W. Jonathan Lederer
Different cardiac cells serve different and very specialized functions, but all are electrically active. The heart’s electrical signal normally originates in a group of cells high in the right atrium that depolarize spontaneously; it then spreads throughout the heart from cell to cell (Fig. 21-1). As this action potential propagates through the heart—sometimes carried by cells that form specialized conducting pathways and sometimes by the very cells that generate the force of contraction—it assumes different appearances within the different cardiac cells (Fig. 21-2). By the speed of the upstroke, we can characterize action potentials as either slow (SA and AV nodes) or fast (atrial myocytes, Purkinje fibers, and ventricular myocytes).
Figure 21-1 Conduction pathways through the heart. A section through the long axis of the heart is shown.
Figure 21-2 Cardiac action potentials. The distinctive shapes of action potentials at five sites along the spread of excitation are shown.
Because the excitation of cardiac myocytes triggers contraction—a process called excitation-contraction coupling (see Chapter 9)—the propagation of action potentials must be carefully timed to synchronize ventricular contraction and thereby optimize the ejection of blood. This chapter focuses on the membrane currents responsible for the generation and transmission of action potentials in heart tissue. We also examine how to record the heart’s electrical flow by placement of electrodes on the surface of the body, creating one of the simplest and yet one of the most useful diagnostic tools available to the clinician—the electrocardiogram.
ELECTROPHYSIOLOGY OF CARDIAC CELLS
The cardiac action potential starts in specialized muscle cells of the sinoatrial node and then propagates in an orderly fashion throughout the heart
The cardiac action potential originates in a group of cells called the sinoatrial (SA) node (Fig. 21-1), located in the right atrium. These cells depolarize spontaneously and fire off action potentials at a regular, intrinsic rate that is usually between 60 and 100 times per minute for an individual at rest. Both parasympathetic and sympathetic neural input can modulate this intrinsic pacemaker activity, or automaticity(see Chapter 16).
Because cardiac cells are electrically coupled through gap junctions (Fig. 21-3A), the action potential propagates from cell to cell in the same way that an action potential in nerve conducts along a single, long axon. A spontaneous action potential originating in the SA node will conduct from cell to cell throughout the right atrial muscle and spread to the left atrium. The existence of discrete conducting pathways in the atria is still disputed. About one tenth of a second after its origination, the signal arrives at the atrioventricular (AV) node (Fig. 21-1). The impulse does not spread directly from the atria to the ventricles because of the presence of a fibrous atrioventricular ring. Instead, the only available pathway is for the impulse to travel from the AV node to the His-Purkinje fiber system, a network of specialized conducting cells that carries the signal to the muscle of both ventricles.
Figure 21-3 Conduction in the heart. A, An action potential conducting from left to right causes intracellular current to flow from fully depolarized cells on the left, through gap junctions, and into cell A. Depolarization of cell A causes current to flow from cell A to cell B (IAB). Part of IAB discharges the capacitance of cell B (depolarizing cell B), and part flows downstream to cell C. B, Subthreshold depolarization of cell A decays with distance. C, The speed of conduction increases with greater depolarization of cell A (blue versus red curves) or with a more negative threshold.
The cardiac action potential conducts from cell to cell through gap junctions
The electrical influence of one cardiac cell on another depends on the voltage difference between the cells and on the resistance of the gap junction connection between them. A gap junction (see Chapter 8) is an electrical synapse(Fig. 21-3A) that permits electrical current to flow between neighboring cells. According to Ohm’s law, the current flowing between cell A and the adjacent cell B (IAB) is proportional to the voltage difference between the two cells (ΔVAB) but inversely proportional to the electrical resistance between them (RAB):
When RAB is very small (i.e., when the cells are tightly coupled), the gap junctions are minimal barriers to the flow of depolarizing current.
Imagine that several interconnected cells are initially all at their normal resting potentials (Fig. 21-3B). An action potential propagating from the left of cell A now injects depolarizing current into cell A. As a result, the cell depolarizes to VA, which is now somewhat positive compared with VB. Thus, a small depolarizing current (i.e., positive charges) will also move from cell A to cell B and depolarize cell B. In turn, current flowing from cell B will then depolarize cell C. By this process, the cells closest to the current source undergo the greatest depolarization.
Imagine that the injected current, coming from the active region of the heart to the left, depolarizes cell A just to its threshold (Fig. 21-3C, red curve) but that cell A has not yet fired an action potential. At this instant, the current passing from cell A to cell B cannot bring cell B to its threshold. Of course, cell A will eventually fire an action potential and, in the process, depolarize enough to inject enough current into cell B to raise cell B to its threshold. Thus, the action potential propagates down the chain of cells, but relatively slowly. On the other hand, if the active region to the left injects more current into cell A (Fig. 21-3C, blue curve)—producing a larger depolarization in cell A—the current passing from cell A to cell B will be greater and sufficient to depolarize cell B beyond its voltage threshold for a regenerative action potential. However, at this instant, the current passing from cell B to cell C is still not sufficient to trigger an action potential in cell C. That will have to wait until the active region moves closer to cell C, but the wait is not as long as in the first example (red curve). Thus, the action potential propagates more rapidly in this second example (blue curve).
In principle, we could make the action potential propagate more rapidly down the chain of cells in two ways. First, we could allow more ion channels to open in the active region of the heart, so that depolarizing current is larger (blue curve in Fig. 21-3C). Second, we could lower the threshold for the regenerative action potential (“more negative threshold” in Fig. 21-3C), so that even the small current represented by the red curve is now sufficient to trigger cell B.
Just as in a nerve axon conducting an action potential, the intracellular and extracellular currents in heart muscle must be equal and opposite. In the active region of the heart (to the left of cell A in Fig. 21-3B), cells have reached threshold and their action potentials provide the source of current that depolarizes cells that are approaching threshold (e.g., cells A and B). As cell A itself is depolarizing to and beyond threshold, its Na+ and Ca2+ channels are opening, enabling these cations (i.e., positive charge) to enter. The positive charge that enters cell A not only depolarizes cell A but also produces a flow of positive charge to cell B—intracellular current. This flow of positive charge discharges the membrane capacitance of cell B, thereby depolarizing cell B and releasing extracellular positive charges that had been associated with the membrane. The movement of this extracellular positive charge from around cell B toward the extracellular region around cell A constitutes the extracellular current. The flow of intracellular current from cell A to cell B and the flow of extracellular current from around cell B to around cell A are equal and opposite. It is the flow of this extracellular current in the heart that gives rise to an instantaneous electrical vector, which changes with time. Each point on an electrocardiogram (ECG) is the sum of the many such electrical vectors, generated by the many cells of the heart.
Cardiac action potentials have as many as five distinctive phases
The initiation time, shape, and duration of the action potential are distinctive for different parts of the heart, reflecting their different functions (Fig. 21-2). These distinctions arise because the myocytes in each region of the heart have a characteristic set of channels and anatomy. Underlying cardiac action potentials are four major time-dependent and voltage-gated membrane currents (Table 21-1):
1. The Na+ current (INa) is responsible for the rapid depolarizing phase of the action potential in atrial and ventricular muscle and in Purkinje fibers.
2. The Ca2+ current (ICa) is responsible for the rapid depolarizing phase of the action potential in the SA node and AV node; it also triggers contraction in all cardiomyocytes.
3. The K+ current (IK) is responsible for the repolarizing phase of the action potential in all cardiomyocytes.
4. The pacemaker current (If) is responsible, in part, for pacemaker activity in SA nodal cells, AV nodal cells, and Purkinje fibers.
Table 21-1 Major Cardiac Membrane Currents That Are Time Dependent and Voltage Gated
Besides these four currents, channels carry numerous other currents in heart muscle. In addition, two electrogenic transporters carry current across plasma membranes: the Na-Ca exchanger (NCX1) and the Na-K pump (see Chapter 5). (See Note: Cardiac Currents Carried by Electrogenic Transporters)
Traditionally, the changes in membrane potential (Vm) during the cardiac action potential are divided into separate phases, as illustrated in Figure 21-4A for cardiac action potentials from the SA node and in Figure 21-4B for those from ventricular muscle.
Figure 21-4 Phases of cardiac action potentials. The records in this figure are idealized. IK, INa, ICa, and If are currents through K+, Na+, Ca2+, and nonselective cation channels, respectively.
Phase 0 is the upstroke of the action potential. If the upstroke is due only to ICa (Fig. 21-4A), it will be slow. If the upstroke is due to both ICa and INa (Fig. 21-4B), it will be fast.
Phase 1 is the rapid repolarization component of the action potential (when it exists). This phase is due to almost total inactivation of INa or ICa and may also depend on the activation of a minor K+ current not listed previously, called Ito (for transient outward current).
