Cardiac muscle cells are responsible for providing the power to drive blood through the circulatory system. Coordination of their activity depends on an electrical stimulus that is regularly initiated at an appropriate rate and reliably conducted through the entire heart. Mechanical pumping action depends on a robust contraction of the muscle cells that results in repeating cycles of tension development, shortening and relaxation. In addition, mechanisms to adjust the excitation and contraction characteristics must be available to meet the changing demands of the circulatory system. This chapter focuses on these electrical and mechanical properties of cardiac muscle cells that underlie normal heart function.
ELECTRICAL ACTIVITY OF CARDIAC MUSCLE CELLS
In all striated muscle cells, contraction is triggered by a rapid voltage change called an action potential that occurs on the cell membrane. Cardiac muscle cell action potentials differ sharply from those of skeletal muscle cells in three important ways that promote synchronous rhythmic excitation of the heart: (1) they can be self-generating; (2) they can be conducted directly from cell to cell; and (3) they have long duration, which precludes fusion of individual twitch contractions. To understand these special electrical properties of the cardiac muscle and how cardiac function depends on them, the basic electrical properties of excitable cell membranes must first be reviewed.
All cells have an electrical potential (voltage) across their membranes. Such transmembrane potentials are caused by a separation of electrical charges across the membrane itself. The only way that the transmembrane potential can change is for electrical charges to move across (ie, current to flow through) the cell membrane.
There are two important corollaries to this statement: (1) the rate of change of transmembrane voltage is directly proportional to the net current across the membrane; and (2) transmembrane voltage is stable (ie, unchanging) only when there is no net current across the membrane.
Unlike a wire, current across cell membranes is not carried by electrons but by the movement of ions through the cell membrane. The three ions that are the most important determinants of cardiac transmembrane potentials are sodium (Na+) and calcium (Ca2+), which are more concentrated in the interstitial fluid than they are inside cells, and potassium (K+), which is more concentrated in intracellular than interstitial fluid. (See Appendix B for normal values of many constituents of adult human plasma.) In general, such ions are very insoluble in lipids. Consequently, they cannot pass into or out of a cell through the lipid bilayer of the membrane itself. Instead, these ions cross the membrane only via various protein structures that are embedded in and span across the lipid cell wall. There are three general types of such transmembrane protein structures that are involved in ion movement across the cell membrane: (1) ion channels; (2) ion exchangers; and (3) ion pumps.1 All are very specific for particular ions. For example, a “sodium channel” is a transmembrane protein structure that allows only Na+ ions to pass into or out of a cell according to the net electrochemical forces acting on Na+ ions.
The subsequent discussion concentrates on ion channel operation because ion channels (as opposed to transporters and pumps) are responsible for the resting membrane potential and for the rapid changes in membrane potential that constitute the cardiac cell action potential. Ion channels are under complex control and can be “opened,” “closed,” or “inactivated.” The net result of the status of membrane channels to a particular ion is commonly referred to as the membrane’s permeability to that ion. For example, “high permeability to sodium” implies that many of the Na+ ion channels are in their open state at that instant. Precise timing of the status of ion channels accounts for the characteristic membrane potential changes that occur when cardiac cells are activated.
Figure 2–1 shows how ion concentration differences can generate an electrical potential across the cell membrane. Consider first, as shown at the top of this figure, a cell that (1) has K+ more concentrated inside the cell than outside, (2) is permeable only to K+ (ie, only K+ channels are open), and (3) has no initial transmembrane potential. Because of the concentration difference, K+ ions (positive charges) will diffuse out of the cell. Meanwhile, negative charges, such as protein anions, cannot leave the cell because the membrane is impermeable to them. Thus, the K+ efflux will make the cytoplasm at the inside surface of the cell membrane more electrically negative (deficient in positively charged ions) and at the same time make the interstitial fluid just outside the cell membrane more electrically positive (rich in positively charged ions). K+ ion, being positively charged, is attracted to regions of electrical negativity. Therefore, when K+ diffuses out of a cell, it creates an electrical potential across the membrane that tends to attract it back into the cell. There exists one membrane potential called the potassium equilibrium potential at which the electrical forces tending to pull K+ into the cell exactly balance the concentration forces tending to drive K+ out. When the membrane potential has this value, there is no net movement of K+ across the membrane. With the normal concentrations of approximately 145 mM K+ inside cells and 4 mM K+ in the extracellular fluid, the K+ equilibrium potential is roughly –90 mV (more negative inside than outside by nine-hundredths of a volt).2 A membrane that is permeable only to K+ will inherently and rapidly (essentially instantaneously) develop the potassium equilibrium potential. In addition, membrane potential changes require the movement of so few ions that concentration differences are not significantly affected by the process.
Figure 2–1. Electrochemical basis of membrane potentials.
As depicted in the bottom half of Figure 2–1, similar reasoning shows how a membrane permeable only to Na+ would have the sodium equilibrium potential across it. The sodium equilibrium potential is approximately +70 mV, with the normal extracellular Na+ concentration of 140 mM and intracellular Na+ concentration of 10 mM. Real cell membranes, however, are never permeable to just Na+ or just K+. When a membrane is permeable to both of these ions, the membrane potential will lie somewhere between the Na+ equilibrium potential and the K+ equilibrium potential. Just what membrane potential will exist at any instant depends on the relative permeability of the membrane to Na+ and K+.
The more permeable the membrane is to K+ than to Na+, the closer the membrane potential will be to –90 mV. Conversely, when the permeability to Na+ is high relative to the permeability to K+, the membrane potential will be closer to +70 mV.3 A stable membrane potential that lies between the sodium and potassium equilibrium potentials implies that there is no net current across the membrane. This situation may well be the result of opposite but balanced sodium and potassium currents across the membrane.
