Preload or Filling Pressure of the heart

The greater the preload of the heart, the greater the cardiac output. In the intact circulation, it will be the pressure in the great veins (i.e., the central venous pressure [CVP]) that constitutes the preload of the heart. In the whole heart, the stretch of the ventricles prior to systole will determine the strength of the subsequent contraction, by the cellular mechanisms discussed earlier (see Chapter 4). The cardiac output is the output of the left ventricle, but it is the preload of the right ventricle that ultimately actually determines the cardiac output. The reason is that, during periods when cardiac output is constant, and within limits, the left ventricle will pump whatever volume of blood comes to it, from the right side of the heart. Thus, it is the filling pressure on the right side of the heart that ultimately determines the output on the left. The filling pressure on the right side of the heart is functionally equal to the central venous pressure. In the intact circulation, the preload is considered to be the CVP, which is approximately equal to the mean right atrial pressure (_ra), which, when the tricuspid valve is open, is approximately equal to the right ventricular pressure. The relationship between preload or filling pressure and stroke volume (or cardiac output) is shown in the cardiac function curve. Cardiac function curves are also known as “Starling curves” or ventricular function curves. Partial curves can be obtained in human subjects, through the use of intracardiac pressure and volume transducers. The cardiac function curve is a manifestation of the Frank-Starling relationship or length-dependence of cardiac contraction.

Cardiac Function Curve

The CFC will be derived by using left ventricular pressure-volume (P-V) loops to illustrate the effect that varying preload has on the stroke volume (SV). In the CFC, stroke volume (or the proportional quantity, CO) is plotted as a function of filling pressure, or preload. For the left ventricle, a measure of preload is the left ventricular end-diastolic pressure (LVEDP). In an experimental situation in which an isolated animal heart is used, the preload of the left ventricle may be varied by changing the height of a reservoir of blood that is connected to the left ventricle (see Chapter 5). Raising or lowering the reservoir increases or decreases the pressure in the left ventricle and is one way in which preload can be changed in an experimental setting. The effect of changing preload on the left ventricular P-V loop is shown in Figure 10-2A. Decreased preload is associated with decreased end-diastolic volume, and increased preload with increased end-diastolic volume. However, the contractility of the ventricle has not changed in this example, and thus the end-systolic pressure-volume relationship (the straight line that indicates the maximum pressure the ventricle can produce at a given volume) has not changed and therefore the end-systolic volume does not change when preload changes. The result is that increased preload results in an increased stroke volume and decreased preload results in a decreased stroke volume. When the different stroke volumes are then plotted against the preload pressures at which they occurred (Figure 10-2B), the entire relationship yields the CFC. A CFC obtained from measurements in 75 patients in whom left ventricular end-diastolic pressure was varied (by various means) (Figure 10-3) verifies that the CFC is a feature of cardiac function in humans.

FIGURE 10-2 The cardiac function curve (CFC) shows the relationship between preload and cardiac output (or stroke volume). A single CFC (panel B) can be obtained by varying preload to produce different stroke volumes of the left ventricle (LV), as shown in the pressure-volume loops (panel A). The straight line represents the end-systolic pressure-volume relationship (ESPVR). Three individual P-V loops are illustrated, and each is characterized by a different stroke volume. The three different stroke volumes are plotted in B vs. the preload at which they were obtained. When stroke volume is measured at many different preloads, the continuous curve in B is obtained, which is the complete cardiac function curve.

FIGURE 10-3 Cardiac function curve in humans. Preload of the left ventricle (measured as left ventricular end-diastolic pressure) was varied by various interventions in 75 patients. A composite graph for 75 patients in whom left ventricular end-diastolic pressure (LVEDP) was modified as shown. Each point represents the mean value for a particular intervention and includes from 4 to 21 patients, with a total of 102 interventions. Left ventricular stroke work index (LVSWI) is positively related to LVEDP up to 10 mm Hg (LVSWI = 24.4 + 2.70 LVEDP); thereafter, there is little increase in LVSWI as LVEDP increases further. NTG, sublingual nitroglycerin; NTGO, nitroglycerin ointment with observations made after 15, 30, and 60 minutes.

