Physiology 5th Ed.


Myocardial Cell Structure

There are several morphologic and functional differences between cardiac muscle and skeletal muscle, but the basic contractile machinery in the two cell types is similar.

As in skeletal muscle, the cardiac muscle cell is composed of sarcomeres. The sarcomeres, which run from Z line to Z line, are composed of thick and thin filaments. The thick filaments are composed of myosin, whose globular heads have actin-binding sites and ATPase activity. The thin filaments are composed of three proteins: actin, tropomyosin, and troponin. Actin is a globular protein with a myosin-binding site, which, when polymerized, forms two twisted strands. Tropomyosin runs along the groove of the twisted actin strands and functions to block the myosin-binding site. Troponin is a globular protein composed of a complex of three subunits; the troponin C subunit binds Ca2+. When Ca2+ is bound to troponin C, a conformational change occurs, which removes the tropomyosin inhibition of actin-myosin interaction.

As in skeletal muscle, contraction occurs according to the sliding filament model, which states that when cross-bridges form between myosin and actin and then break, the thick and thin filaments move past each other. As a result of this cross-bridge cycling, the muscle fiber produces tension.

The transverse (Ttubules invaginate cardiac muscle cells at the Z lines, are continuous with the cell membranes, and function to carry action potentials to the cell interior. The T tubules form dyads with the sarcoplasmic reticulum, which is the site of storage and release of Ca2+ for excitation-contraction coupling.

Excitation-Contraction Coupling

As in skeletal and smooth muscle, excitation-contraction coupling in cardiac muscle translates the action potential into the production of tension. The following steps are involved in excitation-contraction coupling in cardiac muscle. These steps correlate with the circled numbers shown in Figure 4-18


Figure 4–18 Excitation-contraction coupling in myocardial cells. See the text for an explanation of the circled numbers. SR, Sarcoplasmic reticulum.

1.     The cardiac action potential is initiated in the myocardial cell membrane, and the depolarization spreads to the interior of the cell via the T tubules. Recall that a unique feature of the cardiac action potential is its plateau (phase 2), which results from an increase in gCa and an inward Ca2+ current in which Ca2+ flows through L-type Ca2+ channels (dihydropyridine receptors) from extracellular fluid (ECF) to intracellular fluid (ICF).

2.     Entry of Ca2+ into the myocardial cell produces an increase in intracellular Ca2+ concentration. This increase in intracellular Ca2+ concentration is not sufficient alone to initiate contraction, but it triggers the release of moreCa2+ from stores in the sarcoplasmic reticulum through Ca2+ release channels (ryanodine receptors). This process is called Ca2+-induced Ca2+ release, and the Ca2+ that enters during the plateau of the action potential is called the trigger Ca2+. Two factors determine how much Ca2+ is released from the sarcoplasmic reticulum in this step: the amount of Ca2+ previously stored and the size of the inward Ca2+ current during the plateau of the action potential.

3.     and 4. Ca2+ release from the sarcoplasmic reticulum causes the intracellular Ca2+ concentration to increase even further. Ca2+ now binds to troponin C, tropomyosin is moved out of the way, and the interaction of actin and myosin can occur. Actin and myosin bind, cross-bridges form and then break, the thin and thick filaments move past each other, and tension is produced. Cross-bridge cycling continues as long as intracellular Ca2+concentration is high enough to occupy the Ca2+-binding sites on troponin C.

4.     A critically important concept is that the magnitude of the tension developed by myocardial cells is proportional to the intracellular Ca2+ concentration. Therefore, it is reasonable that hormones, neurotransmitters, and drugs that alter the inward Ca2+ current during the action potential plateau or that alter sarcoplasmic reticulum Ca2+ stores would be expected to change the amount of tension produced by myocardial cells.

Relaxation occurs when Ca2+ is reaccumulated in the sarcoplasmic reticulum by the action of the Ca2+ ATPase. This reaccumulation causes the intracellular Ca2+ concentration to decrease to resting levels. In addition, Ca2+, which entered the cell during the plateau of the action potential, is extruded from the cell by Ca2+ ATPase and Ca2+-Na+ exchange in the sarcolemmal membrane. These sarcolemmal transporters pump Ca2+ out of the cell against its electrochemical gradient, with the Ca2+ ATPase using ATP directly and the Ca2+-Na+ exchanger using energy from the inward Na+ gradient.