Phase 2 is the plateau phase of the action potential, which is prominent in ventricular muscle. It depends on the continued entry of Ca2+ or Na+ ions through their major channels and on a minor membrane current due to the Na-Ca exchanger NCX1. (See Note: Cardiac Currents Carried by Electrogenic Transporters)
Phase 3 is the repolarization component of the action potential. It depends on IK (Table 21-1).
Phase 4 constitutes the electrical diastolic phase of the action potential. Vm during phase 4 is termed the diastolic potential; the most negative Vm during phase 4 is the maximum diastolic potential. In SA and AV nodal cells, changes in IK, ICa, and If produce pacemaker activity during phase 4. Purkinje fibers also exhibit pacemaker activity but use only If. Atrial and ventricular muscle have no time-dependent currents during phase 4.
The Na+ current is the largest current in the heart
The Na+ current (INa; Table 21-1) is the largest current in heart muscle, which may have as many as 200 Na+ channels per square micron of membrane. These channels are abundant in ventricular and atrial muscle, in Purkinje fibers, and in specialized conduction pathways of the atria. This current is not present in SA or AV nodal cells.
The channel that underlies INa is a classic voltage-gated Na+ channel, with both α and β1 subunits (see Chapter 7). The unique cardiac α subunit (Nav1.5) has several phosphorylation sites that make it sensitive to stimulation by cAMP-dependent protein kinase (see Chapter 3). (See Note: Cardiac Na+ Channels)
At the negative resting potentials of the ventricular muscle cells, the Na+ channels are closed. However, these channels rapidly activate (in 0.1 to 0.2 ms) in response to local depolarization produced by conducted action potentials and produce a massive inward current that underlies most of the rapid upstroke of the cardiac action potential (phase 0 in Fig. 21-4B). If Vm remains at a positive level, these channels close gradually, in a process known as inactivation. This process, which is slower than activation but still fairly rapid (half-time, ~1 ms), is partly responsible for the rapid repolarization of the action potential (phase 1). At the potentials maintained during the plateau of the cardiac action potential—slightly positive to 0 mV during phase 2—a very small but important component of this current remains. The sustained level of INa helps prolong phase 2.
In cardiac tissues other than the SA and AV nodes, the regenerative spread of the conducted action potential depends in large part on the magnitude of INa (Fig. 21-3C). The depolarization produced by the Na+current not only activates INa in neighboring cells but also activates other membrane currents in the same cell, including ICa and IK. Local anesthetic antiarrhythmic drugs, such as lidocaine, work by partially blocking INa.
The Ca2+ current in the heart passes primarily through L-type Ca2+ channels
The Ca2+ current (ICa; Table 21-1) is present in all cardiac myocytes. The L-type Ca2+ channel (Cav1, see Chapter 7) is the dominant one in the heart. T-type Ca2+ channels, with different biophysical and pharmacological properties, are also present but in smaller amounts.
In the SA node, the role of ICa, like that of the other time-and voltage-dependent membrane currents, is to contribute to pacemaker activity. In both the SA and AV nodes, ICa is the inward current source that is responsible for the upstrokes (phase 0) of the SA and AV nodal action potentials. Because the nodal cells lack the larger INa, their upstrokes are slower than those in atrial and ventricular muscle (compare A and B of Fig. 21-4). Therefore, the smaller ICadischarges the membrane capacitance of neighboring cells in the SA and AV nodes less rapidly, so that the speed of the conducted action potential is much slower than that of any other cardiac tissue. This feature in the AV node leads to an electrical delay between atrial contraction and ventricular contraction that permits more time for the atria to empty blood into the ventricles.
Although it is smaller, ICa sums with INa during the upstroke of the action potentials of the ventricular and atrial muscle and the Purkinje fibers. In this way, it increases the velocity of the conducted action potential in these tissues. Like INa, ICa produces virtually no current at very negative potentials because the channels are closed. At more positive values of Vm, the Ca2+ channels rapidly activate (in ~1 ms) and, by a completely separate and time-dependent process, inactivate (half-time, 10 to 20 ms). A small ICa remains during the phase 2 of the action potential, helping to prolong the plateau. In atrial and ventricular muscle cells, the Ca2+ entering through L-type Ca2+ channels activates the release of Ca2+ from the sarcoplasmic reticulum (SR) by calcium-induced Ca2+ release (see Chapter 9). Blockers of L-type Ca2+ channels—therapeutic agents such as verapamil, diltiazem, and nifedipine—act by inhibiting ICa. (See Note: Time Course of Ca2+ Current in Ventricular Muscle)
The repolarizing K+ current turns on slowly
Cardiac action potentials last two orders of magnitude longer than action potentials in skeletal muscle because the repolarizing K+ current turns on very slowly and—in the case of atrial myocytes, Purkinje fibers, and ventricular myocytes—with a considerable delay. The repolarizing K+ current (IK; Table 21-1) is found in all cardiac myocytes and is responsible for repolarizing the membrane at the end of the action potential (phase 3 in Fig. 21-4A, B). Two currents underlie IK—a relatively rapid component (IKR) carried by heteromeric HERG/miRP1 channels and a relatively slow component (IKS) carried by heteromeric KvLQT1/minK channels (see Chapter 7 for the box about heart defects). The IK membrane current is very small at negative potentials. With depolarization, it slowly activates (20 to 100 ms) but does not inactivate. In SA and AV nodal cells, it contributes to pacemaker activity by deactivating at the diastolic voltage. (See Note: Cardiac K+ Currents)
In addition to IK, several other K+ currents are present in cardiac tissue.
Early Outward K+ Current (A-type Current) Atrial and ventricular muscle cells have some early transient o utward current (Ito). This current is activated by depolarization but rapidly inactivates. It contributes to phase 1 repolarization and is analogous to the A-type currents (see Chapter 7) seen in nerves. A Kv4.3 channel mediates the A-type current in heart and certain other cells.
G Protein–Activated K+ Current Acetylcholine activates muscarinic receptors and, through the βγ subunits of a G protein, activates an outward K+ current mediated by GIRK K+ channels (see Chapter 7). This current is prominent in SA and AV nodal cells, where it decreases pacemaker rate by cell hyperpolarization when it is activated. It also slows the conduction of the action potential through the AV node.
KATP Current ATP-sensitive K+ channels (KATP; see Chapter 7), activated by low intracellular [ATP], are present in abundance and may play a role in electrical regulation of contractile behavior. These channels are heteromultimers of Kir and SUR.
The If current is mediated by a nonselective cation channel
The pacemaker current (If) is found in SA and AV nodal cells and in Purkinje fibers (Fig. 21-4A, blue curve). The channel underlying this current is a nonspecific cation channel called HCN (for hyperpolarization activated, cyclic nucleotide gated), which is related to the cyclic nucleotide–gated channels (see Chapter 6). Because the HCN channels conduct both K+ and Na+, the reversal potential of If is around −20 mV, between the Nernst potentials for K+(about −90 mV) and Na+ (about +50 mV). The HCN channels have the unusual property (hence the subscript f, for “funny” current) that they do not conduct at positive potentials but are activated by hyperpolarization at the end of phase 3. The activation is slow (100 ms), and the current does not inactivate. Thus, If produces an inward, depolarizing current as it slowly activates at the end of phase 3. The If current is not the only current that contributes to pacemaker activity; in SA and AV nodal cells, ICa and IK also contribute significantly to the phase 4 depolarization.
Different cardiac tissues uniquely combine ionic currents to produce distinctive action potentials
The shape of the action potential differs among different cardiac cells because of the unique combination of various currents—both the voltage-gated/time-dependent currents discussed in the preceding four sections and the “background” currents—present in each cell type. In Chapter 6, we introduced Equation 6-12, which describes Vm in terms of the conductances for the different ions (GNa, GK, GCa, GCl) relative to the total membrane conductance (Gm) and the equilibrium potentials (ENa, EK, ECa, ECl): (See Note: Contribution of Ionic Currents to Action Potential)
Therefore, as the relative contribution of a particular membrane current becomes dominant, Vm approaches the equilibrium potential for that membrane current (Table 21-2). How fast Vm changes during the action potential depends on the magnitude of each of the currents (see Equation 6-12). Not only does each current independently affect the shape of the action potential, but the voltage-and time-dependent currents interact with one another because they affect—and are affected by—Vm. Other important influences on the shape of the cardiac action potential are the membrane capacitance of each cell and the geometry of the conduction pathway (e.g., AV node, bundle of His, ventricular muscle) as the action potential propagates from cell to cell in this functional syncytium through gap junctions. Therefore, it is easy to understand, at a conceptual level, how a particular cell’s unique complement of ion channels, the properties of these channels at a particular instant in time, the intracellular ion concentrations, and the cell’s geometry can all contribute to the shape of an action potential.
