA node. Recall that phase 4 depolarization is produced by opening Na+ channels, which leads to a slow depolarizing, inward Na+ current called If. Once the membrane potential is depolarized to the threshold potential, an action potential is initiated.

image Positive chronotropic effects are increases in heart rate. The most important example is that of stimulation of the sympathetic nervous system, as illustrated in Figure 4-16B. Norepinephrine, released from sympathetic nerve fibers, activates β1 receptors in the SA node. These β1 receptors are coupled to adenylyl cyclase through a Gs protein (see also Chapter 2). Activation of β1 receptors in the SA node produces an increase in If, which increases the rate of phase 4 depolarization. In addition, there is an increase in ICa, which means there are more functional Ca2+ channels and thus less depolarization is required to reach threshold (i.e., threshold potential decreases). Increasing the rate of phase 4 depolarization and decreasing the threshold potential means that the SA node is depolarized to threshold potential more frequently and, as a consequence, fires more action potentials per unit time (i.e., increased heart rate).

image Negative chronotropic effects are decreases in heart rate. The most important example is that of stimulation of the parasympathetic nervous system, illustrated in Figure 4-16C. Acetylcholine (ACh), released from parasympathetic nerve fibers, activates muscarinic (M2) receptors in the SA node. Activation of muscarinic receptors in the SA node has two effects that combine to produce a decrease in heart rate. First, these muscarinic receptors are coupled to a type of Gi protein called GK that inhibits adenylyl cyclase and produces a decrease in If. A decrease in If decreases the rate of phase 4 depolarization. Second, Gkdirectly increases the conductance of a K+ channel called K+-ACh and increases an outward K+ current (similar to IK1) called IK-ACh. Enhancing this outward K+ current hyperpolarizes the maximum diastolic potential so that the SA nodal cells are further from threshold potential. In addition, there is a decrease in ICa, which means there are fewer functional Ca2+ channels and thus more depolarization is required to reach threshold (i.e., threshold potential increases). In sum, the parasympathetic nervous system decreases heart rate through three effects on the SA node: (1) slowing the rate of phase 4 depolarization, (2) hyperpolarizing the maximum diastolic potential so that more inward current is required to reach threshold potential, and (3) increasing the threshold potential. As a result, the SA node is depolarized to threshold less frequently and fires fewer action potentials per unit time (i.e., decreased heart rate) (Box 4-1).

BOX 4–1 Clinical Physiology: Sinus Bradycardia

DESCRIPTION OF CASE. A 72-year-old woman with hypertension is being treated with propranolol, a β-adrenergic blocking agent. She has experienced several episodes of light-headedness and syncope (fainting). An ECG shows sinus bradycardia: normal, regular P waves, followed by normal QRS complexes; however, the frequency of P waves is decreased, at 45/min. The physician tapers off and eventually discontinues the propranolol and then changes the woman’s medication to a different class of antihypertensive drugs. Upon discontinuation of propranolol, a repeat ECG shows a normal sinus rhythm with a frequency of P waves of 80/min.

EXPLANATION OF CASE. The heart rate is given by the frequency of P waves. During treatment with propranolol, her heart rate was only 45 beats/min. The presence of P waves on the ECG indicates that the heart is being activated in the SA node, which is the normal pacemaker. However, the frequency of depolarization of the SA node is much lower than normal because she is being treated with propranolol, a β-adrenergic blocking agent. Recall that β-adrenergic agonists increase the rate of phase 4 depolarization in the SA node by increasing If. β-Adrenergic antagonists, therefore, will decrease phase 4 depolarization and decrease the frequency at which the SA nodal cells fire action potentials.

TREATMENT. The woman’s sinus bradycardia was an adverse effect of propranolol therapy. When propranolol was discontinued, her heart rate returned to normal.

Autonomic Effects on Conduction Velocity in the Atrioventricular Node

The effects of the autonomic nervous system on conduction velocity are called dromotropic effects. Increases in conduction velocity are called positive dromotropic effects, and decreases in conduction velocity are called negative dromotropic effects. The most important physiologic effects of the autonomic nervous system on conduction velocity are those on the AV node, which, in effect, alter the rate at which action potentials are conducted from the atria to the ventricles. Recall, in considering the mechanism of these autonomic effects, that conduction velocity correlates with the size of the inward current of the upstroke of the action potential and the rate of rise of the upstroke, dV/dT.

Stimulation of the sympathetic nervous system produces an increase in conduction velocity through the AV node (positive dromotropic effect), which increases the rate at which action potentials are conducted from the atria to the ventricles. The mechanism of the sympathetic effect is increased ICa, which is responsible for the upstroke of the action potential in the AV node (as it is in the SA node). Thus, increased ICa means increased inward current and increased conduction velocity. In a supportive role, the increased ICa shortens the ERP so that the AV nodal cells recover earlier from inactivation and can conduct the increased firing rate.