Contractility, or inotropism, is the intrinsic ability of myocardial cells to develop force at a given muscle cell length. Agents that produce an increase in contractility are said to have positive inotropic effects.Positive inotropic agents increase both the rate of tension development and the peak tension. Agents that produce a decrease in contractility are said to have negative inotropic effects. Negative inotropic agents decrease both the rate of tension development and the peak tension

Mechanisms for Changing Contractility

Contractility correlates directly with the intracellular Ca2+ concentration, which in turn depends on the amount of Ca2+ released from sarcoplasmic reticulum stores during excitation-contraction coupling. The amount of Ca2+released from the sarcoplasmic reticulum depends on two factors: the size of the inward Ca2+ current during the plateau of the myocardial action potential (the size of the trigger Ca2+) and the amount of Ca2+ previously stored in the sarcoplasmic reticulum for release. Therefore, the larger the inward Ca2+ current and the larger the intracellular stores, the greater the increase in intracellular Ca2+ concentration and the greater the contractility.

Effects of the Autonomic Nervous System on Contractility

The effects of the autonomic nervous system on contractility are summarized in Table 4-4. Of these effects, the most important is the positive inotropic effect of the sympathetic nervous system.

image Sympathetic nervous system. Stimulation of the sympathetic nervous system and circulating catecholamines have a positive inotropic effect on the myocardium (i.e., increased contractility). This positive inotropic effect has three important features: increased peak tension, increased rate of tension development, and faster rate of relaxation. Faster relaxation means that the contraction (twitch) is shorter, allowing more time for refilling. This effect, like the sympathetic effect on heart rate, is mediated via activation of β1 receptors, which are coupled via a Gs protein to adenylyl cyclase. Activation of adenylyl cyclase leads to the production of cyclic adenosine monophosphate (cAMP), activation of protein kinases, and phosphorylation of proteins that produce the physiologic effect of increased contractility.

  Two different proteins are phosphorylated to produce the increase in contractility. The coordinated actions of these phosphorylated proteins then produce an increase in intracellular Ca2+ concentration. (1) There is phosphorylation of the sarcolemmal Ca2+ channels that carry inward Ca2+ current during the plateau of the action potential. As a result, there is increased inward Ca2+ current during the plateau and increased trigger Ca2+, which increases the amount of Ca2+ released from the sarcoplasmic reticulum. (2) There is phosphorylation of phospholamban, a protein that regulates Ca2+ ATPase in the sarcoplasmic reticulum. When phosphorylated, phospholamban stimulates the Ca2+ ATPase, resulting in greater uptake and storage of Ca2+ by the sarcoplasmic reticulum. Increased Ca2+ uptake by the sarcoplasmic reticulum has two effects: It causes faster relaxation (i.e., briefer contraction), and it increases the amount of stored Ca2+ for release on subsequent beats.

image Parasympathetic nervous system. Stimulation of the parasympathetic nervous system and ACh have a negative inotropic effect on the atria. This effect is mediated via muscarinic receptors, which are coupled via a Gi protein called GK to adenylyl cyclase. Because the G protein in this case is inhibitory, contractility is decreased (opposite of the effect of activation of β1 receptors by catecholamines). Two factors are responsible for the decrease in atrial contractility caused by parasympathetic stimulation. (1) ACh decreases inward Ca2+ current during the plateau of the action potential. (2) ACh increases IK-ACh, thereby shortening the duration of action potential and, indirectly, decreasing the inward Ca2+ current (by shortening the plateau phase). Together, these two effects decrease the amount of Ca2+ entering atrial cells during the action potential, decrease the trigger Ca2+, and decrease the amount of Ca2+ released from the sarcoplasmic reticulum.

Effect of Heart Rate on Contractility

Perhaps surprisingly, changes in heart rate produce changes in contractility: When the heart rate increases, contractility increases; when the heart rate decreases, contractility decreases. The mechanism can be understood by recalling that contractility correlates directly with intracellular Ca2+ concentration during excitation-contraction coupling.