Table 21-2 Equilibrium Potentials
The sinoatrial node is the primary pacemaker of the heart
The Concept of Pacemaker Activity The normal heart has three intrinsic pacemaking tissues: the SA node, the AV node, and the Purkinje fibers. The term pacemaker activity refers to the spontaneous time-dependent depolarization of the cell membrane that leads to an action potential in an otherwise quiescent cell. Any cardiac cell with pacemaker activity can initiate the heartbeat. The pacemaker with the highest frequency will be the one to trigger an action potential that will propagate throughout the heart. In other words, the fastest pacemaker sets the heart rate and overrides all slower pacemakers. Thus, cardiac pacemakers have a hierarchy among themselves, based on their intrinsic frequency. Two fundamental principles underlie pacemaker activity. The first is that inward or depolarizing membrane currents interact with outward or hyperpolarizing membrane currents to establish regular cycles of spontaneous depolarization and repolarization. The second is that in a particular cell, these currents interact during phase 4 within a narrow range of diastolic potentials: between −70 and −50 mV in SA and AV nodal cells, and between −90 and −65 mV in Purkinje fibers.
Sinoatrial Node The SA node is found in the right atrium and is the primary site of origin of the electrical signal in the mammalian heart (Table 21-3). It is the smallest electrical region of the heart and constitutes the fastest normal pacemaker, with an intrinsic rate of 60 beats per minute or faster in an individual at rest. SA cells are stable oscillators whose currents are always varying with time. The interactions among three time-dependent and voltage-gated membrane currents (ICa, IK, and If) control the intrinsic rhythmicity of the SA node. The sum of a decreasing outward current (IK; green curve in Fig. 21-4A) and two in creasing inward currents (ICa and If; red and blue curves in Fig. 21-4A) produces the slow pacemaker depolarization (phase 4) associated with the SA node. The maximum diastolic potential (i.e., the most negative Vm) of the SA nodal cells, which occurs during phase 4 of the action potential, is between −60 and −70 mV. As Vm rises toward the threshold of about −55 mV, ICa becomes increasingly activated and eventually becomes regenerative, producing the upstroke of the action potential. This depolarization rapidly turns off (i.e., deactivates) If, and the whole process begins again. (See Note: The Action Potential of the SA Node)
Table 21-3 Electrical Properties of Different Cardiac Tissues
These membrane currents are under the control of local and circulating agents (e.g., acetylcholine, epinephrine, and norepinephrine) and are also targets for therapeutic agents designed to modulate the heart’s rhythm (e.g., Ca2+channel blockers and β-adrenergic blockers).
Atrioventricular Node The AV node, located just above the atrioventricular ring, is the secondary site of origin of the electrical signal in the mammalian heart. Normally, the AV node may be excited by an impulse reaching it by way of the specialized atrial conduction pathways (see later). Like that of the SA node, the intrinsic rhythmicity of the AV node depends on the interaction of three time-dependent and voltage-gated currents: IK, ICa, and If. Electrically, the SA and AV nodes share many properties; they have similar action potentials, pacemaker mechanisms, and drug sensitivities and a similarly slow conduction of action potentials. Because the intrinsic pacemaker rate of the AV node is slower (~40 beats/min) than that of the SA node, it does not set the heart rate; its pacemaker activity is considered secondary. However, if the SA node should fail, the AV node can assume control of the heart and drive it successfully.
Purkinje Fibers The His-Purkinje fiber system originates at the AV node with the bundle of His and splits to form the left and right bundle branches (Fig. 21-1). The right bundle conducts the electrical signal to the right ventricle, and the left bundle conducts the signal to the left ventricle. The anatomy of the left bundle is variable, but this bundle frequently divides into two main branches—the left anterosuperior fascicle (or hemibundle) and the left posteroinferior fascicle.
Purkinje fiber cells have the slowest intrinsic pacemaker rate (20 beats/min or less). Thus, Purkinje fiber cells become functional pacemakers only if the SA and AV pacemakers fail and are considered tertiary pacemakers. On the other hand, the bundle of His and the Purkinje fibers are an effective conduction system within the ventricles because they conduct action potentials more quickly than any other tissue within the heart (Table 21-4).
Table 21-4 Conduction Velocity in Different Cardiac Tissues
Conduction Velocity (m/s)
Bundle of His
The action potential of the Purkinje fibers depends on four time-and voltage-dependent membrane currents: INa (not present in the SA and AV nodal cells), ICa, IK, and If. The maximum diastolic potential is −80 mV. From that negative Vm, these cells produce a very slow pacemaker depolarization (phase 4) that depends on If. Because of their low rate of pacemaker depolarization and therefore the uncertainty of reaching the threshold for triggering of an action potential, Purkinje fiber cells are unreliable as pacemakers. Normally, the action potential passing through the AV node activates the Purkinje fiber cells, resulting in a rapid upstroke (phase 0), mediated by INa and ICa. Because INa is large, Purkinje fibers conduct action potentials rapidly. (See Note: The Action Potential of the Purkinje Fiber)
Atrial and ventricular myocytes fire action potentials but do not have pacemaker activity
The resting potential of atrial and ventricular myocytes is substantially more negative (about −80 mV) than the maximum diastolic potential of SA and AV node pacemaker cells (Fig. 21-1).
Atrial Muscle Within each atrium, the action potential spreads among cardiac myocytes by a direct cell-to-cell pathway. The atrial action potential depends on three primary time-and voltage-dependent membrane currents: INa, IK, and ICa. There is no normal spontaneous (i.e., pacemaker) activity in atrial muscle. It has been proposed that atrial muscle has four special conducting bundles (Fig. 21-1). One, Bachman’s bundle (anterior interatrial myocardial band), is interatrial and conducts the cardiac action potential from the SA node to the left atrium. Three other internodal pathways—the anterior, middle, and posterior internodal pathways—appear to conduct the action potential from the SA node to the AV node. Therefore, the first step in propagation of the cardiac action potential is the depolarization of the atria, following a general axis from right to left and downward (Fig. 21-5, step 1).
Figure 21-5 Sequence of depolarization in cardiac tissue.
If the conduction path through the AV node is blocked, the ventricles will not be activated electrically and will not contract. The spontaneous activity that can arise in the Purkinje fiber cells may provide the necessary electrical signal to activate the ventricles, but this activation occurs normally only at a very low rate, and Purkinje fiber pacemaker activity is fairly unreliable.
Ventricular Muscle After the action potential reaches the AV node, it travels to the His-Purkinje fiber network and out into the ventricular muscle. The only normal electrical access between atrial muscle and the ventricles is the AV node. Because of this single electrical connection between the atria and the ventricles, there is a well-defined and orderly sequence of electrical activity through the rapidly conducting His-Purkinje network to the ventricles. Within the ventricular muscle, the action potential conducts from cell to cell. Steps 2 to 6 in Figure 21-5 summarize the sequence of events in ventricular activation, which is completed in ~100 ms:
Step 2: The septum depolarizes from left to right.
Step 3: The anteroseptal region depolarizes.
Step 4: The myocardium always depolarizes from the endocardium (the cells lining the ventricles) toward the epicardium (cells on the outer surface of the heart). The left ventricle depolarizes at the apex while the Purkinje fibers are still in the process of conducting the action potential toward the base of the left ventricle.
Step 5: Depolarization spreads from the apex toward the base, carried by the Purkinje fibers. This spread to the base begins even as the signal in the apex is still spreading from the endocardium to the epicardium. The last region to depolarize is the posterobasal region of the left ventricle.
Step 6: The ventricles are fully depolarized.
Ventricular muscle has three major time-and voltage-gated membrane currents: INa, ICa, and IK (Fig. 21-4B). Ventricular muscle has no If, and healthy ventricular muscle cells show no pacemaker activity. Starting from a resting potential of −80 mV, the rapid upstroke of the ventricular action potential results from the activation of INa by an external stimulus (e.g., an impulse conducted to the muscle by a Purkinje fiber or by a neighboring ventricular muscle cell). The Ca2+ current is of particular importance to ventricular muscle because it provides the Ca2+ influx that activates the release of Ca2+ from the SR. The rapid repolarization (phase 1), the plateau (phase 2), and the repolarization (phase 3) all appear to be governed by mechanisms similar to those found in the Purkinje fibers. However, the plateau phase is prolonged in ventricular muscle because the inward and outward currents are rather stable during that time (green, orange, and red curves in Fig. 21-4B). (See Note: The Action Potential of the Purkinje Fiber)
Once a ventricular muscle cell is activated electrically, it is refractory to additional activation. This effective refractory period arises because the inward currents (INa and ICa) that are responsible for activation are largely inactivated by the membrane depolarization (Fig. 21-4B). The effective refractory period is the same as the absolute refractory period in nerve and skeletal muscle. During the effective refractory period, an additional electrical stimulus has no effect on the action potential. At the end of the plateau, the cell begins to repolarize as IK increases in magnitude. As ICa and INa begin to recover from inactivation, the relative refractory period begins. During this period, an additional electrical stimulus can produce an action potential, but a smaller one than usual. Refractoriness provides the heart with a measure of electrical safety because it prevents extraneous pacemakers (which may arise pathologically) from triggering ectopic beats. An extrasystolic contraction would make the heart a less efficient pump. Refractoriness also prevents tetanus (see Chapter 9), a feature observed in skeletal muscle. Tetanus of the heart would mean perpetual systole and no further contractions.