Because of low or unchanging permeability or low concentration, roles played by ions other than Na+ and K+ in determining membrane potential are usually minor and often ignored. However, as discussed later, calcium ions (Ca2+) do participate in the cardiac muscle action potential. Like Na+, Ca2+ is more concentrated outside cells than inside. The equilibrium potential for Ca2+ is approximately +100 mV, and the cell membrane tends to become more positive on the inside when the membrane’s permeability to Ca2+ rises.
Under resting conditions, most heart muscle cells have membrane potentials that are quite close to the potassium equilibrium potential. Thus, both electrical and concentration gradients favor the entry of Na+ and Ca2+ into the resting cell. However, the very low permeability of the resting membrane to Na+ and Ca2+, in combination with an energy-requiring sodium pump that extrudes Na+ from the cell, prevents Na+ and Ca2+ from gradually accumulating inside the resting cell.4,5
Action potentials of cells from different regions of the heart are not identical but have varying characteristics that are important to the overall process of cardiac excitation.
Some cells within a specialized conduction system have the ability to act as pacemakers and to spontaneously initiate action potentials, whereas ordinary cardiac muscle cells do not (except under unusual conditions). Basic membrane electrical features of an ordinary cardiac muscle cell and a cardiac pacemaker-type cell are shown in Figure 2–2. Action potentials from these cell types are referred to as “fast-response” and “slow-response” action potentials, respectively.
Figure 2–2. Time course of membrane potential (A and B) and ion permeability changes (C and D) that occur during “fast-response” (left) and “slow-response” (right) action potentials.
As shown in Figure 2–2A, fast-response action potentials are characterized by a rapid depolarization (phase 0) with a substantial overshoot (positive inside voltage), a rapid reversal of the overshoot potential (phase 1), a long plateau (phase 2), and a repolarization (phase 3) to a stable, high (ie, large negative) resting membrane potential (phase 4). In comparison, the slow-response action potentials are characterized by a slower initial depolarization phase, a lower amplitude overshoot, a shorter and less stable plateau phase, and a repolarization to an unstable, slowly depolarizing “resting” potential (Figure 2–2B). The unstable resting potential seen in pacemaker cells with slow-response action potentials is variously referred to as phase 4 depolarization, diastolic depolarization, or pacemaker potential. Such cells are usually found in the sinoatrial (SA) and atrioventricular (AV) nodes.
As indicated at the bottom of Figure 2–2A, cells are in an absolute refractory state during most of the action potential (ie, they cannot be stimulated to fire another action potential). Near the end of the action potential, the membrane is relatively refractory and can be reexcited only by a larger-than-normal stimulus. This long refractory state precludes summated or tetanic contractions from occurring in normal cardiac muscle. Immediately after the action potential, the membrane is transiently hyperexcitable and is said to be in a “vulnerable” or “supranormal” period. Similar alterations in membrane excitability occur during slow action potentials but are not well characterized at present.
Recall that the membrane potential of any cell at any given instant depends on the relative permeability of the cell membrane to specific ions. As in all excitable cells, cardiac cell action potentials are the result of transient changes in the ionic permeability of the cell membrane that are triggered by an initial depolarization. Figure 2–2C and 2–2D indicates the changes in the membrane’s permeabilities to K+, Na+, and Ca2+ that produce the various phases of the fast- and slow-response action potentials.6 Note that during the resting phase, the membranes of both types of cells are more permeable to K+ than to Na+ or Ca2+. Therefore, the membrane potentials are close to the potassium equilibrium potential (of –90 mV) during this period.
In pacemaker-type cells, at least three mechanisms are thought to contribute to the slow depolarization of the membrane observed during the diastolic interval. First, there is a progressive decrease in the membrane’s permeability to K+ during the resting phase, and second, the permeability to Na+ increases slowly. This gradual increase in the Na+/K+ permeability ratio will cause the membrane potential to move slowly away from the K+ equilibrium potential (–90 mV) in the direction of the Na+ equilibrium potential. Third, there is a slight increase in the permeability of the membrane to calcium ions late in diastole, which results in an inward movement of these positively charged ions and also contributes to the diastolic depolarization. These permeability changes result in a specific current that occurs during diastole called the i-funny (if) current.
When the membrane potential depolarizes to a certain threshold potential in either type of cell, major rapid alterations in the permeability of the membrane to specific ions are triggered. Once initiated, these permeability changes cannot be stopped and they proceed to completion.
The characteristic rapid rising phase of the fast-response action potential is a result of a sudden increase in Na+ permeability. This produces what is referred to as the fast inward current of Na+ and causes the membrane potential to move rapidly toward the sodium equilibrium potential. As indicated in Figure 2–2C, this period of very high sodium permeability (phase 0) is short-lived.7 Development and maintenance of a depolarized plateau state (phase 2) is accomplished by the interactions of at least two separate processes: (1) a sustained reduction in K+ permeability and (2) a slowly developed and sustained increase in the membrane’s permeability to Ca2+. In addition, under certain conditions, the electrogenic action of a Na+–Ca2+ exchanger (in which 3 Na+ ions move into the cell in exchange for a single Ca2+ ion moving out of the cell) may contribute to the maintenance of the plateau phase of the cardiac action potential.
The initial fast inward current is small (or even absent) in cells that have slow-response action potentials (Figure 2–2D). Therefore, the initial depolarization phase of these action potentials is somewhat slower than that of the fast-response action potentials and is primarily a result of an inward movement of Ca2+ ions. In both types of cells, the membrane is repolarized (during phase 3) to its original resting potential as the K+ permeability increases to its high resting value and the Ca2+ and Na+ permeabilities return to their low resting values. These late permeability changes produce what is referred to as the delayed outward current.