For example, an increase in heart rate produces an increase in contractility, which can be explained as follows: (1) When heart rate increases, there are more action potentials per unit time and an increase in the total amount of trigger Ca2+ that enters the cell during the plateau phases of the action potentials. Furthermore, if the increase in heart rate is caused by sympathetic stimulation or by catecholamines, then the size of the inward Ca2+ current with each action potential also is increased. (2) Because there is greater influx of Ca2+ into the cell during the action potentials, the sarcoplasmic reticulum accumulates more Ca2+ for subsequent release (i.e., increased stored Ca2+). Again, if the increase in heart rate is caused by sympathetic stimulation, then phospholamban, which augments Ca2+ uptake by the sarcoplasmic reticulum, will be phosphorylated, further increasing the uptake process. Two specific examples of the effect of heart rate on contractility, the positive staircase effect and postextrasystolic potentiation, are illustrated in Figure 4-19.

image Positive staircase effect. The positive staircase effect is also called the Bowditch staircase, or Treppe (see Fig. 4-19A). When heart rate doubles, for example, the tension developed on each beat increases in a stepwise fashion to a maximal value. This increase in tension occurs because there are more action potentials per unit time, more total Ca2+ entering the cell during the plateau phases, and more Ca2+ for accumulation by the sarcoplasmic reticulum (i.e., more stored Ca2+). Notice that the very first beat after the increase in heart rate shows no increase in tension because extra Ca2+ has not yet accumulated. On subsequent beats, the effect of the extra accumulation of Ca2+ by the sarcoplasmic reticulum becomes evident. Tension rises stepwise, like a staircase: With each beat, more Ca2+ is accumulated by the sarcoplasmic reticulum, until a maximum storage level is achieved.

image Postextrasystolic potentiation. When an extrasystole occurs (an anomalous “extra” beat generated by a latent pacemaker), the tension developed on the next beat is greater than normal (see Fig. 4-19B). Although the tension developed on the extrasystolic beat itself is less than normal, the very next beat exhibits increased tension. An unexpected or “extra” amount of Ca2+ entered the cell during the extrasystole and was accumulated by the sarcoplasmic reticulum (i.e., increased stored Ca2+).


Figure 4–19 Examples of the effect of heart rate on contractility. A, Positive staircase; B, postextrasystolic potentiation. Tension is used as a measure of contractility. The frequency of the bars shows the heart rate, and the height of the bars shows the tension produced on each beat.

Effect of Cardiac Glycosides on Contractility

Cardiac glycosides are a class of drugs that act as positive inotropic agents. These drugs are derived from extracts of the foxglove plant, Digitalis purpurea. The prototype drug is digoxin; other drugs in this class include digitoxin and ouabain.

The well-known action of the cardiac glycosides is inhibition of Na+-K+ ATPase. In the myocardium, inhibition of Na+-K+ ATPase underlies the positive inotropic effect of the cardiac glycosides, as explained in Figure 4-20. The circled numbers in the figure correlate with the following steps:


Figure 4–20 Mechanism of the positive inotropic effect of cardiac glycosides. See the text for an explanation of the circled numbers.

1.     The Na+-K+ ATPase is located in the cell membrane of the myocardial cell. Cardiac glycosides inhibit Na+-K+ ATPase at the extracellular K+-binding site.

2.     When the Na+-K+ ATPase is inhibited, less Na+ is pumped out of the cell, increasing the intracellular Na+ concentration.

3.     The increase in intracellular Na+ concentration alters the Na+ gradient across the myocardial cell membrane, thereby altering the function of a Ca2+-Na+ exchanger. This exchanger pumps Ca2+ out of the cell against an electrochemical gradient in exchange for Na+ moving into the cell down an electrochemical gradient. (Recall that Ca2+-Na+ exchange is one of the mechanisms that extrudes the Ca2+ that entered the cell during the plateau of the myocardial cell action potential.) The energy for pumping Ca2+uphill comes from the downhill Na+ gradient, which is normally maintained by the Na+-K+ ATPase. When the intracellular Na+ concentration increases, the inwardly directed Na+ gradient decreases. As a result, Ca2+-Na+ exchange decreases because it depends on the Na+ gradient for its energy source.

4.     As less Ca2+ is pumped out of the cell by the Ca2+-Na+ exchanger, the intracellular Ca2+ concentration increases.

5.     Since tension is directly proportional to the intracellular Ca2+ concentration, cardiac glycosides produce an increase in tension by increasing intracellular Ca2+ concentration—a positive inotropic effect.