Acetylcholine and catecholamines modulate pacemaker activity, conduction velocity, and contractility
In principle, the SA node can slow the firing rate of its pacemaker (i.e., negative chronotropic effect) by three mechanisms. First, the steepness of the depolarization during phase 4 can decrease, thereby lengthening the time necessary for Vm to reach threshold (Fig. 21-6A, blue curve). In this way, diastole is longer and the heart rate falls. Second, the maximum diastolic potential can become more negative (Fig. 21-6B, green curve). In this case, beginning at a lower value, Vm requires a longer time to reach the threshold, assuming no change in the steepness of the phase 4 depolarization. Third, the threshold for the action potential can become more positive (Fig. 21-6C, purple curve). Assuming no change in either the maximum diastolic potential (i.e., starting point) or the steepness of the phase 4 depolarization, Vmrequires a longer time to reach a more positive threshold. Obviously, a combination of these three mechanisms would have an enhanced effect. Conversely, the SA node cells can use each of these three mechanisms in the opposite sense to increase their firing rate (positive chronotropic effect).
Figure 21-6 Modulation of pacemaker activity.
Acetylcholine The vagus nerve, which is parasympathetic (see Chapter 14), releases acetylcholine onto the SA and AV nodes and slows the intrinsic pacemaker activity by all three mechanisms discussed in the preceding paragraph. First, acetylcholine decreases If in the SA node (Table 21-1), reducing the steepness of the phase 4 depolarization (Fig. 21-6A). Second, acetylcholine opens GIRK channels, increasing relative K+ conductance and making the maximum diastolic potential of SA nodal cells more negative (Fig. 21-6B). Third, acetylcholine reduces ICa in the SA node, thereby reducing the steepness of the phase 4 depolarization (Fig. 21-6A) and also moving the threshold to more positive values (Fig. 21-6C). All three effects cooperate to lengthen the time for the SA node to depolarize to threshold; the net effect is to lower the heart rate.
The effects of acetylcholine on currents in the AV node are similar to those in the SA node. However, because the pacemaker normally does not reside in the AV node, the physiological effect of acetylcholine on the AV node is to slow conduction velocity. The mechanism is an inhibition of ICa that also makes the threshold more positive for AV nodal cells. Because it is more difficult for one cell to depolarize its neighbors to threshold, conduction velocity falls. (See Note: Effect of Acetylcholine on Purkinje Fiber Conduction Velocity)
Catecholamines Sympathetic innervation to the heart is plentiful, releasing mostly norepinephrine. In addition, the adrenal medulla releases epinephrine into the circulation. Catecholamines, which act through β1-adrenergic receptors, produce an increase in heart rate by two mechanisms. First, catecholamines increase If in the nodal cells, thereby increasing the steepness of the phase 4 depolarization (i.e., opposite to the effect in Fig. 21-6A). Second, catecholamines increase ICa in all myocardial cells. The increase in ICa in the SA and AV nodal cells steepens the phase 4 depolarization (i.e., opposite to the effect in Fig. 21-6A) and also makes the threshold more negative (i.e., opposite to the effect in Fig. 21-6C). Note that catecholamines do not appear to change the maximum diastolic potential. They do, however, produce shorter action potentials as a result of the actions they have on several specific currents.
In atrial and ventricular muscle, catecholamines cause an increase in the strength of contraction (positive inotropic effect) for four reasons. First, the increased ICa (i.e., Ca2+ influx) leads to a greater local increase in [Ca2+]i and also a greater Ca2+-induced Ca2+ release from the SR. Second, the catecholamines increase the sensitivity of the SR Ca2+ release channel to cytoplasmic Ca2+ (see Chapter 9). Third, catecholamines also enhance Ca2+ pumping into the SR by stimulation of the SERCA Ca2+ pump (see Chapter 5), thereby increasing Ca2+ stores for later release. Fourth, the increased ICa presents more Ca2+ to SERCA, so that SR Ca2+ stores increase over time. The four mechanisms make more Ca2+ available to troponin C, enabling a more forceful contraction.
An electrocardiogram generally includes five waves
The electrocardiogram (ECG) is the standard clinical tool used to measure the electrical activity of the heart. It is a recording of the small extracellular signals produced by the movement of action potentials through cardiac myocytes. To obtain a standard 12-lead ECG, one places two electrodes on the upper extremities, two on the lower extremities, and six on standard locations across the chest. In various combinations, the electrodes on the extremities generate the six limb leads (three standard and three augmented), and the chest electrodes produce the six precordial leads. In a lead, one electrode is treated as the positive side of a voltmeter and one or more electrodes as the negative side. Therefore, a lead records the fluctuation in voltage difference between positive and negative electrodes. By the variation of which electrodes are positive and which are negative, a standard 12-lead ECG is recorded. Each lead looks at the heart from a unique angle and plane, that is, from what is essentially its own unique point of view.
The fluctuations in extracellular voltage recorded by each lead vary from fractions of a millivolt to several millivolts. These fluctuations are called waves and are named with the letters of the alphabet (Fig. 21-7). The P wave reflects depolarization of the right and left atrial muscle. The QRS complex represents depolarization of ventricular muscle. The T wave represents repolarization of both ventricles. Finally, the rarely seen U wave may reflect repolarization of the papillary muscle. The shape and magnitude of these waves are different in each lead because each lead views the electrical activity of the heart from a unique position in space. For his discovery of the mechanism of the electrocardiogram, Willem Einthoven was awarded the 1924 Nobel Prize in Physiology or Medicine. (See Note: Nomenclature and Durations of ECG Waves; Willem Einthoven)
Figure 21-7 Components of the ECG recording.
If a patient has an atrial tachycardia, such as atrial flutter or atrial fibrillation, electrical impulses from the AV node and above may pummel the ventricles and drive them at a very high rate. The ventricular rate may become so high that the effectiveness of their pumping is hindered. Because all impulses activating the ventricles must pass through the AV node, use of acetylcholine to slow impulse conduction through the AV node can slow the ventricular rate. Thus, so-called vagal maneuvers, which increase parasympathetic activity, can also decrease ventricular rate. One example is the release from a Valsalva maneuver. During a Valsalva maneuver, one makes a forced expiratory effort against a closed airway (e.g., grunting while lifting a heavy object), raising intrathoracic pressure. Subsequently, opening of the airway allows intrathoracic pressure to fall, so that the now-increased transmural pressure stretches the aorta, stimulating the aortic baroreceptors and triggering a reflex activation of the vagus nerve (see Chapter 23). Alternatively, massage of the bifurcation of the carotid artery in the neck directly stretches the wall of the carotid sinus, thereby stimulating the baroreceptors. Therefore, by either maneuver, the baroreceptor output signals brainstem centers to stimulate the vagus nerve, thereby slowing the heart.
Digitalis compounds (see Chapter 5) may also be used to treat supraventricular tachycardias because these drugs may increase vagal tone and decrease sympathetic tone, thereby slowing the conduction of atrial impulses through the AV node. Patients with congestive heart failure may have a low baseline vagal tone and a high baseline sympathetic tone. In these patients, digitalis-like drugs increase myocardial contractility (see Chapter 22) and cardiac output, causing a reflex increase in vagal tone. (See Note: How Does Digitalis Increase Vagal Tone?)
Because the ECG machine uses electrodes attached to the skin to measure the sum of the heart’s electrical activity, it requires special amplifiers. The ECG machine also has electrical filters that reduce the electrical noise. Moving limbs, breathing, coughing, shivering, and faulty contact between the skin and an electrode produce artifacts on the recorded ECG.
Because the movement of charge (i.e., the spreading wave of electrical activity in the heart) has both a three-dimensional direction and a magnitude, the signal measured on an ECG is a vector. The system that clinicians use to measure the heart’s three-dimensional, time-dependent electrical vector is simple to understand and easy to implement, but it can be challenging to interpret.
A pair of electrocardiogram electrodes defines a lead
To record the complicated time-dependent electrical vector of the heart, the physician or ECG technician constructs a system of leads in two planes that are perpendicular to each other. One plane, the frontal plane, is defined by the six limb leads (Fig. 21-8A). A perpendicular transverse plane is defined by the six precordial leads (Fig. 21-8B). Each lead is an axis in one of the two planes, onto which the heart projects its electrical activity. The ECG recording from a single lead shows how that lead views the time-dependent changes in voltage of the heart.