(Modified from Parker JO, Case RB: Normal left ventricular function. Circulation 60:4, 1979.)

Factors that Change the Cardiac Function Curve

Contractility

Increases in cardiac contractility, as produced by the actions of norepinephrine or epinephrine on the heart, are a primary way in which cardiac output is increased physiologically. These substances, acting to increase contractility by the cellular mechanisms already presented (see Chapters 4 and 5), have the effect of raising the peak pressure that can be developed at a given left ventricular volume. Increases in contractility are reflected in an end-systolic pressure-volume relationship that is shifted upward and to the left (increased slope), and vice versa for decreases in contractility, as might occur with cardiac damage. Increases in contractility thus increase stroke volume by decreasing end-systolic volume (Figure 10-4A). At each preload, stroke volume is increased with increased contractility, and thus the entire cardiac function curve is increased upwardly (Figure 10-4B). Decreased contractility results in a decreased stroke volume at all preloads. With a change in contractility, the heart will be characterized by a completely new cardiac function curve, which still, however, reflects the Frank-Starling relationship or the length-dependence of cardiac contraction.

FIGURE 10-4 Effect of altered contractility on left ventricular (L.V.) pressure-volume loops (A) and cardiac function curves (B). Increasing left ventricular contractility increases the slope of the end-systolic pressure volume relation, decreases end-systolic volume, and increases stroke volume. Solid black lines represent the normal, basal state; dotted blue lines, decreased contractility; and solid blue lines, increased contractility. Filled circles in (B) represent the stroke volumes of the correspondingly colored pressure-volume loops in (A).

Afterload

Afterload is the load experienced by the left ventricle after the aortic valve opens (ending the isovolumic contraction phase). Afterload is thus related to the arterial blood pressure as well as to the hemodynamic properties of the arterial system (which will influence the dynamics of the arterial blood pressure during ejection of the stroke volume into the arterial system; see Chapter 7). Increases in afterload are represented on the left ventricular P-V loop as a higher pressure throughout the ejection phase (Figure 10-5A). When the diastolic arterial blood pressure is elevated, the isovolumic contraction must then develop a higher pressure in the left ventricle (compared with normal basal state) before the aortic valve can be forced open. If ventricular contractility is constant, the end-systolic P-V relationship is not altered, and therefore the stroke volume is reduced, because the heart is not able to achieve a lower end-systolic volume (it does not have an increased ability to “squeeze down” against the elevated pressure). Conversely, decreases in afterload result in increased stroke volume, because the heart is able to squeeze down more, achieving a lower end-systolic volume. A change in afterload places the left ventricle on a completely new function curve (Figure 10-5B), which still displays the length-dependence of cardiac contraction.

FIGURE 10-5 Effect of altered afterload on left ventricular (L.V.) pressure-volume loops (A) and cardiac function curves (B). Increasing afterload results in decreased stroke volume, because of increased end-systolic volume. Black solid lines represent normal basal state; blue dotted lines, increased afterload; and solid blue lines, decreased afterload. Filled circles in (B) represent the stroke volumes of the correspondingly colored pressure-volume loops in (A).

Myocardial Compliance

Damaged or ischemic heart muscle is less compliant (“stiffer”) than normal heart muscle. In the absence of any other changes, the result is less filling during diastole and a reduced end-diastolic volume (Figure 10-6A). If contractility is not changed, then the stroke volume will be markedly reduced and the left ventricle will operate on a new cardiac function curve (Figure 10-6B) that is depressed compared with the normal basal state.

FIGURE 10-6 Effect of decreasing ventricular compliance on the left ventricular (L.V.) pressure-volume loop (A) and the cardiac function curve (B). Decreased myocardial compliance results in reduced filling during diastole, hence decreased end-diastolic volume and stroke volume. Black solid lines represent normal basal state; and dotted blue line, decreased ventricular compliance. Filled circles in (B) represent the stroke volumes of the correspondingly colored pressure-volume loops in (A).