The major therapeutic use of cardiac glycosides is in the treatment of congestive heart failure, a condition characterized by decreased contractility of ventricular muscle (i.e., negative inotropism). When the failure occurs on the left side of the heart, the left ventricle is unable to develop normal tension when it contracts and is unable to eject a normal stroke volume into the aorta. When the failure occurs on the right side of the heart, the right ventricle is unable to develop normal tension and is unable to eject a normal stroke volume into the pulmonary artery. Either situation is serious and potentially life threatening. By increasing the intracellular Ca2+ concentration of the ventricular cells, cardiac glycosides have a positive inotropic action, which may counteract the negative inotropism of the failed ventricle.

Length-Tension Relationship in Cardiac Muscle

Just as in skeletal muscle, the maximal tension that can be developed by a myocardial cell depends on its resting length. Recall that the physiologic basis for the length-tension relationship is the degree of overlap of thick and thin filaments and the number of possible sites for cross-bridge formation. (The intracellular Ca2+ concentration then determines what fraction of these possible cross-bridges will actuallyform and cycle.) In myocardial cells, maximal tension development occurs at cell lengths of about 2.2 µm, or Lmax. At this length, there is maximal overlap of thick and thin filaments; at either shorter or longer cell lengths, the tension developed will be less than maximal. In addition to the degree of overlap of thick and thin filaments, there are two additional length-dependent mechanisms in cardiac muscle that alter the tension developed: Increasing muscle length increases the Ca2+-sensitivity of troponin C and increasing muscle length increases Ca2+ release from the sarcoplasmic reticulum

The length-tension relationship for single myocardial cells can be extended to a length-tension relationship for the ventricles. For example, consider the left ventricle. The length of a single left ventricular muscle fiber just prior to contraction corresponds to left ventricular end-diastolic volume. The tension of a single left ventricular muscle fiber corresponds to the tension or pressure developed by the entire left ventricle. When these substitutions are made, a curve can be developed that shows ventricular pressure during systole as a function of ventricular end-diastolic volume (Fig. 4-21).


Figure 4–21 Systolic and diastolic left ventricular pressure-volume curves. The systolic curve shows active pressure as a function of end-diastolic volume (fiber length). The diastolic curve shows passive pressure as a function of end-diastolic volume.

The upper curve is the relationship between ventricular pressure developed during systole and end-diastolic volume (or end-diastolic fiber length). This pressure development is an active mechanism. On the ascending limb of the curve, pressure increases steeply as fiber length increases, reflecting greater degrees of overlap of thick and thin filaments, greater cross-bridge formation and cycling, and greater tension developed. The curve eventually levels off when overlap is maximal. If end-diastolic volume were to increase further and the fibers were stretched to even longer lengths, overlap would decrease and the pressure would decrease (descending limb of the curve). In contrast to skeletal muscle, which operates over the entire length-tension curve (see Chapter 1Fig. 1-26), cardiac muscle normally operates only on the ascending limb of the curve. The reason for this difference is that cardiac muscle is much stiffer than skeletal muscle. Thus, cardiac muscle has high resting tension, and small increases in length produce large increases in resting tension. For this reason, cardiac muscle is “held” on the ascending limb of its length-tension curve, and it is difficult to lengthen cardiac muscle fibers beyond Lmax. For example, the “working length” of cardiac muscle fibers (the length at the end of diastole) is 1.9 µm (<lmax, which is 2.2 µm). This systolic pressure-volume (i.e., length-tension) relationship for the ventricle is the basis for the Frank-Starling relationship in the heart.</l

The lower curve is the relationship between ventricular pressure and ventricular volume during diastole, when the heart is not contracting. As end-diastolic volume increases, ventricular pressure increases through passive mechanisms. The increasing pressure in the ventricle reflects the increasing tension of the muscle fibers as they are stretched to longer lengths.

The terms “preload” and “afterload” can be applied to cardiac muscle just as they are applied to skeletal muscle.

image The preload for the left ventricle is left ventricular end-diastolic volume, or end-diastolic fiber length; that is, preload is the resting length from which the muscle contracts. The relationship between preload and developed tension or pressure, illustrated in the upper (systolic) curve in Figure 4-21, is based on the degree of overlap of thick and thin filaments.

image The afterload for the left ventricle is aortic pressure. The velocity of shortening of cardiac muscle is maximal when afterload is zero, and velocity of shortening decreases as afterload increases. (The relationship between the ventricular pressure developed and aortic pressure or afterload is discussed more fully in the section on ventricular pressure-volume loops.)