Figure 21-8 The ECG leads.
Older ECG machines recorded data from the 12 leads one at a time, sequentially. Thus, relatively rare events captured by the recording in one lead might not be reflected in any of the others, which were obtained at different times. Modern ECG machines obtain leads synchronously in groups of 3 or 12. Because the real electrical vector of the heart consists of just one time-dependent vector signal, you might think that a three-lead recording would suffice to localize the vector signal in space. In principle, this is true: only two leads in one plane and one lead in another plane are needed to fully define the original electrical vector of the heart at all moments. However, recording from all 12 leads is extremely useful because a signal of interest may be easier to see in one lead than in another. For example, an acute myocardial infarction involving the inferior (diaphragmatic) portion of the heart might be easily visualized in leads II, III, and aVF but go completely undetected (or produce so-called reciprocal changes) in the other leads.
The Limb Leads One obtains a 12-lead ECG by having the patient relax in a supine position and connecting four electrodes to the limbs (Fig. 21-8A). Electrically, the torso and limbs are viewed as an equilateral triangle (Einthoven’s triangle) with one vertex on the groin and the other two on the shoulder joints (Fig. 21-9A). Because the body is an electrical “volume conductor,” an electrical attachment to an arm is electrically equivalent to a connection at the shoulder joint, and an attachment to either leg is equivalent to a connection at the groin. By convention, the left leg represents the groin. The fourth electrode, connected to the right leg, is used for electrical grounding. The three initial limb leads represent the difference between two of the limb electrodes:
I (positive connection to left arm, negative connection to right arm). This lead defines an axis in the frontal plane at 0 degrees (Fig. 21-9A, B).
II (positive to left leg, negative to right arm). This lead defines an axis in the frontal plane at 60 degrees.
III (positive to left leg, negative to left arm). This lead defines an axis in the frontal plane at 120 degrees.
Figure 21-9 Axes of the limb leads. A, The frontal plane limb leads behave as if they are located at the shoulders (RA, right arm; LA, left arm) and groin (LL, left leg). Leads I, II, and III are separated from one another by 60 degrees. The augmented leads, referenced to the center of the heart, bisect each of the 60-degree angles formed by leads I, II, and III. B, Translating each of the six frontal leads so that they pass through a common point defines a polar coordinate system, providing views of the heart at 30-degree intervals.
An electronic reconstruction of the three limb connection defines an electrical reference point in the middle of the heart (Fig. 21-9A) that constitutes the negative connection for the augmented “unipolar” limb leads and for the chest leads. The three augmented unipolar limb leads compare one limb electrode to the average of the other two:
aVR (positive connection to right arm, negative connection is electronically defined in the middle of the heart). The axis defined by this limb lead in the frontal plane is −150 degrees (Fig. 21-9B). The a stands for augmented, and the V represents unipolar.
aVL (positive to left arm, negative is middle of the heart). The axis defined by this limb lead in the frontal plane is −30 degrees.
aVF (positive to left leg [foot], negative is middle of the heart). The axis defined by this limb lead in the frontal plane is +90 degrees.
Thus, the positive and negative ends of these six leads define axes every 30 degrees in the frontal plane (Fig. 21-9B).
The Precordial Leads These leads lie in the transverse plane, perpendicular to the plane of the frontal leads. The positive connection is one of six different locations on the chest wall (Fig. 21-8B), and the negative connection is electronically defined in the middle of the heart by averaging of the three limb electrodes. The resultant leads are named V1 to V6, where the V stands for unipolar:
V1: fourth intercostal space to the right of the sternum
V2: fourth intercostal space to the left of the sternum
V4: fifth intercostal space at the midclavicular line
V3: halfway between V2 and V4
V6: fifth intercostal space at the midaxillary line
V5: halfway between V4 and V6
It is also possible, on rare occasions, to obtain special leads by employing the same negative connection used for the unipolar limb and precordial leads and a positive “probe” connection. Special leads that are used include esophageal leads and an intracardiac lead (e.g., that used to obtain a recording from the His bundle).
A simple two-cell model can explain how a simple electrocardiogram can arise
We can illustrate how the ECG arises from the propagation of action potentials through the functional syncytium of myocytes by examining the electrical activity in two neighboring cardiac cells, A and B, connected by gap junctions (Fig. 21-10A). The depolarization and action potential begin first in cell A (VA in Fig. 21-10A, green record). The current from cell A then depolarizes cell B through the gap junctions and a brief time later triggers an action potential in cell B (VB). If we subtract the VB record from the VA record, we obtain a record of the intracellular voltage difference VA − VB (Fig. 21-10B).
Figure 21-10 Two-cell model of the ECG.
We have already seen that according to Ohm’s law (Equation 21-1), the intracellular current from cell A to cell B (IAB) is proportional to (VA − VB). The extracellular current flowing from the region of cell B to the region of cell A is equal but opposite in direction to the intracellular current flowing from cell A to cell B. Imagine that an extracellular voltmeter has its negative electrode placed to the left of cell A and its positive electrode to the right of cell B (forming a lead with an axis of 0 degrees). During the upswing in the action potential of cell A, while cell B is still at rest, (VA − VB) and IAB are both positive, and the voltmeter detects a positive difference in voltage (Fig. 21-10C)—analogous to the QRS complex in a real ECG. Later, during the recovery from the action potential in cell A, while cell B is still depolarized, (VA − VB) and IAB are both negative, and the voltmeter would detect a negative difference in voltage. From the extracellular voltage difference in Figure 21-10C, we can conclude that when the wave of depolarization moves toward the positive lead, there is a positive deflection in the extracellular voltage difference.
If we place the two electrodes at the junction between the two cells, with the positive connection on the bottom and the negative connection on the top, we create a lead with an axis of 90 degrees to the direction of current flow (Fig. 21-10D). Under these conditions, we observe no voltage difference because both extracellular electrodes sense the same voltage at each instant in time. Thus, when a lead is perpendicular to the wave of depolarization, the measured deflection on that lead is isoelectric.
If we put our extracellular electrodes in yet a third configuration—with the positive electrode on the left and the negative electrode on the right—we observe a negative deflection during the depolarization of cell A because the wave of depolarization is moving away from the positive electrode (Fig. 21-10E).
This simple two-cell model demonstrates that the wave of depolarization behaves like a vector, with both magnitude and direction. Two practical methods to determine the direction (or axis) of the vector are presented in the box, Basic Interpretation of the Electrocardiogram.
The QRS equivalent in the extracellular voltage record of our simplistic two-cell analysis is due to a spreading wave of depolarization. The T-wave equivalent is negative compared with the QRS equivalent, and it reflects the wave of repolarization. If cell A has an action potential that is much longer than cell B (so that positive current again propagates from A to B after the action potential in B is completed), then the T-wave equivalent will be upright, as it is in most ECGs. Thus, on average, the ventricular myocytes that depolarize last are the first to repolarize. In other words, the B cells have shorter action potentials than the A cells.
What happened to the P wave that we see in a real ECG? The P wave reflects the depolarization of the atrial myocytes. In our model, we could represent the P wave by introducing a second pair of myocytes (i.e., the atrial cells) and allowing them to fire their action potentials much earlier than the two ventricular myocytes.
Any change in cardiac rhythm from the normal sinus rhythm is defined as an arrhythmia. Although some arrhythmias are pathological and even life-threatening, others are normal and appropriately adaptive, including sinus tachycardia and sinus arrhythmia.
Sinus tachycardia is a heart rate faster than normal, driven by the sinus node. This arrhythmia is seen in frightened or startled individuals or during normal exercise. Rarely, sinus tachycardia can be pathological, for example, in patients with acute hyperthyroidism (see Chapter 49).
Basic Interpretation of the Electrocardiogram
An ECG provides a direct measurement of the rate, rhythm, and time-dependent electrical vector of the heart. It also provides fundamental information about the origin and conduction of the cardiac action potential within the heart. Because the different parts of the heart activate sequentially, we can attribute the time-dependent changes in the electrical vector of the heart to different regions of the heart. The P wave reflects the atrial depolarization. The QRS complex corresponds to ventricular depolarization. The T wave reflects ventricular repolarization.
ECG paper has a grid of small 1-mm square boxes and larger 5-mm square boxes. The vertical axis is calibrated at 0.1 mV/mm; the horizontal (time) axis, at 0.04 s/mm (small box) or 0.2 s/5 mm (large box). Thus, five large boxes correspond to 1.0 second (Fig. 21-11). Table 21-5summarizes the steps for interpretation of an ECG.
Figure 21-11 A normal 12-lead ECG recording. The recordings were obtained synchronously, three leads at a time (I, II, and III simultaneously; aVR, aVL, and aVF simultaneously; V1, V2, and V3 simultaneously; and V4, V5, and V6 simultaneously). A 1-mV, 200-ms calibration pulse is visible on the left of each of the three rows. The leads are marked on the traces. (We thank the Division of Cardiology, University of Maryland School of Medicine, for obtaining this ECG recording from the author.)