The overall smoothly graded permeability changes that produce action potentials are the net result of alterations in each of the many individual ion channels within the plasma membrane of a single cell.8 These ion channels are generally made up of very long polypeptide chains that loop repeatedly across the cell membrane. These loops form a hollow conduction channel between the intracellular and extracellular fluids that are structurally quite specific for a particular ion. The open/closed status of the channels can be altered by configurational changes in certain subunits of the molecules within the channel (referred to as “gates” or plugs) so that when open, ions move down their electrochemical gradient either into or out of the cell (high permeability).
The specific mechanisms that control the operation of these channels during the action potential are not fully understood. Certain types of channels are called voltage-gated channels (or voltage-operated channels) because their probability of being open varies with membrane potential. Other types of channels, called ligand-gated channels (or receptor-operated channels), are activated by certain neuro-transmitters or other specific signal molecules. Table 2–1 lists some of the major important currents and channel types involved in cardiac cell electrical activity.
Table 2–1. Characteristics of Important Cardiac Ion Channels in Order of Their Participation in an Action Potential
Some of the voltage-gated channels respond to a sudden-onset, sustained change in membrane potential by only a brief period of activation. However, changes in membrane potential of slower onset, but the same magnitude, may fail to activate these channels at all. To explain such behavior, it is postulated that these channels have 2 independently operating “gates”—an activation gate and an inactivation gate—both of which must be open for the channel as a whole to be open. Both these gates respond to changes in membrane potential but do so with different voltage sensitivities and time courses.
These concepts are illustrated in Figure 2–3. In the resting state, with the membrane polarized to approximately –80 mV, the activation (or m) gate of the fast Na+ channel is closed, but its inactivation (or h) gate is open (Figure 2–3A). With a rapid depolarization of the membrane to threshold, the Na+ channels will be activated strongly to allow an inrush of positive sodium ions that further depolarizes the membrane and thus accounts for the rising phase of a “fast” response action potential, as illustrated in Figure 2–3B. This occurs because the activation gate responds to membrane depolarization by opening more quickly than the inactivation gate responds by closing. Thus, a small initial rapid depolarization to threshold is followed by a brief, but strong, period of Na+ channel activation wherein the activation gate is open but the inactivation gate is yet to close. Within a few milliseconds, however, the inactivation gates of the fast sodium channels close and shut off the inward movement of Na+.
Figure 2–3. A conceptual model of cardiac membrane fast sodium and slow calcium ion channels: at rest (A), during the initial phases of the fast-response (B and C), and the slow-response action potentials (D and E). Activation gates are labeled “m” and “d.” Inactivation gates are labeled “h” and “f.”
After a brief delay, the large membrane depolarization of the rising phase of the fast action potential causes the activation (or d) gate of the Ca2+ channel to open. This permits the slow inward movement of Ca2+ ions, which helps maintain the depolarization through the plateau phase of the action potential (Figure 2–3C). Ultimately, repolarization occurs because of both a delayed inactivation of the Ca2+ channel (by closure of the inactivation (or f) gates) and a delayed opening of K+ channels (which are not shown in Figure 2–3).
Multiple factors influence the operation of K+ channels. For example, high intracellular Ca2+ concentration during systole contributes to activation of certain K+ channels and increases the rate of repolarization. The inactivation gates of sodium channels remain closed during the remainder of the action potential, effectively inactivating the Na+ channel. This sustained sodium channel inactivation, combined with activation of calcium channels and the delay in opening of potassium channels, accounts for the long plateau phase and the long cardiac refractory period, which lasts until the end of phase 3. With repolarization, both gates of the sodium channel return to their original position and the channel is now ready to be reactivated by a subsequent depolarization.
The slow-response action potential shown in the right half of Figure 2–3 differs from the fast-response action potential primarily because of the lack of a strong activation of the fast Na+ channel at its onset. This accounts for the slow rate of rise of the action potential in these cells. The slow diastolic depolarization that occurs in these pacemaker-type cells is primarily a result of an inward current flowing through an isoform of the family of hyperpolarization-activated, cyclic nucleotide-gated (HCN) channels. These channels are activated at the end of the repolarization phase and promote a slow sodium and calcium influx that gradually depolarizes the cells during diastole. This slow diastolic depolarization gives the inactivating h gates of many of the fast sodium channels time to close before threshold is even reached (Figure 2–3D). Thus, in a slow-response action potential, there is no initial period where all the fast sodium channels of a cell are essentially open at once. The depolarization beyond threshold during the rising phase of the action potential in these “pacemaker” cells is slow and caused primarily by the influx of Ca2+ through slow channels (Figure 2–3E).
Although cells in certain areas of the heart typically have fast-type action potentials and cells in other areas normally have slow-type action potentials, it is important to recognize that all cardiac cells are potentially capable of having either type of action potential, depending on their maximum resting membrane potential and how fast they depolarize to the threshold potential. As we shall see, rapid depolarization to the threshold potential is usually an event forced on a cell by the occurrence of an action potential in an adjacent cell. Slow depolarization to threshold occurs when a cell itself spontaneously and gradually loses its resting polarization, which normally happens only in the SA or AV node. A chronic moderate depolarization of the resting membrane (caused, eg, by moderately high extracellular K+ concentrations of 5-7 mM) can inactivate the fast channels (by closing the h gates) without inactivating the slow Ca2+ channels. Under these conditions, all cardiac cell action potentials will be of the slow type. Large, sustained depolarizations (as might be caused by very high extracellular K+ concentration such as more than 8 mM), however, can inactivate both the fast and slow channels and thus make the cardiac muscle cells completely inexcitable.
Conduction of Cardiac Action Potentials
Action potentials are conducted over the surface of individual cells because active depolarization in any one area of the membrane produces local currents in the intracellular and extracellular fluids. These currents passively depolarize immediately adjacent areas of the membrane to their voltage thresholds to initiate an action potential at this new site.