Stroke Volume, Ejection Fraction, and Cardiac Output

The function of the ventricles is described by the following three parameters: (1) Stroke volume is the volume of blood ejected by the ventricle on each beat; (2) Ejection fraction is the fraction of the end-diastolic volume ejected in each stroke volume, which is a measure of ventricular efficiency; and (3) Cardiac output is the total volume ejected by the ventricle per unit time

Stroke Volume

The volume of blood ejected on one ventricular contraction is the stroke volume. Stroke volume is the difference between the volume of blood in the ventricle before ejection (end-diastolic volume) and the volume remaining in the ventricle after ejection (end-systolic volume). Typically, stroke volume is about 70 mL. Thus,



Stroke volume

= Volume ejected on one beat (mL)

End-diastolic volume

= Volume in the ventricle before ejection (mL)

End-systolic volume

= Volume in the ventricle after ejection (mL)

Ejection Fraction

The effectiveness of the ventricles in ejecting blood is described by the ejection fraction, which is the fraction of the end-diastolic volume that is ejected in one stroke volume. Normally, ejection fraction is approximately 0.55, or 55%. The ejection fraction is an indicator ofcontractility, with increases in ejection fraction reflecting an increase in contractility and decreases in ejection fraction reflecting a decrease in contractility. Thus,


Cardiac Output

The total volume of blood ejected per unit time is the cardiac output. Thus, cardiac output depends on the volume ejected on a single beat (stroke volume) and the number of beats per minute (heart rate). Cardiac output is approximately 5000 mL/min in a 70-kg man (based on a stroke volume of 70 mL and a heart rate of 72 beats/min). Thus,



Cardiac output

= Volume ejected per minute (mL/min)

Stroke volume

= Volume ejected in one beat (mL)

Heart rate

= Beats per minute (beats/min)

SAMPLE PROBLEM. A man has an end-diastolic volume of 140 mL, an end-systolic volume of 70 mL, and a heart rate of 75 beats/min. What is his stroke volume, his cardiac output, and his ejection fraction?

SOLUTION. These calculations are basic and important. The stroke volume is the volume ejected from the ventricle on a single beat; therefore, it is the difference between the volume in the ventricle before and after it contracts. Cardiac output is stroke volume multiplied by heart rate. The ejection fraction is the efficiency of the ventricle in ejecting blood, and it is the stroke volume divided by the end-diastolic volume.




Frank-Starling Relationship

The length-tension relationship for ventricular systole has already been described. This relationship now can be understood, using the parameters of stroke volume, ejection fraction, and cardiac output

The German physiologist Otto Frank first described the relationship between the pressure developed during systole in a frog ventricle and the volume present in the ventricle just prior to systole. Building on Frank’s observations, the British physiologist Ernest Starling demonstrated, in an isolated dog heart, that the volume the ventricle ejected in systole was determined by the end-diastolic volume. Recall that the principle underlying this relationship is the length-tension relationship in cardiac muscle fibers.

The Frank-Starling law of the heart, or the Frank-Starling relationship, is based on these landmark experiments. It states that the volume of blood ejected by the ventricle depends on the volume present in the ventricle at the end of diastole. The volume present at the end of diastole, in turn, depends on the volume returned to the heart, or the venous return. Therefore, stroke volume and cardiac output correlate directly with end-diastolic volume, which correlates with venous return. The Frank-Starling relationship governs normal ventricular function and ensures that the volume the heart ejects in systole equals the volume it receives in venous return. Recall from a previous discussion that, in the steady state, cardiac output equals venous return. It is the Frank-Starling law of the heart that underlies and ensures this equality.

The Frank-Starling relationship is illustrated in Figure 4-22. Cardiac output and stroke volume are plotted as a function of ventricular end-diastolic volume or right atrial pressure. (Right atrial pressure may be substituted for end-diastolic volume because both parameters are related to venous return.) There is a curvilinear relationship between stroke volume or cardiac output and ventricular end-diastolic volume. As venous return increases, end-diastolic volume increases, and because of the length-tension relationship in the ventricles, stroke volume increases accordingly. In the physiologic range, the relationship between stroke volume and end-diastolic volume is nearly linear. Only when end-diastolic volume becomes high does the curve start to bend: At these high levels, the ventricle reaches a limit and simply is not able to “keep up” with venous return.