Table 21-5 Approach for Reading an ECG
Search for P waves.
Determine the relationship of P waves and QRS complexes.
Measure the heart rates from different waves (e.g., P-P interval, R-R interval).
Characterize QRS shape (i.e., narrow versus wide).
Examine features of ST segment.
Estimate the mean QRS axis (and the axes of the other waves of interest).
Examine the cardiac rhythm (e.g., look at a 20-to 30-s ECG record from lead II).
We can measure rate in two ways. The direct method is to measure the number of seconds between waves of the same type, for example, the R-R interval. The quotient of 60 divided by the interval in seconds is the heart rate in beats per minute:
Rate (beats/min) = (60 s/min)/(R-R interval (s/beat))
A quick, alternative method is quite popular (Table 21-6). Measure the number of large boxes that form the R-R interval and remember the series: 300, 150, 100, 75, 60, 50—which corresponds to an interval of 1, 2, 3, 4, 5, or 6 large boxes. Thus,
Rate = 300/(number of large boxes)
Table 21-6 Determination of Heart Rate from the ECG
For example, if 4 large boxes separate the R waves, the heart rate is 75 beats/min.
The determination of rhythm is more complex. One must answer the following questions: Where is the heart’s pacemaker? What is the conduction path from the pacemaker to the last cell in the ventricles? Is the pacemaker functioning regularly and at the correct speed? The normal pacemaker is the SA node; the signal then propagates through the AV node and activates the ventricles. When the heart follows this pathway at a normal rate and in this sequence, the rhythm is called a normal sinus rhythm. (See Note: ECG Rhythm Strip)
Careful examination of the intervals, durations, and segments in the ECG tracing can reveal a great deal about the conducted action potential (Fig. 21-7). The P-wave duration indicates how long atrial depolarization takes. The PR interval indicates how long it takes the action potential to conduct through the AV node before activating the ventricles. The QRS duration reveals how long it takes for the wave of depolarization to spread throughout the ventricles. The QT interval indicates how long the ventricles remain depolarized and is thus a rough measure of the duration of the overall “ventricular” action potential. The QT segment gets shorter as the heart rate increases, reflecting the shorter action potentials that are observed at high rates. In addition, many other alterations in these waves—and the segments separating them—reflect important physiological and pathophysiological changes in the heart.
Vector (or Axis) of a Wave in the Frontal Plane
Determination of the vector of current flow through the heart is not just an intellectual exercise but can be of great clinical importance. The normal axis of ventricular depolarization in the frontal plane lies between −30 and +90 degrees. However, this axis can change in a number of pathological situations, including hypertrophy of one or both ventricular walls (a common sequela of severe or prolonged hypertension) and conduction blocks in one or several of the ventricular conducting pathways.
We can use two approaches to measure the axis of a wave within the frontal plane (i.e., with use of limb leads). The first is more accurate, but the second is quicker and easier and is usually sufficient for clinical purposes.
The first approach is a geometric method. It uses our knowledge of the axes of the different leads and the measured magnitude of the wave projected onto at least two leads in the frontal plane. It involves five steps:
Step 1: Measure the height of the wave on the ECG records in two leads, using any arbitrary unit (e.g., number of boxes). A positive deflection is one that rises above the baseline, and a negative deflection is one that falls below the baseline. In the example in Figure 21-12A, we are estimating the axis of the R wave of the QRS complex. The R wave is +2 units in lead II and −1 unit in lead aVR.
Figure 21-12 Estimation of the ECG axis in the frontal plane.
Step 2: Mark the height of the measured deflections on the corresponding lead lines on a circle of axes. Any unit of measure will suffice, as long as you use the same unit for both markings. Starting at the center of the circle, mark a positive deflection toward the arrowhead and a negative deflection toward the tail of the arrow.
Step 3: Draw lines, perpendicular to the lead axes, through each of your two marks.
Step 4: Connect the center of the circle of axes (tail of vector) to the intersection of the two perpendicular lines (head of vector). In our example, the intersection is close to the aVF axis.
Step 5: Estimate the axis of the vector that corresponds to the R wave, using the “angle” scale of the circle of axes. In this case, the vector is at about 95 degrees, just clockwise to the aVF lead (i.e., 90 degrees).
The second approach is a qualitative inspection method. It exploits the varying magnitudes of the wave of interest in recordings from different leads. When the wave is isoelectric (i.e., no deflection, or equal positive and negative deflections), then the electrical vector responsible for that projection must be perpendicular to the isoelectric lead, as we already saw for the two-cell model in Figure 21-10D. The inspection approach requires two steps:
Step 1: Identify a lead in which the wave of interest is isoelectric (or nearly isoelectric). In the example in Figure 21-12B, the QRS complex is isoelectric in aVL (−30 degrees). The vector must be perpendicular (or nearly perpendicular) to that lead (i.e., aVL). In our example, the vector must point 90 degrees from −30 degrees and therefore is at either +60 degrees or −120 degrees. Because the leads in the frontal plane define axes every 30 degrees, every lead has another lead to which it is perpendicular.
Step 2: Identify a lead in which the wave is largely positive. In Figure 21-12B, this would be lead II. The vector must lie roughly in the same direction as the orientation of that lead. Because lead II is at +60 degrees, the axis of the vector of the QRS wave must be about +60 degrees and not −120 degrees.
If the wave of interest is not isoelectric in any lead, then find two leads onto which the projections are of similar magnitude and sign. The vector has an axis halfway between those two leads.
Sinus arrhythmia is the name given to a normal phenomenon: a subtle change in heart rate that occurs with each respiratory cycle. Inspiration accelerates the heart rate (see Chapter 19); expiration slows it. Deepening of the respirations exaggerates these cyclic changes. The magnitude of the effect can vary significantly among individuals. The heart rate is still under the control of the SA node, but cyclic variations in sympathetic and parasympathetic tone modulate the SA node’s pacemaker rate. The loss of sinus arrhythmia can be a sign of autonomic system dysfunction, as may be seen in patients with diabetes.
Although the list of pathological arrhythmias is long, two basic problems are responsible for nearly all arrhythmias: altered conduction and altered automaticity.
Conduction abnormalities are a major cause of arrhythmias
Disturbances of conduction make up the first major category of cardiac arrhythmias. Conduction disturbances can have multiple causes and can occur at any point in the conduction pathway. Conduction disturbances can be partial or complete. The two major causes of conduction disturbances are depolarization and abnormal anatomy.
If a tissue is injured (e.g., by stretch or anoxia), an altered balance of ionic currents can lead to a depolarization. The depolarization, in turn, partially inactivates INa and ICa, slowing the spread of current (i.e., slowing conduction). As a result, the tissue may become less excitable (partial conduction block) or completely inexcitable (complete conduction block).
Another type of conduction disturbance is the presence of an aberrant conduction pathway, reflecting abnormal anatomy. One such example is an accessory conduction pathway that rapidly transmits the action potential from the atria to the ventricles, bypassing the AV node, which normally imposes a conduction delay. Patients with the common Wolff-Parkinson-White syndrome have a bypass pathway called the bundle of Kent. The existence of a second pathway between the atria and ventricles predisposes affected individuals to supraventricular arrhythmias (see Accessory Conduction Pathways).
An acute myocardial infarction, or heart attack, begins with the occlusion of a coronary artery. The region of myocardium subserved by that coronary artery is deprived of oxygen and will die unless blood flow resumes shortly. During the initial stages, the myocardial cells are electrically active but their function is impaired, producing characteristic changes in the ECG. Complete but transient blockade of blood flow to the myocardium—even though it does not lead to cell death—may lead to a pattern of ECG changes similar to that seen during the acute phase of myocardial infarction. Because blood flow is regional, the areas of infarction are also regional. Thus, the physician can best observe the changes in electrical activity by examining the specific ECG leads that provide the best view of the involved region of myocardium.
The first electrical change associated with an acute myocardial infarction is peaking of the T waves, followed soon after by T-wave inversion. These T-wave changes are not specific for infarction and are reversible if blood flow is restored.
The next change, and one that is more characteristic of an acute myocardial infarction, is elevation of the ST segment. This change occurs because the myocytes closest to the epicardium become depolarized by the cellular anoxic injury, but they are still electrically coupled. Returning to the two-cell model (Fig. 21-13A), consider the cell on the left (cell A) to be normal and the cell on the right (cell B) to be damaged. Figure 21-13B shows the extracellular current, which is proportional to the differences in the action potentials of the two cells shown in Figure 21-13A. Because cell B has a more positive resting potential than cell A but the same plateau during the action potential, the difference in voltage between cell A and cell B is depressed everywhere but at the ST segment—making the ST segment appear elevated. This is also the ECG change that one views with an acute myocardial infarction.