Cardiac Function Curves and Physiological Function

Heart rate is a major physiological determinant of cardiac output, because CO = HR × SV. Thus, it is useful to plot cardiac output, rather than stroke volume, as a function of preload (Figure 10-7). Increased heart rate, increased contractility, and decreased afterload are all factors that increase cardiac output at a given preload. Conversely, decreased heart rate, decreased contractility, increased afterload, and decreased compliance all decrease cardiac output at a given preload. Physiologically, the changes in cardiac function are rarely (if ever) as simple as can be achieved in isolated heart preparations, as illustrated in the simple schemes shown in Figures 10-2, and 10-4 through 10-6). For example, an increase in contractility produced by increased sympathetic drive to the heart (increased release of norepinephrine) tends to raise stroke volume as shown (see Figure 10-4), but heart rate also increases, with a resultant greater cardiac output. Because mean arterial pressure is the arithmetic product of cardiac output and total peripheral resistance, there is an increase in mean arterial pressure, which constitutes an increase in afterload, an effect that tends to decrease stroke volume. Thus, it is important to remember that physiologically, multiple changes usually occur simultaneously. Most importantly, the filling pressure of the heart is greatly influenced by conditions in the systemic blood vessels. The effect that factors in the systemic vasculature have on the filling pressure of the heart, and hence on cardiac output, are quantified with the vascular function curve, or VFC, as discussed next.

FIGURE 10-7 Summary of factors that change the cardiac function curve and can thus affect cardiac output. HR, heart rate.

Mathematical Analysis of the Vascular Function Curve

From the definition of peripheral resistance (see Chapter 6):

     (2)

where R is resistance, P_a is arterial pressure, P_v is venous pressure, and Q_r is blood flow through the resistance vessels. At equilibrium, Q_r equals cardiac output, Q_h. Assume that R = 20 and that Q_h had been 0 but that it had then been increased to a constant value of 1 L/min (Figure 10-10, arrow 1). If we solve Equation 2 for P_a when the system is in equilibrium (i.e., Q_r = Q_h), then:

FIGURE 10-10 Changes in arterial (P_a) and venous (P_v) pressures in the circulatory model shown in Figure 10-8. The total peripheral resistance is 20 mm Hg/l/min, and the ratio of C_v to C_a is 19:1. The cardiac output (CO) is 0 to the left of arrow 1. It is increased to 1 L/min at arrow i, and to 5 L/min at arrow 2.

     (3)

Thus P_a increases to a value 20 mm Hg greater than P_v. It continues to be 20 mm Hg above P_v, as long as the pump output is maintained at 1 L/min and the peripheral resistance remains at 20 mm Hg/L/min. We can calculate what the actual changes in P_a and P_v will be when Q_r attains a constant value of 1 L/min. The arterial volume increment needed to achieve the required level of P_a depends entirely on the arterial compliance, C_a. For a rigid arterial system (low compliance), this volume is small; for a distensible system, the volume is large. Whatever the magnitude, however, the change in volume represents the translocation of some quantity of blood from the venous to the arterial side of the circuit.

For a given total blood volume, any increment in arterial volume (ΔV_a) must equal the decrement in venous volume (ΔV_v); that is:

     (4)

From the definition of compliance:

     (5)

and

     (6)

By substitution into equation 4:

     (7)

Given that C_v is 19 times as great as C_a, the increment in P_a is 19 times as great as the decrement in P_v; that is:

     (8)

To calculate the absolute values of P_a and P_v, let ΔP_a represent the difference between the prevailing P_a and the mean circulatory pressure (P_mc); that is, let:

     (9)

and let ΔP_v represent the difference between the prevailing P_v and the mean circulatory pressure. Then:

     (10)

Substituting these values for ΔP_a and ΔP_v into Equation 8:

     (11)

By solving equations 3 and 11 simultaneously:

     (12)

and

     (13)

Hence, for a mean circulatory pressure of 7 mm Hg, P_a increases to 26 mm Hg and P_v decreases to 6 mm Hg when Q_h increases from 0 to 1 L/min (see Figure 10-10). These pressure changes provide the required arteriovenous pressure gradient of 20 mm Hg.