Figure 4–22 Frank-Starling relationship in the heart. The effects of positive and negative inotropic agents are shown with respect to the normal Frank-Starling relationship.

Also illustrated in Figure 4-22 are the effects of changing contractility on the Frank-Starling relationship. Agents that increase contractility have a positive inotropic effect (uppermost curve). Positive inotropic agents (e.g., digoxin) produce increases in stroke volume and cardiac output for a given end-diastolic volume. The result is that a larger fraction of the end-diastolic volume is ejected per beat and there is an increase in ejection fraction.

Agents that decrease contractility have a negative inotropic effect (lowermost curve). Negative inotropic agents produce decreases in stroke volume and cardiac output for a given end-diastolic volume. The result is that a smaller fraction of the end-diastolic volume is ejected per beat and there is a decrease in ejection fraction.

Ventricular Pressure-Volume Loops

Normal Ventricular Pressure-Volume Loop

The function of the left ventricle can be observed over an entire cardiac cycle (diastole plus systole) by combining the two pressure-volume relationships from Figure 4-21. By connecting these two pressure-volume curves, it is possible to construct a so-called ventricular pressure-volume loop (Fig. 4-23). Recall that the systolic pressure-volume relationship in Figure 4-21 shows the maximum developed ventricular pressure for a given ventricular volume. To facilitate understanding, a portion of that systolic pressure-volume curve is superimposed as a gold dashed line on the ventricular pressure-volume loop. The dashed line shows the maximum possible pressure that can be developed for a given ventricular volume during systole (i.e., when the ventricle is contracting). Note that point 3 on the pressure-volume loop touches the systolic pressure-volume curve (dashed line). Also, it may not be evident that the portion of the loop between points 4 and 1 corresponds to a portion of the diastolic pressure-volume curve from Figure 4-21.


Figure 4–23 Left ventricular pressure-volume loop. One complete left ventricular cycle is shown. (Refer to the text for a complete explanation.) The dashed line shows a portion of the systolic pressure-volume curve from Figure 4-21.

The ventricular pressure-volume loop describes one complete cycle of ventricular contraction, ejection, relaxation, and refilling as follows:

image Isovolumetric contraction (1 → 2). Begin the cycle at point 1, which marks the end of diastole. The left ventricle has filled with blood from the left atrium, and its volume is the end-diastolic volume, 140 mL. The corresponding pressure is quite low because the ventricular muscle is relaxed. At this point, the ventricle is activated, it contracts, and ventricular pressure increases dramatically. Because all valves are closed, no blood can be ejected from the left ventricle, and ventricular volume is constant, although ventricular pressure becomes quite high (point 2). Thus, this phase of the cycle is called isovolumetric contraction.

image Ventricular ejection (2 → 3). At point 2, left ventricular pressure becomes higher than aortic pressure, causing the aortic valve to open. (You may wonder why the pressure at point 2 does not reach the systolic pressure-volume curve shown by the dashed gold line. The simple reason is that it does not have to. The pressure at point 2 is determined by aortic pressure. Once ventricular pressure reaches the value of aortic pressure, the aortic valve opens and the rest of the contraction is used for ejection of the stroke volume through the open aortic valve.) Once the valve is open, blood is rapidly ejected, driven by the pressure gradient between the left ventricle and the aorta. During this phase, left ventricular pressure remains high because the ventricle is still contracting. Ventricular volume decreases dramatically, however, as blood is ejected into the aorta. The volume remaining in the ventricle at point 3 is the end-systolic volume, 70 mL. The width of the pressure-volume loop is the volume of blood ejected, or the stroke volume. The stroke volume in this ventricular cycle is 70 mL (140 mL − 70 mL).

image Isovolumetric relaxation (3 → 4). At point 3, systole ends and the ventricle relaxes. Ventricular pressure decreases below aortic pressure and the aortic valve closes. Although ventricular pressure decreases rapidly during this phase, ventricular volume remains constant (isovolumetric) at the end-systolic value of 70 mL because all valves are closed again.

image Ventricular filling (4 → 1). At point 4, ventricular pressure has fallen to a level that now is less than left atrial pressure, causing the mitral (AV) valve to open. The left ventricle fills with blood from the left atrium passively and also actively, as a result of atrial contraction in the next cycle. Left ventricular volume increases back to the end-diastolic volume of 140 mL. During this last phase, the ventricular muscle is relaxed, and pressure increases only slightly as the compliant ventricle fills with blood.