Figure 21-13 Two-cell model of a myocardial infarction. A, The damaged cell B (blue record) has a lower resting potential, but the plateau of its action potential is at the same level as the normal cell A (green record). B, After the records in A are subtracted, the apparent elevation of ST segment is the same as the difference in resting potentials; the TP and PR regions are actually depressed.
Brief periods of coronary artery spasm can also produce ST elevation, presumably by the same mechanism. Rapid reperfusion of coronary arteries after acute blockage may lead to rapid and complete recovery of the myocardial cells, as indicated by the evanescent nature of the ECG changes.
Ischemia without cell death due to a “fixed” degree of occlusion (e.g., that caused by a thrombus or atherosclerosis) is often associated with changes in the ECG, typically ST-segment and T-wave changes. However, these changes are quite variable, presumably brought about by altered action potential duration in the affected regions. Patients experiencing exertional chest pain (angina) due to diminished coronary blood flow frequently have ECG changes during the anginal episode that include ST-segment depression and T-wave inversion.
With irreversible cell death, the ECG typically shows the evolution of deep Q waves (a large negative deflection at the beginning of the QRS complex). Q waves develop only in those leads overlying or near the region of the infarction. The Q waves indicate an area of myocardium that has become electrically silent. Because action potentials cannot propagate into the infarcted area, the net vector of the remaining areas of ventricular depolarization—by default—points away from this area. The result is a deep negative deflection on the ECG in the appropriate leads. Thus, an inferior wall infarction inscribes deep Q waves in leads II, III, and aVF. An infarction affecting the large, muscular anterior wall of the heart will inscribe deep Q waves in some of the precordial leads (V1 through V6).
Not all infarctions create deep Q waves; the only visible changes may be T-wave inversion and ST-segment depression. Clinically, these infarctions behave like incomplete infarctions, and patients are at risk of a second, “completing” event. Therefore, these patients are investigated and treated aggressively to prevent further infarction.
Partial (or Incomplete) Conduction Block Three major types of partial conduction block exist: slowed conduction, intermittent block, and unidirectional block. We defer the discussion of unidirectional block until we consider re-entry phenomena.
In slowed conduction, the tissue conducts all the impulses, but more slowly than normal. First-degree AV block reflects a slowing of conduction through the AV node. On an ECG, first-degree AV block appears as an unusually long PR interval (compare A and B of Fig. 21-14).
Figure 21-14 Pathological ECGs. In E, right bundle branch block is visible in the V1 or V2 precordial leads; left bundle branch block is visible in the V5 or V6 leads. (Data from Chernoff HM: Workbook in Clinical Electrocardiography. New York, Medcom, 1972.)
A second example of partial conduction block is intermittent block, in which the tissue conducts some impulses but not others. In the AV node, intermittent block leads to second-degree AV block, of which there are two types. Both reflect incomplete (i.e., intermittent) coupling of the atria to the ventricles. In a Mobitz type I block (or Wenckebach block), the PR interval gradually lengthens from one cycle to the next until the AV node fails completely, skipping a ventricular depolarization (Fig. 21-14C). With Mobitz type I block, it is most common to see every third or fourth atrial beat fail to conduct to the ventricles. In a Mobitz type II block, the PR interval is constant from beat to beat, but every nth ventricular depolarization is missing. In Figure 21-14D, the first cardiac cycle is normal. However, the second P wave is not followed by a QRS or T. Instead, the ECG record is flat until the third P wave arrives at the expected time, followed by a QRS and a T. Thus, we say that every second QRS is dropped (2 : 1 block).
Another form of intermittent conduction block, called rate-dependent block, reflects disease often seen in the large branches of the His-Purkinje fiber system (i.e., the bundle branches). When the heart rate exceeds a critical level, the ventricular conduction system fails, presumably because a part of the conducting system lacks sufficient time to repolarize. With intermittent failure of the His-Purkinje fiber system, the impulse is left to spread slowly and inefficiently through the ventricles by conducting from one myocyte to the next. Such a failure, whether intermittent or continuous, is known as a bundle branch block and appears on the ECG as an intermittently wide QRS complex (Fig. 21-14E). Because this block impairs the coordinated spread of the action potential throughout the ventricles, the resulting contraction loses some efficiency.
Complete Conduction Block In complete block, or third-degree AV block, no impulses conduct through the affected area, in either direction. For example, complete block at the AV node stops any supraventricular electrical impulse from triggering a ventricular contraction. Thus, AV nodal block electrically severs the atria and ventricles, each of which beats under control of its own pacemakers. This situation is called AV dissociation. The only ventricular pacemakers that are available to initiate cardiac contraction are the Purkinje fiber cells, which are notoriously unreliable and slow. Thus, cardiac output may fall, and blood pressure along with it. AV dissociation can therefore constitute a medical emergency, and placement of an artificial ventricular pacemaker can prove lifesaving. On an ECG, complete block appears as regularly spaced P waves (i.e., the SA node properly triggers the atria) and as irregularly spaced QRS and T waves that have a low frequency and no fixed relationship to the P waves (Fig. 21-14F).
Re-entry An independent focus of pacemaker activity can develop as a consequence of a conduction disturbance. This class of conduction disturbance is called re-entry (or re-entrant excitation or circus movement). It is one of the major causes of clinical arrhythmias. It occurs when a wave of depolarization travels in an apparently endless circle. Re-entry has three requirements: (1) a closed conduction loop, (2) a region of unidirectional block (at least briefly), and (3) a sufficiently slow conduction of action potentials around the loop.
Before further considering re-entry, we need to discuss a conduction defect that is essential for re-entry—unidirectional block. Unidirectional block is a type of partial conduction block in which impulses travel in one direction but not in the opposite one. Unidirectional block may arise as a result of a local depolarization or may be due to pathological changes in functional anatomy. Normal cardiac tissue can conduct impulses in both directions (Fig. 21-15A). However, after an asymmetric anatomical lesion develops, many more healthy cells may remain on one side of the lesion than on the other. When conduction proceeds in the direction from the many healthy cells to the few healthy cells, the current from the many may be sufficient to excite the few (right to left in Fig. 21-15B). On the other hand, when conduction proceeds in the opposite direction, the few healthy cells cannot generate enough current to excite the region of many healthy cells (left to right in Fig. 21-15B). The result is a unidirectional block.
Figure 21-15 Abnormal conduction.
We return now to the problem of re-entry. Imagine that an impulse is traveling down a bifurcating Purkinje fiber and is about to reach a group of ventricular myocytes—a closed conduction loop (Fig. 21-15C). However, the refractory zones prevent the re-entry of impulses from the right to the left, and vice versa. We now introduce a lesion that causes a unidirectional conduction block in the left branch of the Purkinje fiber. When the impulse reaches the fork in the road, it spreads in both directions (Fig. 21-15D, step 1). However, the impulse cannot continue past the unidirectional block in the left branch. The impulse traveling down the right branch stimulates the distal conducting cells (Fig. 21-15D, step 2), leaving them in an effective refractory period. When the impulse reaches the ventricular muscle, it begins to travel back toward the damaged left branch (step 3). At this point, the cells in the normal right branch may still be refractory to excitation. The impulse finally reaches the damaged left branch and travels in a retrograde fashion up this branch, reaching and passing through the region of the unidirectional conduction block (step 4). Finally, the impulse again reaches the bifurcation (step 5). Because enough time has elapsed for the cells at the bifurcation as well as in the right branch to recover from their refractory period, the impulse can now travel retrograde up the main part of the Purkinje fiber as well as orthograde down the right branch—for a second time.
If this re-entrant movement (steps 2 → 5 → 2, and so on) continues, the frequency of re-entry will generally outpace the SA nodal pacemaker (frequency of step 1) and is often responsible for diverse tachyarrhythmias because the fastest pacemaker sets the heart rate. Re-entry excitation may be responsible for atrial and ventricular tachycardia, atrial and ventricular fibrillation, and many other arrhythmias. Re-entry can occur in big loops (Fig. 21-15D) or in small loops consisting entirely of myocardial cells.
Accessory Conduction Pathways The Wolff-Parkinson-White (WPW) syndrome, briefly mentioned earlier, is a common example of an accessory conduction pathway, which in this case provides a short circuit (i.e., bundle of Kent) around the delay in the AV node. The fast accessory pathway is composed not of Purkinje fibers but instead of muscle cells. It conducts the action potential directly from the atria to the ventricular septum, depolarizing some of the septal muscle earlier than if the depolarization had reached it by the slower, normal AV nodal pathway. As a result, ventricular depolarization is more spread out in time than is normal, giving rise to a broader than normal QRS complex. The general direction of ventricular depolarization is reversed, so that the events normally underlying the Q wave of the QRS complex have an axis opposite to that normally seen. This early depolarization, or pre-excitation, appears as a small, positive delta wave at the beginning of the QRS complex (Fig. 21-14G). In addition, because the time between atrial depolarization and ventricular depolarization (i.e., beginning of delta wave) is shortened, the interval between the P wave and the QRS complex is shortened.