In the heart, cardiac muscle cells are branching and connected end to end to neighboring cells by structures called intercalated disks. These disks contain the following: (1) firm mechanical attachments between adjacent cell membranes by proteins called adherins in structures called desmosomes and (2) low-resistance electrical connections between adjacent cells through channels formed by proteins called connexin in structures called gap junctions. Figure 2–4 shows schematically how these gap junctions allow action potential propagation from cell to cell.
Figure 2–4. Local currents and cell-to-cell conduction of cardiac muscle cell action potentials.
Cells B, C, and D are shown in the resting phase with more negative charges inside than outside. Cell A is shown in the plateau phase of an action potential and has more positive charges inside than outside. Because of the gap junctions, electrostatic attraction can cause a local current flow (ion movement) between the depolarized membrane of active cell A and the polarized membrane of resting cell B, as indicated by the arrows in the figure. This ion movement depolarizes the membrane of cell B. Once the local currents from active cell A depolarize the membrane of cell B near the gap junction to the threshold level, an action potential will be triggered at that site and will be conducted over cell B. Because cell B branches (a common morphological characteristic of cardiac muscle fibers), its action potential will evoke action potentials on cells C and D. This process is continued through the entire myocardium. Thus, an action potential initiated at any site in the myocardium will be conducted from cell to cell throughout the entire myocardium.
The speed at which an action potential propagates through a region of cardiac tissue is called the conduction velocity. The conduction velocity varies considerably in different areas in the heart and is determined by three variables. (1) Conduction velocity is directly dependent on the diameter of the muscle fiber involved. Thus, conduction over small-diameter cells in the AV node is significantly slower than conduction over large-diameter cells in the ventricular Purkinje system. (2) Conduction velocity is also directly dependent on the intensity of the local depolarizing currents, which are in turn directly determined by the rate of rise of the action potential. Rapid action potential depolarization favors rapid conduction to the neighboring segment or cell. (3) Conduction velocity is dependent on the capacitive and/or resistive properties of the cell membranes, gap junctions, and cytoplasm. Electrical characteristics of gap junctions can be influenced by external conditions that promote phosphorylation/dephosphorylation of the connexin proteins.
Details of the overall consequences of the cardiac conduction system are shown in Figure 2–5. As noted earlier, the specific electrical adaptations of various cells in the heart are reflected in the characteristic shape of their action potentials that are shown in the right half of Figure 2–5. Note that the action potentials shown in Figure 2–5 have been positioned to indicate the time when the electrical impulse that originates in the SA node reaches other areas of the heart. Cells of the SA node act as the heart’s normal pacemaker and determine the heart rate. This is because the slow spontaneous diastolic depolarization of the membrane is normally most rapid in SA nodal cells, and therefore, the cells in this region reach their threshold potential and fire before cells elsewhere.
Figure 2–5. Time records of electrical activity at different sites in the heart wall: single-cell voltage recordings (traces A to G) and lead II electrocardiogram.
The action potential initiated by an SA nodal cell first spreads progressively throughout the branching and interconnected cardiac muscle cells of the atrial wall. Action potentials from cells in two different regions of the atria are shown in Figure 2–5: one close to the SA node and one more distant from the SA node. Both cells have similarly shaped fast response-type action potentials, but their temporal displacement reflects the fact that it takes some time for the impulse to spread over the atria. As shown in Figure 2–5, action potential conduction is greatly slowed as it passes through the AV node. This is because of the small size of the AV nodal cells and the slow rate of rise of their action potentials. Since the AV node delays the transfer of the cardiac excitation from the atria to the ventricles, atrial contraction can contribute to ventricular filling before the ventricles begin to contract. Note also that AV nodal cells have a faster spontaneous depolarization during the diastolic period than other cells of the heart except those of the SA node. For this reason, the AV node is sometimes referred to as a latent pacemaker, and in many pathological situations, it (rather than the SA node) controls the heart rhythm.
Because of sharply rising action potentials and other factors, such as large cell diameters, electrical conduction is extremely rapid in Purkinje fibers. This allows the Purkinje system to transfer the cardiac impulse to cells in many areas of the ventricle nearly in unison. Action potentials from muscle cells in two areas of the ventricle are shown in Figure 2–5. Because of the high conduction velocity in ventricular tissue, there is only a small discrepancy in their time of onset. Note in Figure 2–5 that the ventricular cells that are the last to depolarize have shorter-duration action potentials and thus are the first to repolarize. The physiological importance of this behavior is not clear, but it does have an influence on the electrocardiograms discussed in Chapter 4.
Fields of electrical potential caused by the electrical activity of the heart extend through the extracellular fluid of the body and can be measured with electrodes placed on the body surface. Electrocardiography provides a record of how the voltage between two points on the body surface changes with time as a result of the electrical events of the cardiac cycle. At any instant of the cardiac cycle, the electrocardiogram indicates the net electrical field that is the summation of many weak electrical fields being produced by voltage changes occurring on individual cardiac cells at that instant. When a large number of cells are simultaneously depolarizing or repolarizing, large voltages are observed on the electrocardiogram. Because the electrical impulse spreads through the heart tissue in a consistent pathway, the temporal pattern of voltage change recorded between two points on the body surface is also consistent and repeats itself with each heart cycle.
The lower trace of Figure 2–5 represents a typical recording of the voltage changes normally measured between the right arm and the left leg as the heart goes through two cycles of electrical excitation; this record is called a lead II electrocardiogram and is discussed in detail in Chapter 4. The major features of an electrocardiogram are indicated on this record and include the P wave, the PR interval, the QRS complex, the QT interval, the ST segment, and the T wave. The P wave corresponds to atrial depolarization; the PR interval to the conduction time through the atria and AV node: the QRS complex to ventricular depolarization; the ST segment to the plateau phase of ventricular action potentials; the QT interval to the total duration of ventricular systole; and the T wave to ventricular repolarization. (See Chapter 5 for a further information about electrocardiograms.)