Changes in Ventricular Pressure-Volume Loops

Ventricular pressure-volume loops can be used to visualize the effects of changes in preload (i.e., changes in venous return or end-diastolic volume), changes in afterload (i.e., changes in aortic pressure), or changes in contractility (Fig. 4-24). The solid lines depict a single, normal ventricular cycle and are identical to the pressure-volume loop shown in Figure 4-23. The dashed lines demonstrate the effects of various changes on a single ventricular cycle (but they do not include any compensatory responses that may occur later).

image Figure 4-24A illustrates the effect of increased preload on the ventricular cycle. Recall that preload is end-diastolic volume. In this example, preload is increased because venous return is increased, which increases end-diastolic volume (point 1). Afterload and contractility remain constant. As the ventricle proceeds through its cycle of contraction, ejection, relaxation, and refilling, the effect of this increase in preload can be appreciated: Stroke volume, as measured by the width of the pressure-volume loop, increases. This increase in stroke volumeis based on the Frank-Starling relationship, which states that the greater the end-diastolic volume (end-diastolic fiber length), the greater the stroke volume ejected in systole.

image Figure 4-24B illustrates the effect of increased afterload or increased aortic pressure on the ventricular cycle. In this example, the left ventricle must eject blood against a greater-than-normal pressure. To eject blood, ventricular pressure must rise to a greater than normal level during isovolumetric contraction (point 2) and during ventricular ejection (i.e., 2 → 3). A consequence of the increased afterload is that less blood is ejected from the ventricle during systole; thus, stroke volume decreases, more blood remains in the ventricle at the end of systole, and end-systolic volume increases. One can envision the effect of increased afterload as follows: if more of the contraction is “spent” in isovolumetric contraction to match the higher afterload, then less of the contraction is “leftover” and available for ejection of the stroke volume.

image Figure 4-24C illustrates the effect of increased contractility on the ventricular cycle. When contractility increases, the ventricle can develop greater tension and pressure during systole and eject a larger volume of blood than normal. Stroke volume increases, as does ejection fraction; less blood remains in the ventricle at the end of systole, and, consequently, end-systolic volume decreases (points 3 and 4).


Figure 4–24 Changes in the left ventricular pressure-volume loop. A, Increased preload; B, increased afterload; C, increased contractility. The normal ventricular cycle is shown by the solid lines, and the effect of the change is shown by the dashed lines.

Cardiac Work

Work is defined as force times distance. In terms of myocardial function, “work” is stroke work or the work the heart performs on each beat. For the left ventricle, stroke work is stroke volume multiplied by aortic pressure, where aortic pressure corresponds to force and stroke volume corresponds to distance. The work of the left ventricle can also be thought of as the area within the pressure-volume loop, such as the loop illustrated in Figure 4-23

Minute work or power is defined as work per unit time. In terms of myocardial function, cardiac minute work is cardiac output multiplied by aortic pressure. Therefore, cardiac minute work can be considered to have two components: volume work (i.e., cardiac output) andpressure work (i.e., aortic pressure).

Sometimes the volume work component is called “external” work, and the pressure work component is called “internal” work. Thus, increases in cardiac output (due to an increase in stroke volume and/or an increase in heart rate) or increases in aortic pressure will increase the work of the heart.

Myocardial Oxygen Consumption

Myocardial O2 consumption correlates directly with cardiac minute work. Of the two components of cardiac minute work, in terms of O2 consumption, pressure work is far more costly than volume work. In other words, pressure work constitutes a large percentage of the total cardiac work, and volume work contributes a small percentage. These observations explain why overall myocardial O2 consumption correlates poorly with cardiac output: The largest percentage of the O2 consumption is for pressure work (or internal work), which is not cardiac output.

It can be further concluded that, in conditions where a larger than normal percentage of the total cardiac work is pressure work, the cost in terms of O2 consumption increases. For example, in aortic stenosis, myocardial O2consumption is greatly increased because the left ventricle must develop extremely high pressures to pump blood through the stenosed aortic valve (even though cardiac output actually is reduced).

On the other hand, during strenuous exercise when cardiac output becomes very high, volume work contributes a greater-than-normal percentage of the total cardiac work (up to 50%). Although myocardial O2 consumption increases during exercise, it does not increase as much as when pressure work increases.