The aberrant conduction pathway in WPW syndrome also establishes a loop that may meet the requirements for re-entry and may therefore be associated with a supraventricular tachycardia. Although in general a benign condition, WPW syndrome is associated with at least one attack of supraventricular tachycardia in at least 50% of affected individuals. The two most common supraventricular tachycardias seen in this population are paroxysmal supraventricular tachycardia and atrial fibrillation (described later). Paroxysmal supraventricular tachycardia (PSVT) is a regular tachycardia with a ventricular rate usually exceeding 150 beats per minute. Because ventricular depolarization still occurs through the normal conducting pathways, the QRS complex appears normal.
If, during an episode of PSVT, the conduction direction for re-entry is in the reverse direction (i.e., down the accessory pathway and back up through the AV node), the QRS shape may be unusual. This arrangement may produce a PSVT with wide and bizarre QRS complexes because ventricular depolarization does not occur along the normal bundle branches. A small number of people with WPW syndrome have more than one accessory pathway, so that multiple re-entry loops are possible.
Fibrillation In fibrillation, many regions of re-entrant electrical activity are present, creating electrical chaos that is not associated with useful contraction. Atrial fibrillation (Fig. 21-14H) is commonly found in elderly patients, sometimes with mitral valve or coronary artery disease, but often without any evidence of underlying cardiac disease. The re-entry loop within the atria moves wildly and rapidly, generating a rapid succession of action potentials—as many as 500 per minute. This wandering re-entry circuit easily becomes the fastest pacemaker in the heart, outpacing the SA node and bombarding the AV node. Fortunately, the AV node cannot repolarize fast enough to pass along all of these impulses. Only some make it through to the ventricles, resulting in the irregular appearance of QRS complexes without any detectable P waves. The baseline between QRS complexes may appear straight or may show small, rapid fluctuations. Although only some atrial impulses reach the ventricles, the ventricular rate can still be quite high.
Because the atria function mainly as a booster pump (see the box on atrial contraction in Chapter 22), many patients tolerate atrial fibrillation without harm and may even be unaware that they have it. Others may suffer greatly from the loss of a coordinated atrial contraction, particularly the elderly or those with coexisting cardiac disease. If possible, attempts should be made to convert most individuals back to normal sinus rhythm by either electrical or chemical means. If this is not possible, then attempts can be made to at least slow conduction through the AV node. For example, digitalis compounds increase parasympathetic and decrease sympathetic stimulation to the AV node, decreasing the speed of AV conduction and thus reducing the ventricular rate. β-Adrenergic blockers or Ca2+ channel blockers are also used to control ventricular rate.
Ventricular fibrillation (Fig. 21-14I) is a life-threatening medical emergency. The heart cannot generate cardiac output because the ventricles are not able to pump blood without a coordinated ventricular depolarization.
Altered automaticity can originate from the sinus node or from an ectopic locus
The automaticity of any cardiac tissue can change. Pacemaker cells can experience an alteration or even a complete absence of automaticity. Conversely, other cells that normally have no automaticity (e.g., ventricular muscle) can become “ectopic” pacemakers. These disturbances of automaticity make up the second major category of cardiac arrhythmias.
Depolarization-Dependent Triggered Activity A positive shift in the maximum diastolic potential brings Vm closer to the threshold for an action potential and can induce automaticity in cardiac tissue that otherwise has no pacemaker activity. The development of depolarization-induced triggered activity depends on the interaction of the Ca2+ current (ICa) and the repolarizing K+ current (IK). This mechanism can produce a more rapid pacemaker depolarization in the SA or AV nodal cells, causing them to accelerate their pacemakers. It can also increase the intrinsic pacemaker rate in Purkinje fiber cells, which normally have a very slow pacemaker.
Depolarization-induced triggered activity is particularly dramatic in non-pacemaker tissues (e.g., ventricular muscle), which normally exhibit no diastolic depolarization. Factors that significantly prolong action potential duration can cause depolarization-dependent triggered activity. During the repolarization phase, INa remains inactivated because the cell is so depolarized (Fig. 21-16A). On the other hand, ICahas had enough time to recover from inactivation and—because the cell is still depolarized—triggers a slow, positive deflection in Vm known as an early afterdepolarization. Eventually, IK increases and returns Vm toward the resting potential. Such early afterdepolarizations, if they are larger than the one shown in Figure 21-16A, may trigger an extrasystole. Isolated ventricular extrasystoles (known by many names, including premature ventricular contractions, or PVCs) may occur in normal individuals. Alterations in cellular Ca2+ metabolism (discussed in the next section) may increase the tendency of a prolonged action potential to produce an extrasystole. Ironically, a class of drugs used to treat arrhythmias can become arrhythmogenic by producing early afterdepolarizations. For example, quinidine can produce this dangerous adverse effect, presumably by inhibiting Na+ channels and some K+ channels and thus prolonging the ventricular muscle action potential. (See Note: Triggered Activity)
Figure 21-16 Abnormal automaticity in ventricular muscle. The records in this figure are idealized. A, The prolonged action potential keeps INa inactivated but permits ICa and IK to interact and thereby produce a spontaneous depolarization—the early afterdepolarization. B, The afterdepolarization reaches threshold, triggering a sequence of several slow pacemaker-like action potentials that generate extrasystoles.
More than one extrasystole—a run of extrasystoles (Fig. 21-16B)—is pathological. A run of three or more ventricular extrasystoles is the minimal requirement for diagnosis of ventricular tachycardia. This arrhythmia is life-threatening because it can degenerate into ventricular fibrillation (Fig. 21-14I), which is associated with no meaningful cardiac output. The heart rate in ventricular tachycardia is much faster than normal, usually between 120 and 150 beats per minute (or faster), and the pacemaker driving the heartbeat is located in the ventricle itself. The heart rate in ventricular tachycardia may be so fast that the heart cannot pump blood effectively.
Long QT Syndrome (LQTS) Patients with LQTS have a prolonged ventricular action potential and are prone to ventricular arrhythmias. In particular, these patients are susceptible to a form of ventricular tachycardia called torsades de pointes, or “twisting of the points,” in which the QRS complexes appear to spiral around the baseline, constantly changing their axes and amplitude. LQTS can be congenital or acquired. The congenital form can involve mutations of cardiac Na+ channels or K+ channels (see the boxes on Na+ channel and human heart defects in Chapter 7). The acquired form of LQTS, which is much more common, can result from various electrolyte disturbances (especially hypokalemia and hypocalcemia) or from prescribed or over-the-counter medications (e.g., several antiarrhythmic drugs, tricyclic antidepressants, and some nonsedating antihistamines when they are taken together with certain antibiotics, notably erythromycin).
Ca2+ overload and metabolic changes can also cause arrhythmias
Ca2+ Overload Ca2+ overload in the heart has many potential causes. One frequent factor is digitalis intoxication. Another is injury-related cellular depolarization. Ca2+ overload occurs when [Ca2+]i increases, causing the SR to sequester too much Ca2+. Thus overloaded, the SR begins to cyclically—and spontaneously—dump Ca2+ and then take it back up. The Ca2+ release may be large enough to stimulate a Ca2+-activated nonselective cation channel and the Na-Ca exchanger (see Chapter 5). These current sources combine to produce Iti, a transient inward current that produces a delayed afterdepolarization. When it is large enough, Iti can depolarize the cell beyond threshold and produce a spontaneous action potential. (See Note: Cardiac Currents Carried by Electrogenic Transporters; Triggered Activity)
Metabolism-Dependent Conduction Changes During ischemia and anoxia, many cellular events take place, including a fall in intracellular ATP levels. This fall in [ATP]i activates the ATP-sensitive K+ channel (KATP), which is plentiful in cardiac myocytes. Thus, when [ATP]i falls sufficiently, KATP is less inhibited and the cells tend to become less excitable (i.e., KATP helps keep Vm close to EK). The activation of this channel may explain, in part, the slowing or blocking of conduction that may occur during ischemia or in the peri-infarction period.
Electromechanical Dissociation Rarely, patients being resuscitated from cardiac arrest exhibit a phenomenon called electromechanical dissociation, in which the heart’s ECG activity is not accompanied by the pumping of blood. In many cases, the basis of electromechanical dissociation is not understood. However, in other cases, the cause is obvious. For example, the heart of a patient with a large pericardial effusion may manifest normal electrical activity, but the fluid between the heart and the pericardium may press in on the heart (cardiac tamponade) and prevent effective pumping.
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