If the pump output is abruptly increased to a constant level of 5 L/min (Figure 10-10, arrow 2) and peripheral resistance remains constant at 20 mm Hg/L/min, an additional volume of blood is translocated from the venous to the arterial side of the circuit. The blood progressively accumulates in the arteries until P_a reaches a level of 100 mm Hg above P_v, as shown by substitution into Equation 3:

     (14)

By solving equations 11 and 14 simultaneously, we find that P_a rises to a value of 95 mm Hg above P_mc, and P_v falls to a value 5 mm Hg below P_mc. In Figure 10-10, therefore, P_v declines to 2 mm Hg and P_a rises to 102 mm Hg. The resulting pressure gradient of 100 mm Hg will force a cardiac output of 5 L/min through a constant peripheral resistance of 20 mm Hg/L/min.

The following equation for P_v as a function of Q_r in the model is derived from equations 2, 7, 9, and 10:

     (15)

Equation 15 has the form of a straight line and satisfies the relation y = mx + b. Note that the slope (m) depends only on R, C_a and C_v. Note also that when Q_r = 0, then P_v = P_mc; that is, at zero flow, P_v equals the mean circulatory pressure.

Venous Pressure Depends on Cardiac Output

Experimental and clinical observations have shown that changes in cardiac output do indeed evoke the alterations in P_a and P_v that have been predicted previously for our simplified model. In an experiment on an anesthetized dog, for example, a mechanical pump was substituted for the right ventricle (Figure 10-11). As the cardiac output, Q, was diminished in a series of small steps, P_a fell and P_v rose.

FIGURE 10-11 Changes in arterial (P_a) and central venous (P_v) pressures produced by changes in systemic blood flow (Q_r) in a canine right-heart bypass preparation. Stepwise changes in Q_r were produced by altering the rate of a mechanical pump.

(From Levy MN: The cardiac and vascular factors that determine systemic blood flow. Circ Res 44:739, 1979.)

Blood Volume

The vascular function curve is affected by variations in total blood volume. During circulatory standstill (i.e., zero cardiac output), the mean circulatory pressure depends only on total vascular compliance and blood volume, as stated previously. Thus, for a given vascular compliance, the mean circulatory pressure will increase when the blood volume is expanded (hypervolemia), and it will decrease when the blood volume is diminished (hypovolemia). This is illustrated by the y-axis intercepts in Figure 10-12, in which the mean circulatory pressure is 5 mm Hg after hemorrhage and is 9 mm Hg after transfusion. These values compare with that of 7 mm Hg when the blood volume is normal (normovolemia).

FIGURE 10-12 Effects of increased blood volume (Transfusion curve) and of decreased blood volume (Hemorrhage curve) on the vascular function curve. Similar shifts in the vascular function curve are produced by increases and decreases, respectively, in venomotor tone.

Figure 10-12 shows that the cardiac output at which P_v = 0 varies directly with the blood volume. Therefore, the maximal value of cardiac output becomes progressively more limited as the total blood volume is reduced. However, the pressure (P_v = 0) at which the veins collapse (denoted by the sharp change in slope of the vascular function curve) is not altered appreciably by changes in blood volume. This pressure depends only on the pressure surrounding the central veins.