Another consequence of the greater O2 consumption of pressure work is that the left ventricle must work harder than the right ventricle. Although cardiac output is the same on both sides of the heart, mean aortic pressure (100 mm Hg) is much higher than mean pulmonary artery pressure (15 mm Hg). Thus, the pressure work of the left ventricle is much greater than the pressure work of the right ventricle, although the volume work is the same. In fact, the left ventricular wall is thicker than the right ventricular wall as a compensatory mechanism for performing more pressure work.

In pathologic conditions such as systemic hypertension (elevated arterial pressure in the systemic circulation), the left ventricle must perform even more pressure work than it does normally. Because aortic pressure is elevated, the left ventricular wall hypertrophies (thickens) as a compensation for the increased workload.

The greater thickness of the normal left ventricular wall and the compensatory hypertrophy of the left ventricular wall in systemic hypertension are adaptive mechanisms for performing more pressure work. These adaptive mechanisms are explained by the law of Laplace. The law of Laplace for a sphere (i.e., the approximate shape of the heart) states that pressure correlates directly with tension and wall thickness and correlates inversely with radius. Thus,




= Pressure


= Thickness (height)


= Tension


= Radius

In words, the law of Laplace for a sphere states that the greater the thickness of the wall of the sphere (e.g., left ventricle), the greater the pressure that can be developed. Illustrating this point, the left ventricular wall is thicker than the right ventricular wall because the left ventricle must develop greater pressure to eject blood.

It can be further concluded that ventricular wall thickness will increase as a compensatory mechanism if the ventricle has to pump against increased aortic pressure (e.g., hypertension). Thus, in systemic hypertension, the left ventricle hypertrophies; in pulmonary hypertension, the right ventricle hypertrophies. Unfortunately, this type of compensatory ventricular hypertrophy also may lead to ventricular failure and, eventually, be harmful or even fatal.

Measurement of Cardiac Output—Fick Principle

Cardiac output has previously been defined as the volume ejected by the left ventricle per unit time and is calculated as the product of stroke volume and heart rate. Cardiac output can be measured using the Fick principle, whose fundamental assumption is that, in the steady state, the cardiac output of the left and right ventricles is equal.

The Fick principle states that there is conservation of mass, a concept that can be applied to the utilization of O2 by the body. In the steady state, the rate of O2 consumption by the body must equal the amount of O2 leaving the lungs in the pulmonary vein minus the amount of O2 returning to the lungs in the pulmonary artery. Each of these parameters can be measured. Total O2 consumption can be measured directly. The amount of O2 in the pulmonary veins is pulmonary blood flow multiplied by the O2 content of pulmonary venous blood. Likewise, the amount of O2 returned to the lungs via the pulmonary artery is pulmonary blood flow multiplied by the O2 content of pulmonary arterial blood. Recall that pulmonary blood flow is the cardiac output of the right heart and is equal to the cardiac output of the left heart. Thus, stating these equalities mathematically,


or, rearranging to solve for cardiac output:



Cardiac output

= Cardiac output (mL/min)

O2 consumption

= O2 consumption by whole body (mL O2/min)

[O2]pulmonary vein

= O2 content of pulmonary venous blood (mL O2/mL blood)

[O2]pulmonary artery

= O2 content of pulmonary arterial blood (mL O2/mL blood)

The total O2 consumption of the body typically is 250 mL/min in a 70-kg man. The O2 content of pulmonary venous blood can be measured by sampling blood from a peripheral artery (because none of the O2added to blood in the lungs has been consumed by the tissues yet). The O2 content of pulmonary arterial blood is equal to that of mixed venous blood and can be sampled either in the pulmonary artery itself or in the right ventricle.

SAMPLE PROBLEM. A man has a resting O2 consumption of 250 mL O2/min, a femoral arterial O2 content of 0.20 mL O2/mL blood, and a pulmonary arterial O2 content of 0.15 mL O2/mL blood. What is his cardiac output?

SOLUTION. To calculate cardiac output using the Fick principle, the following values are required: total body O2 consumption, pulmonary venous O2 content (in this example, femoral arterial O2 content), and pulmonary arterial O2 content.



Not only is the Fick principle applicable to measurement of cardiac output (essentially the blood flow to the whole body), but it also can be applied to the measurement of blood flow to individual organs. For example, renal blood flow can be measured by dividing the O2 consumption of the kidneys by the difference in O2 content of renal arterial blood and renal venous blood.