Control of Heart Beating Rate
Normal rhythmic contractions of the heart occur because of spontaneous electrical pacemaker activity (automaticity) of cells in the SA node. The interval between heartbeats (and thus the heart rate) is determined by how long it takes the membranes of these pacemaker cells to spontaneously depolarize during the diastolic interval to the threshold level. The SA nodal cells fire at a spontaneous or intrinsic rate (≈100 beats/min) in the absence of any outside influences. Outside influences are required, however, to increase or decrease automaticity from its intrinsic level.
The two most important outside influences on automaticity of SA nodal cells come from the autonomic nervous system. Fibers from both the sympathetic and parasympathetic divisions of the autonomic system terminate on cells in the SA node, and these fibers can modify the intrinsic heart rate. Activating the cardiac sympathetic nerves (increasing cardiac sympathetic tone) increases the heart rate. Increasing the cardiac parasympathetic tone slows the heart rate. As shown in Figure 2–6, both the parasympathetic and sympathetic nerves influence the heart rate by altering the course of spontaneous diastolic depolarization of the resting potential in SA pacemaker cells.
Figure 2–6. The effect of sympathetic and parasympathetic activity on cardiac pacemaker potentials.
Cardiac parasympathetic fibers, which travel to the heart through the vagus nerves, release the transmitter substance acetylcholine on SA nodal cells. Acetylcholine increases the permeability of the resting membrane to K+ and decreases the diastolic if current flowing through the HCN channels.9 As indicated in Figure 2–6, these changes have two effects on the resting potential of cardiac pacemaker cells: (1) they cause an initial hyperpolarization of the resting membrane potential by bringing it closer to the K+ equilibrium potential and (2) they slow the rate of spontaneous depolarization of the resting membrane. Both of these effects increase the time between beats by prolonging the time required for the resting membrane to depolarize to the threshold level. Because there is normally some continuous tonic activity of cardiac parasympathetic nerves, the normal resting heart rate is approximately 70 beats/min.
Sympathetic nerves release the transmitter substance norepinephrine on cardiac cells. In addition to other effects discussed later, norepinephrine acts on SA nodal cells to increase the inward currents (if) carried by Na+and by Ca2+ through the HCN channels during the diastolic interval.10 These changes will increase the heart rate by increasing the rate of diastolic depolarization as shown in Figure 2–6.
In addition to sympathetic and parasympathetic nerves, there are many (albeit usually less important) factors that can alter the heart rate. These include a number of ions and circulating hormones, as well as physical influences such as body temperature and atrial wall stretch. All act by somehow altering the time required for the resting membrane to depolarize to the threshold potential. An abnormally high concentration of Ca2+ in the extracellular fluid, for example, tends to decrease the heart rate by shifting the threshold potential. Factors that increase the heart rate are said to have a positive chronotropic effect. Those that decrease the heart rate have a negative chronotropic effect.
Besides their effect on the heart rate, autonomic fibers also influence the conduction velocity of action potentials through the heart. Increases in sympathetic activity increase conduction velocity (have a positive dromotropic effect), whereas increases in parasympathetic activity decrease conduction velocity (have a negative dromotropic effect). These dromotropic effects are primarily a result of autonomic influences on the initial rate of depolarization of the action potential and/or influences on conduction characteristics of gap junctions between cardiac cells. These effects are most notable at the AV node and can influence the duration of the PR interval.
MECHANICAL ACTIVITY OF THE HEART
Cardiac Muscle Cell Contraction
Contraction of the cardiac muscle cell is initiated by the action potential signal acting on intracellular organelles to evoke tension generation and/or shortening of the cell. In this section, we describe (1) the subcellular processes involved in coupling the excitation to the contraction of the cell (EC coupling) and (2) the mechanical properties of cardiac cells.
Basic histological features of cardiac muscle cells are quite similar to those of skeletal muscle cells and include (1) an extensive myofibrillar structure made up of parallel interdigitating thick and thin filaments arranged in serial units called sarcomeres, which are responsible for the mechanical processes of shortening and tension development11; (2) a complex internal compartmentation of the cytoplasm by an intracellular membrane system called the sarcoplasmic reticulum (SR), which actively sequesters calcium during the diastolic interval with the help of the sarco/endoplasmic reticulum Ca2+-ATPase (SERCA) and calcium-binding storage proteins, the most abundant of which is calsequestrin; (3) regularly spaced, extensive invaginations of the cell membrane (sarcolemma), called T tubules, which appear to be connected to parts of the SR (“junctional” SR) by dense strands (“feet”) and which carry the action potential signal to the inner parts of the cell; and (4) a large number of mitochondria that provide the oxidative phosphorylation pathways needed to ensure a ready supply of adenosine triphosphate (ATP) to meet the high metabolic needs of the cardiac muscle. Students are encouraged to consult current histology references for specific cellular, morphological details.
Muscle action potentials trigger mechanical contraction through a process called excitation–contraction coupling, which is illustrated in Figure 2–7. The major event of excitation–contraction coupling is a dramatic rise in the intracellular free Ca2+ concentration. The “resting” intracellular free Ca2+ concentration is less than 0.1 μM. In contrast, during maximum activation of the contractile apparatus, the intracellular free Ca2+ concentration may reach nearly 100 μM. When the wave of depolarization passes over the muscle cell membrane and down the T tubules, Ca2+ is released from the SR into the intracellular fluid.
Figure 2–7. Excitation–contraction coupling, sarcomere shortening, and relaxation.