Furthermore, the differences in P_v during hypervolemia, normovolemia, and hypovolemia in the static system are preserved at each level of cardiac output, such that the vascular function curves parallel one another (see Figure 10-12). To illustrate, consider the example of hypervolemia, in which the mean circulatory pressure is 9 mm Hg. In Figure 10-12, both P_a and P_v would be 9 mm Hg, instead of 7 mm Hg, when the cardiac output is zero. With a sudden increase in cardiac output to 1 L/min (at arrow 1 in Figure 10-10), if the peripheral resistance were still 20 mm Hg/L/min, an arteriovenous pressure gradient of 20 mm Hg would still be necessary for 1 L/min to flow through the resistance vessels. This does not differ from the example for normovolemia. If we assume the same C_v:C_a ratio of 19:1, the pressure gradient would be achieved by a 1–mm Hg decline in P_v and a 19–mm Hg rise in P_a. Hence a change in cardiac output from 0 to 1 L/min would evoke the same 1–mm Hg reduction in P_v. This change in P_v would apply, irrespective of the blood volume, as long as C_a, C_v, and the peripheral resistance were independent of the blood volume. Equation 15 also discloses that the slope of the vascular function curve remains constant as long as R, C_v, and C_a do not change.

Venomotor Tone

The effects of changes in venomotor tone on the vascular function curve closely resemble those of changes in blood volume. In Figure 10-12, for example, the transfusion curve could just as well represent increased venomotor tone, whereas the hemorrhage curve could represent decreased tone. During circulatory standstill, for a given blood volume, the pressure within the vascular system will rise as the tension exerted by the smooth muscle within the vascular walls increases. It is principally the arteriolar and venous smooth muscles that are mainly under nervous or humoral control. The fraction of the blood volume located within the arterioles is very small, whereas the blood volume in the veins is large (see Table 1-1). Therefore, if the blood volume remains constant, only changes in venous tone can alter the mean circulatory pressure appreciably. Hence, mean circulatory pressure rises with increased venomotor tone and falls with diminished tone.

Experimentally, the pressure attained shortly after abrupt circulatory standstill is usually above 7 mm Hg, even when blood volume is normal. The pressure change is attributable to the generalized venoconstriction elicited by cerebral ischemia, activation of the arterial and central chemoreceptors, and reduced excitation of the arterial baroreceptors. If resuscitation is not successful, this reflex response subsides as central nervous activity ceases. When blood volume is normal, the mean circulatory pressure usually approaches a value close to 7 mm Hg.

Blood Reservoirs

Venoconstriction is considerably greater in certain regions of the body than in others. Large vascular beds that undergo appreciable venoconstriction constitute blood reservoirs. The vascular bed of the skin is one of the major blood reservoirs in humans. Blood loss evokes profound subcutaneous venoconstriction, which is responsible for the characteristic pale appearance of the skin in people who have lost a substantial amount of blood. The resulting diversion of blood away from the skin liberates several hundred milliliters of blood, to be perfused through more vital regions. The vascular beds of the liver, lungs, and spleen are also important blood reservoirs. In the dog, the spleen is packed with red blood cells, and it can constrict to a small fraction of its normal size. During hemorrhage, this mechanism autotransfuses blood of high erythrocyte content into the general circulation. However, in humans the volume changes of the spleen are considerably smaller (see also Chapter 13).

Peripheral Resistance

The changes in the vascular function curve induced by changes in arteriolar tone are shown in Figure 10-13. The arterioles contain only about 3% of the total blood volume (see Table 1-1). Changes in the contractile state of these vessels do not significantly alter the mean circulatory pressure, as stated previously. Thus, the family of vascular function curves that represent different peripheral resistances converges at a common point on the ordinate.

FIGURE 10-13 Effects of arteriolar vasodilation and vasoconstriction on the vascular function curve.

At any given cardiac output, P_v varies inversely with the arteriolar tone, all other factors remaining constant. Arteriolar constriction sufficient to double the peripheral resistance causes a twofold rise in P_a (see Chapter 7). In the example shown in Figure 10-10, a change in the cardiac output from 0 to 1 L/min (arrow 1) caused P_a to rise from 7 to 26 mm Hg, an increment of 19 mm Hg. If peripheral resistance had been twice as great, the same change in cardiac output would have evoked twice as great an increment in P_a.