Stimulation of the parasympathetic nervous system produces a decrease in conduction velocity through the AV node (negative dromotropic effect), which decreases the rate at which action potentials are conducted from the atria to the ventricles. The mechanism of the parasympathetic effect is a combination of decreased ICa (decreased inward current) and increased IK-ACh (increased outward K+ current, which further reduces net inward current). Additionally, the ERP of AV nodal cells is prolonged. If conduction velocity through the AV node is slowed sufficiently (e.g., by increased parasympathetic activity or by damage to the AV node), some action potentials may not be conducted at all from the atria to the ventricles, producing heart block. The degree of heart block may vary: In the milder forms, conduction of action potentials from atria to ventricles is simply slowed; in more severe cases, action potentials may not be conducted to the ventricles at all.

Electrocardiogram

The electrocardiogram (ECG or EKG) is a measurement of tiny potential differences on the surface of the body that reflect the electrical activity of the heart. Briefly, these potential differences or voltages are measurable on the body’s surface because of the timing and sequence of depolarization and repolarization of the heart. Recall that the entire myocardium is not depolarized at once: The atria depolarize before the ventricles; the ventricles depolarize in a specific sequence; the atria repolarize while the ventricles are depolarizing; and the ventricles repolarize in a specific sequence. As a result of the sequence and the timing of the spread of depolarization and repolarization in the myocardium, potential differences are established between different portions of the heart, which can be detected by electrodes placed on the body surface

The configuration of a normal ECG is shown in Figure 4-17. The nomenclature of the ECG is as follows: The various waves represent depolarization or repolarization of different portions of the myocardium and are given lettered names. Intervals and segments between the waves also are named. The difference between intervals and segments is that intervals include the waves, and segments do not. The following waves, intervals, and segments are seen on the ECG:

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Figure 4–17 The electrocardiogram measured from lead II.

1.     P wave. The P wave represents depolarization of the atria. The duration of the P wave correlates with conduction time through the atria; for example, if conduction velocity through the atria decreases, the P wave will spread out. Atrial repolarization is not seen on a normal ECG because it is “buried” in the QRS complex.

2.     PR interval. The PR interval is the time from initial depolarization of the atria to initial depolarization of the ventricles. Thus, the PR interval includes the P wave and the PR segment, an isoelectric (flat) portion of the ECG that corresponds to AV node conduction. Because the PR interval includes the PR segment, it also correlates with conduction time through the AV node.

  Normally, the PR interval is 160 msec, which is the cumulative time from first depolarization of the atria to first depolarization of the ventricles (see Fig. 4-14). Increases in conduction velocity through the AV node decreasethe PR interval (e.g., due to sympathetic stimulation), and decreases in conduction velocity through the AV node increase the PR interval (e.g., due to parasympathetic stimulation).

3.     QRS complex. The QRS complex consists of three waves: Q, R, and S. Collectively, these waves represent depolarization of the ventricles. Note that the total duration of the QRS complex is similar to that of the P wave. This fact may seem surprising because the ventricles are so much larger than the atria; however, the ventricles depolarize just as quickly as the atria because conduction velocity in the His-Purkinje system is much faster than in the atrial conducting system.

4.     T wave. The T wave represents repolarization of the ventricles.

5.     QT interval. The QT interval includes the QRS complex, the ST segment, and the T wave. It represents first ventricular depolarization to last ventricular repolarization. The ST segment is an isoelectric portion of the QT interval that correlates with the plateau of the ventricular action potential.

Heart rate is measured by counting the number of QRS complexes (or R waves because they are most prominent) per minute. Cycle length is the R-R interval (the time between one R wave and the next). Heart rate is related to cycle length as follows:

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SAMPLE PROBLEM. If the R-R interval is 800 msec (0.8 sec), what is the heart rate? If the heart rate is 90 beats/min, what is the cycle length?

SOLUTION. The R-R interval is the cycle length. If the cycle length is 0.8 sec, then the heart rate = 1/cycle length or 1.25 beats/sec or 75 beats/min (1 beat/0.8 sec). If the heart rate is 90 beats/min, then the cycle length = 1/heart rate or 0.66 sec or 660 msec. A longer cycle length signifies a slower heart rate, and a shorter cycle length signifies a faster heart rate.

Changes in heart rate (and cycle length) change the duration of the action potential and, as a result, change the durations of the refractory periods and excitability. For example, if heart rate increases (and cycle length decreases), there is a decrease in the duration of the action potential. Not only will there be more action potentials per time, but those action potentials will have a shorter duration and shorter refractory periods. Because of the relationship between heart rate and refractory period, increases in heart rate may be a factor in producing arrhythmias (abnormal heart rhythms). As heart rate increases and refractory periods shorten, the myocardial cells are excitable earlier and more often.