As indicated on the left side of Figure 2–7, the specific trigger for this release appears to be the entry of calcium into the cell via the L-type calcium channels in the t-tubules and an increase in Ca2+ concentration just under the sarcolemma of the t-tubular system. Unlike the skeletal muscle, this highly localized increase in calcium is essential for triggering the major release of calcium from the SR. This calcium-induced calcium release is a result of opening calcium-sensitive release channels on the junctional SR.12 Although the amount of Ca2+ that enters the cell during a single action potential is quite small compared with that released from the SR, it is essential not only for triggering the SR calcium release but also for maintaining adequate levels of Ca2+ in the intracellular stores over the long run.
When the intracellular free Ca2+ concentration is high (>1.0 μM), links called cross-bridges form between the thick and thin filaments found within the muscle. Sarcomere units, as depicted in the lower part of Figure 2–7, are joined end to end at Z lines to form myofibrils, which run the length of the muscle cell. During contraction, thick and thin filaments slide past one another to shorten each sarcomere and thus the muscle as a whole. The cross-bridges form when the regularly spaced myosin heads from thick filaments attach to regularly spaced sites on the actin molecules in the thin filaments. Subsequent deformation of the bridges results in a pulling of the actin molecules toward the center of the sarcomere. This actin–myosin interaction requires energy from ATP. In resting muscles, the attachment of myosin to the actin sites is inhibited by troponin and tropomyosin. Calcium causes muscle contraction by interacting with troponin C to cause a configurational change that removes the inhibition of the actin sites on the thin filament. Because a single cross-bridge is a very short structure, gross muscle shortening requires that cross-bridges repetitively form, produce incremental movement between the myofilaments, detach, and form again at a new actin site, and so on in a cyclic manner.
There are several processes that participate in the reduction of intracellular Ca2+ that terminates the contraction. These processes are illustrated on the right side of Figure 2–7. Approximately 80% of the calcium is actively taken back up into the SR by the action of SERCA pumps located in the longitudinal part of the SR.13 About 20% of the calcium is extruded from the cell into the extracellular fluid either via the Na+–Ca2+ exchanger located in the sarcolemma14 or via sarcolemmal Ca2+-ATPase pumps.
Excitation–contraction coupling in the cardiac muscle is different from that in the skeletal muscle in that it may be modulated; different intensities of actin–myosin interaction (contraction) can result from a single action potential trigger in the cardiac muscle. The mechanism for this is largely dependent on variations in the amount of Ca2+ reaching the myofilaments and therefore the number of cross-bridges activated during the twitch. This ability of the cardiac muscle to vary its contractile strength—that is, change its contractility—is extremely important to cardiac function, as discussed in a later section of this chapter.
The duration of the cardiac muscle cell contraction is approximately the same as that of its action potential. Therefore, the electrical refractory period of a cardiac muscle cell is not over until the mechanical response is completed. As a consequence, heart muscle cells cannot be activated rapidly enough to cause a fused (tetanic) state of prolonged contraction. This is fortunate because intermittent contraction and relaxation are essential for the heart’s pumping action.
Cardiac Muscle Mechanics
The cross-bridge interaction that occurs after a muscle is activated to contract gives the muscle the potential to develop force and/or shorten. Whether it does one, the other, or some combination of the two depends primarily on what is allowed to happen by the external constraints placed on the muscle during the contraction. For example, activating a muscle whose ends are held rigidly causes it to develop tension, but it cannot shorten. This is called an isometric (“fixed length”) contraction. The force that a muscle produces during an isometric contraction indicates its maximum ability to develop tension. At the other extreme, activating an unrestrained muscle causes it to shorten without force development because it has nothing to develop force against. This type of contraction is called an isotonic (“fixed tension”) contraction. Under such conditions, a muscle shortens with its maximum possible velocity (called Vmax), which is determined by the maximum possible rate of cross-bridge cycling. Adding load to the muscle decreases the velocity and extent of its shortening. Thus, the course of a muscle contraction depends on both the inherent capabilities of the muscle and the external constraints placed on the muscle during contraction. Muscle cells in the ventricular wall operate under different constraints during different phases of each cardiac cycle. To understand ventricular function, the manner in which the cardiac muscle behaves when constrained in several different ways must first be examined.
Isometric Contractions: Length–Tension Relationships
The influence of muscle length on the behavior of the cardiac muscle during isometric contraction is illustrated in Figure 2–8. The top panel shows the experimental arrangement for measuring muscle force at rest and during contraction at three different lengths. The middle panel shows time records of muscle tensions recorded at each of the three lengths in response to an external stimulus, and the bottom panel shows a graph of the resting and peak tension results plotted against muscle length.
Figure 2–8. Isometric contractions and the effect of muscle length on resting tension and active tension development.
The first important fact illustrated in Figure 2–8 is that force is required to stretch a resting muscle to different lengths. This force is called the resting tension. The lower curve in the graph in Figure 2–8 shows the resting tension measured at different muscle lengths and is referred to as the resting length–tension curve. When a muscle is stimulated to contract while its length is held constant, it develops an additional component of tension called active or developed tension. The total tension exerted by a muscle during contraction is the sum of the active and resting tensions.
The second important fact illustrated in Figure 2–8 is that the active tension developed by the cardiac muscle during the course of an isometric contraction depends very much on the muscle length at which the contraction occurs. Active tension development is maximal at some intermediate length referred to as Lmax. Little active tension is developed at very short or very long muscle lengths. Normally, the cardiac muscle operates at lengths well below Lmax so that increasing muscle length increases the tension developed during an isometric contraction.