To achieve this greater rise in P_a, twice as great an increment in blood volume would be required on the arterial side of the circulation, if the arterial compliance remained constant. Given a constant total blood volume, this larger arterial volume signifies a corresponding reduction in venous volume. Hence, the decrement in venous volume would be twice as great when the peripheral resistance was doubled.

If venous compliance remained constant, a twofold reduction in venous volume would be reflected by a twofold decline in P_v. Therefore, an increase in cardiac output from 0 L/min to 1 L/min (Figure 10-10, arrow 1) would have caused a 2–mm Hg decrement in P_v, to a level of 5 mm Hg. Similarly, greater increases in cardiac output would have evoked proportionately greater decrements in P_v under conditions of increased peripheral resistance than when the levels of resistance were normal.

This relationship between the peripheral resistance and the decrement in P_v, together with the failure of peripheral resistance to affect the mean circulatory pressure, accounts for the clockwise rotation of the vascular function curves with increased peripheral resistance (see Figure 10-13). Conversely, arteriolar vasodilation is associated with a counterclockwise rotation from the same vertical axis intercept. A higher maximal level of cardiac output is attainable when the resistance vessels are dilated than when they are constricted.

Myocardial Contractility

Combinations of cardiac and vascular function curves help explain the effects of alterations in ventricular contractility. In Figure 10-15, the lower cardiac function curve represents the control state, whereas the upper curve reflects an increased contractility. This pair of curves is analogous to the family of ventricular function curves shown in Figure 5-23. The enhancement of ventricular contractility might be achieved by electrical stimulation of the cardiac sympathetic nerves. If the effects of such stimulation were restricted to the heart, the vascular function curve would be unaffected. Therefore one vascular function curve would suffice, as shown in Figure 10-15.

FIGURE 10-15 Enhancement of myocardial contractility, as by cardiac sympathetic nerve stimulation, causes the equilibrium values of cardiac output and venous pressure (P_v) to shift from the intersection (point A) of the control vascular and cardiac function curves (solid lines) to the intersection (point D) of the same vascular function curve with the cardiac function curve (dashed line) that represents enhanced myocardial contractility. See text for explanation of points B and C.

During the control state, the equilibrium values for cardiac output and P_v are designated by point A. Cardiac sympathetic nerve stimulation would abruptly raise cardiac output to point B, because of the enhanced contractility, before P_v would change appreciably. However, this high cardiac output would increase the net transfer of blood from the venous to the arterial side of the circuit. Consequently, P_v would begin to fall (point C). Cardiac output would continue to fall until a new equilibrium point (D) was reached. This point is located at the intersection of the vascular function curve with the new cardiac function curve. The new equilibrium point (D) lies above and to the left of the control equilibrium point (A). This shift reveals that sympathetic stimulation evokes a greater cardiac output at a lower level of P_v.

Such a change accurately describes the true response. In the experiment depicted in Figure 10-16, the left stellate ganglion was stimulated between the two arrows. During stimulation, aortic flow (cardiac output) rose quickly to a peak value. The flow then fell gradually to a steady-state value, which was significantly greater than the control level. The increased aortic flow was accompanied by reductions in right and left atrial pressures (P_RA and P_LA). The initial, abrupt rise in cardiac output in this experiment represents the shift from A to B in Figure 10-15, whereas the subsequent, more gradual reductions in cardiac output and atrial pressure in the experiment represent the progressive shift from B to D.

FIGURE 10-16 During electrical stimulation of the left stellate ganglion (containing cardiac sympathetic nerve fibers), aortic blood flow increased while pressures in the left atrium (P_LA) and right atrium (P_RA) diminished. These data conform to the conclusions derived from Figure 10-15, in which the equilibrium values of cardiac output and venous pressure are observed to shift from point A to point D during cardiac sympathetic nerve stimulation.

(Redrawn from Sarnoff SJ, Brockman SK, Gilmore JP, et al: Regulation of ventricular contraction. Influence of cardiac sympathetic and vagal nerve stimulation on atrial and ventricular dynamics. Circ Res 8:1108, 1960.)