There are three separate mechanisms that have been proposed to explain the relationship between muscle length and developed tension. The first mechanism to be identified suggests that this relationship depends on the extent of overlap of the thick and thin filaments in the sarcomere at rest. Histological studies indicate that the changes in the resting length of the whole muscle are associated with proportional changes in the individual sarcomeres. Peak tension development occurs at sarcomere lengths of 2.2 to 2.3 μm. At sarcomere lengths shorter than approximately 2.0 μm, the opposing thin filaments may overlap or buckle and thus interfere with active tension development, as shown at the top of Figure 2–8. At long sarcomere lengths, the reduced myofilament overlap in the resting muscle cells may be insufficient for optimal cross-bridge formation during contraction.
The second (and perhaps more important) mechanism is based on a length-dependent change in sensitivity of the myofilaments to calcium. At short lengths, only a fraction of the potential cross-bridges are apparently activated by a given increase in intracellular calcium. At longer lengths, more of the cross-bridges become activated, leading to an increase in active tension development. This change in calcium sensitivity occurs immediately after a change in length with no time delay. The “sensor” responsible for the length-dependent activation of the cardiac muscle seems to reside with the troponin C molecule, but how it happens is not fully understood.
The third mechanism rests on the observation that within several minutes after increasing the resting length of the cardiac muscle, there is an increase in the amount of calcium that is released with excitation, which is coupled to a further increase in force development. It is thought that stretch-sensitive ion channels in the cell membranes may be responsible for this delayed response.
To what extent each of these mechanisms is contributing to the length dependency of cardiac contractile force at any instant is neither clear nor important in this discussion. The important point is that the dependence of active tension development on muscle length is a fundamental property of the cardiac muscle that has extremely powerful effects on heart function.
Isotonic and Afterloaded Contractions
During what is termed isotonic (“fixed load”) contraction, a muscle shortens against a constant load. A muscle contracts isotonically when it develops sufficient tension to lift a fixed weight such as the 1-g load shown in Figure 2–9. Such a 1-g weight placed on a resting muscle will result in some specific resting muscle length, which is determined by the muscle’s resting length–tension curve. If the ends of the muscle were to be fixed between two immoveable objects and the muscle were to be activated at this fixed length, it would contract isometrically and be capable of generating a certain amount of tension, for example, 4.5 g as indicated by the dashed line in the graph in Figure 2–9. A contractile tension of 4.5 g obviously cannot be generated if the muscle is allowed to shorten and actually lift the 1-g weight. When a muscle has contractile potential in excess of the tension required to move the load, it will shorten. Thus, in an isotonic contraction, muscle length decreases at constant tension, as illustrated by the horizontal arrow from point 1 to point 3 in Figure 2–9. As the muscle shortens, however, its contractile potential inherently decreases, as indicated by the downward slope of the peak isometric tension curve in Figure 2–9. There exists some short length at which the muscle is capable of generating only 1 g of tension, and when this length is reached, shortening must cease.15 Therefore, the peak isometric curve on a cardiac muscle length–tension diagram (that indicates how much isometric tension a muscle can develop at various lengths) also establishes the limit on how far muscle shortening can proceed with different loads.
Figure 2–9. Description of isotonic and afterloaded contractions within the constraints of the cardiac muscle length–tension diagram.
Figure 2–9 also shows a complex type of muscle contraction that is typical of the way cardiac muscle cells actually contract in the heart. This is called an afterloaded isotonic contraction, in which the load on the muscle at rest (the preload) and the load on the muscle during contraction (the total load) are different. In the example of Figure 2–9, the preload is equal to 1 g, and because an additional 2-g weight (the afterload) is engaged during contraction, the total load equals 3 g.
Because preload determines the resting muscle length, both contractions shown at the top of Figure 2–9 begin from the same length. Because of the different loading arrangement, however, the afterloaded muscle must increase its total active tension to 3 g before it can shorten. This initial tension will be developed isometrically and can be represented as going from point 1 to point 4 on the length–tension diagram. Once the muscle generates enough tension to equal the total load, its tension output is fixed at 3 g and it will now shorten isotonically because its contractile potential still exceeds its tension output. This isotonic shortening is represented as a horizontal movement on the length–tension diagram along the line from point 4 to point 5. As in any isotonic contraction, shortening must cease when the muscle’s tension-producing potential is decreased sufficiently by the length change to be equal to the load on the muscle. Note that the afterloaded muscle shortens less than the non-afterloaded muscle, even though both muscles began contracting at the same initial length. The factors that affect the extent of cardiac muscle shortening during an afterloaded contraction are of special interest to us, because, as we shall see, stroke volume is determined by how far the cardiac muscle shortens under these conditions.
Cardiac Muscle Contractility
A number of factors in addition to initial muscle length can affect the tension-generating potential of the cardiac muscle. Any intervention that increases the peak isometric tension that a muscle can develop at a fixed length is said to increase cardiac muscle contractility. Such an agent is said to have a positive inotropic effect on the heart.
The most important physiological regulator of cardiac muscle contractility is norepinephrine. When norepinephrine is released on cardiac muscle cells from sympathetic nerves, it has not only the chronotropic effect on the heart rate discussed earlier but also a pronounced, positive inotropic effect that causes cardiac muscle cells to contract more forcefully and more rapidly.
The positive effect of norepinephrine on the isometric tension-generating potential is illustrated in Figure 2–10A. When norepinephrine is present in the solution bathing the cardiac muscle, the muscle will, at every length, develop more isometric tension when stimulated than it would in the absence of norepinephrine. In short, norepinephrine raises the peak isometric tension curve on the cardiac muscle length–tension graph. Norepinephrine is said to increase cardiac muscle contractility because it enhances the forcefulness of muscle contraction even when length is constant. Changes in contractility and initial length can occur simultaneously, but by definition, a change in contractility must involve a shift from one peak isometric length–tension curve to another.
Figure 2–10. The effect of norepinephrine (NE) on isometric (A) and afterloaded (B) contractions of the cardiac muscle.