Blood Volume

Changes in blood volume affect the vascular function curve in the manner shown in Figure 10-12. To understand the circulatory alterations evoked by a given change in blood volume, the appropriate cardiac function curve should be plotted along with the vascular function curves that represent the control and experimental states.

Figure 10-17 illustrates the response to a blood transfusion. Equilibrium point B, which denotes the values for cardiac output and P_v after transfusion, lies above and to the right of the control equilibrium point, A. Thus the transfusion increases both cardiac output and P_v. Hemorrhage has the opposite effect. Mechanistically, the change in ventricular filling pressure (central venous pressure), evoked by a given change in blood volume, alters cardiac output. This is accomplished by changing the sensitivity of the contractile proteins to the prevailing level of intracellular Ca⁺⁺, as explained in Chapters 4 and 5. Pure increases or decreases in venomotor tone elicit responses analogous to those evoked by augmentations or reductions, respectively, of the total blood volume, for reasons discussed later.

FIGURE 10-17 After a blood transfusion, the vascular function curve is shifted to the right. Therefore, cardiac output and venous pressure are both increased, as denoted by the translocation of the equilibrium point from A to B.

Peripheral Resistance

Predictions concerning the effects of changes in peripheral vascular resistance are complex because both the cardiac and vascular function curves shift. With increased peripheral resistance (Figure 10-18), the vascular function curve is rotated counterclockwise. However, it converges to the same P_v-axis intercept as does the control curve (see Figure 10-13); the directions of rotation differ in Figures 10-13 and 10-18 because the axes were switched for the vascular function curves in the two figures. The cardiac function curve is also shifted downward because (1) as peripheral resistance increases, arterial pressure (afterload) tends to rise and (2) at any given P_v, the heart is able to pump less blood against a greater afterload. Because the cardiac and vascular function curves are both displaced downward, the new equilibrium point, B, falls below the control point, A.

FIGURE 10-18 An increase in peripheral resistance shifts the cardiac and vascular function curves downward. At equilibrium the cardiac output is less (point B) when the peripheral resistance is high than when it is normal (point A).

Whether point B falls directly below point A or lies to the right or left of it depends on the magnitude of the shift in each curve. For example, if a given increase in peripheral resistance shifts the vascular function curve more than it does the cardiac function curve, the equilibrium point B will fall below and to the left of A; that is, both cardiac output and P_v will diminish. Conversely, if the cardiac function curve is displaced more than the vascular function curve, point B will fall below and to the right of point A; that is, cardiac output will decrease but P_v will rise somewhat.

CLINICAL BOX

“Heart failure” is the general term that refers to those conditions in which the heart is not able to provide adequate blood flow to the tissues of the body. Heart failure may be acute or chronic. Acute heart failure may be caused by toxic quantities of drugs and anesthetics or by certain pathological conditions, such as a sudden coronary artery occlusion. Chronic heart failure may occur in such conditions as essential hypertension and ischemic heart disease. In these various forms of heart failure, myocardial contractility is impaired. Consequently, the cardiac function curve is shifted downward and to the right, as shown in Figure 10-19.

FIGURE 10-19 With moderate or severe heart failure, the cardiac function curves are shifted to the right. Before any change in blood volume, cardiac output decreases and central venous pressure rises (from control equilibrium point A to point B or C). After the increase in blood volume that usually occurs in heart failure, the vascular function curve is shifted to the right. Hence, central venous pressure may be elevated with no reduction in cardiac output (point D) or (in severe heart failure) with some diminution in cardiac output (point E).

In acute heart failure, blood volume does not change immediately. Therefore, the equilibrium point of the cardiac and vascular function curves will shift from the intersection of the normal curves (Figure 10-19, point A) to the intersection of the normal vascular function curve, with a cardiac function curve that denotes impaired contractility (point B or C).