Figure 2–10B shows how raising the peak isometric length–tension curve with norepinephrine increases the amount of shortening in afterloaded contractions of the cardiac muscle. With preload and total load constant, more shortening occurs in the presence of norepinephrine than in its absence. This is because when contractility is increased, the tension-generating potential is equal to the total load at a shorter muscle length. Note that norepinephrine has no effect on the resting length–tension relationship of the cardiac muscle. Thus, norepinephrine causes increased shortening by changing the final but not the initial muscle length associated with afterloaded contractions. The added presence of norepinephrine will increase the fractional shortening (ie, percent shortening) of cardiac muscle at any given resting length.
The cellular mechanism of the effect of norepinephrine on contractility is mediated by its interaction with a β1-adrenergic receptor. The primary signaling pathway involves an activation of the Gs protein–cAMP–protein kinase A, which then phosphorylates the Ca2+ channel, increasing the inward calcium current during the plateau of the action potential. This increase in calcium influx not only contributes to the magnitude of the rise in intracellular Ca2+ for a given beat but also loads the internal calcium stores, which allows more to be released during subsequent depolarizations. This increase in free Ca2+ during activation allows more cross-bridges to be formed and greater tension to be developed.
In addition to its effect on force development and/or shortening, norepinephrine also has two other important effects on the cardiac muscle cell behavior. (1) There is a norepinephrine-induced increase in the rate of muscle relaxation. This is because norepinephrine causes phosphorylation of the regulatory protein, phospholamban, on the sarcoplasmic reticular Ca2+-ATPase pump and the rate of calcium retrapping into the SR is enhanced. This is called a positive lusitropic effect. (2) There is a norepinephrine-induced decrease in the action potential duration. This effect is achieved by a potassium channel alteration, occurring in response to the elevated intracellular [Ca2+] that increases potassium permeability, terminates the plateau phase of the action potential, and contributes to the early relaxation. Such shortening of the systolic interval by these two effects of norepinephrine is very helpful in the presence of elevated heart rates that might otherwise significantly compromise diastolic filling time.
Enhanced parasympathetic activity has been shown to have a small negative inotropic effect on the heart. In the atria, where this effect is most pronounced, the negative inotropic effect is thought to be due to a shortening of the action potential and a decrease in the amount of Ca2+ that enters the cell during the action potential.
Changes in the heart rate also influence cardiac contractility. Recall that a small amount of extracellular Ca2+ enters the cell during the plateau phase of each action potential. As the heart rate increases, more Ca2+ enters the cells per minute. There is a buildup of intracellular Ca2+ and a greater amount of Ca2+ is released into the sarcoplasm with each action potential. Thus, a sudden increase in beating rate is followed by a progressive increase in contractile force to a higher plateau. This behavior is called the staircase phenomenon (or treppe). The importance of such rate-dependent modulation of contractility in normal ventricular function is not clear at present.
RELATING CARDIAC MUSCLE CELL MECHANICS TO VENTRICULAR FUNCTION
Certain geometric factors dictate how the length–tension relationships of cardiac muscle fibers in the ventricular wall determine the volume and pressure relationships of the ventricular chamber. The actual relationships are complex because the shape of the ventricle is complex. The ventricle is often modeled as either a cylinder or a sphere, although its actual shape lies somewhere between the two. Because cardiac muscle cells are oriented circumferentially in the ventricular wall, either model can be used to illustrate three important functional points:
1. An increase in ventricular volume causes an increase in ventricular circumference and therefore an increase in the length of the individual cardiac muscle cells. Thus, the extent of diastolic filling of the ventricle is the major determinant of cardiac “preload.”
2. At any given ventricular volume, an increase in the tension of individual cardiac muscle cells in the wall causes an increase in intraventricular pressure. The intraventricular pressure that has to be developed in order to eject blood from the ventricle is largely dependent on the arterial blood pressure, which is therefore a major determinant of cardiac “afterload.”
3. As ventricular volume decreases (ie, as the ventricular radius decreases), a lesser total (collective) force is required by the muscle cells in the ventricular walls to produce any given intraventricular pressure (and vice versa).
The last point is a reflection of the law of Laplace that states the physical relationship that must exist between total wall tension and internal pressure in any hollow vessel with circular containing walls. Regardless of whether the ventricle is envisioned as a hollow cylinder or a hollow sphere or whether it is thick- or thin-walled, the law of Laplace says that the total wall tension (T) depends on both intraventricular pressure (P) and its internal radius (r) as T = P × r.
One implication of the law of Laplace is that the muscle cells in the ventricular wall have a somewhat easier job of producing internal pressure at the end of ejection (when the radius is small) than at the beginning of ejection (when the radius is large). More importantly, the law of Laplace has important clinical relevance in pathological situations such as “cardiac dilation” and “cardiac hypertrophy.” These are discussed in detail in Chapter 11.
The importance of all these relationships will become more apparent in the subsequent chapter as we consider how cardiac muscle cell behavior determines how the heart functions as a pump.
It is easy to get overwhelmed by the impressive amount of information that is available concerning the excitation, contraction, and underlying biochemical processes responsible for cardiac muscle cell behavior. Our intent has been to present the basic vocabulary and essential information about excitation and contraction at the cellular level, to introduce areas of promising new information (ie, channel function, calcium cycling, contractile processes), and perhaps to raise questions about what we don’t know (eg, What other cellular processes besides contraction does the calcium oscillation influence? How do these cells sense and adapt to altered pre- and afterloads? How does repair of cell structures and protein synthesis occur in these constantly contracting cells?). However, at this point, we put these questions aside and hope that the student will appreciate the amazing ability of these contracting cells when assembled into a functional pump to effectively move as much as 200 million liters of blood against a substantial pressure during the course of a normal human lifetime.