In chronic heart failure, both the cardiac function and vascular function curves shift. The vascular function curve shifts because of an increase in blood volume caused in part by fluid retention by the kidneys. The fluid retention is related to the concomitant reduction in glomerular filtration rate and to the greater secretion of aldosterone by the adrenal cortex. The resulting hypervolemia is reflected by a rightward shift of the vascular function curve, as shown in Figure 10-19. Hence, with moderate degrees of heart failure, P_v is elevated, but cardiac output is approximately normal (point D). With more severe degrees of heart failure, P_v will be still higher but cardiac output will be subnormal (point E).

Gravity

Gravitational forces may affect cardiac output profoundly. It is not unusual for some soldiers standing at attention to faint because cardiac output is reduced. Gravitational effects are exaggerated in airplane pilots during pullouts from dives. The centrifugal force in the footward direction may be several times greater than the force of gravity. Such individuals characteristically black out momentarily during the maneuver, as blood is drained from the cephalic regions and pooled in the lower parts of the body.

The explanation for the reduction in cardiac output under such conditions is often specious. It is frequently argued that when an individual is standing, the forces of gravity impede venous return from the dependent regions of the body. This statement is incomplete, however, because it ignores the facilitative counterforce on the arterial side of the same circuit.

In this sense the vascular system resembles a U tube. To comprehend the action of gravity on flow through such a system, the models depicted in Figures 10-23 and 10-24 are analyzed. In Figure 10-23, for example, all the U tubes represent rigid cylinders of constant diameter. With both limbs of the U tube oriented horizontally (Figure 10-23A), the flow depends only on the pressures at the inflow and outflow ends of the tube (P_i and P_o, respectively), the viscosity of the fluid, and the length and radius of the tube, in accordance with Poiseuille’s equation (see Chapter 6). With a constant cross section, the pressure gradient is uniform; hence, the pressure midway down the tube (P_m) equals the average of the inflow and outflow pressures.

FIGURE 10-23 Pressure distributions in rigid U tubes with constant internal diameters, all with the same dimensions. For a given inflow pressure (P_i = 100) and outflow pressure (P_o = 0), the pressure at the midpoint (P_m) depends on the orientation of the U tube, but the flow through the tube is independent of the orientation.

FIGURE 10-24 In U tubes with distensible sections at the bends, even when inflow (P_i) and outflow (P_o) pressures are the same, the resistance to flow, and the fluid volume contained within each tube, varies with the orientation of the tube. P_m, pressure at the midpoint of the tube.

When the U tube is oriented vertically (Figure 10-23B to D), hydrostatic forces must be taken into consideration. In tube B, both limbs are open to atmospheric pressure, and both ends are located at the same hydrostatic level; hence, there is no flow. The pressure at the midpoint of the tube is simply ρhg. The pressure depends on the density of the fluid, r; the height of the U tube, h; and the acceleration of gravity, g. In the example in Figure 10-23, the length of the U tube is such that the midpoint pressure is 80 mm Hg.

Now consider tube C, which is oriented the same as is tube B but in which a 100–mm Hg pressure difference is applied across the two ends. The flow precisely equals that in tube A, because the pressure gradient, tube dimensions, and fluid viscosity are all the same. Gravitational forces are precisely equal in magnitude, but opposite in direction, in the two limbs of the U tube. Because the flow is the same as that in A, there is a pressure drop of 50 mm Hg at the midpoint as a result of the viscous losses that result from flow. Furthermore, gravity tends to increase pressure by 80 mm Hg at the midpoint, just as in tube B. The actual pressure at the midpoint of tube C is the result of the viscous loss and hydrostatic gain, or 130 mm Hg in this example.

In tube D, a pressure gradient of 100 mm Hg is applied to the same U tube, but the tube is oriented in the opposite direction. Gravitational forces are so directed that the pressure at the midpoint tends to be 80 mm Hg less than that at the end of the U tube. Viscous losses still produce a 50–mm Hg pressure drop at the midpoint, relative to P_i. With this orientation, pressure at the midpoint of the U tube is 30 mm Hg below ambient pressure. Flow is the same as in tubes A and C, for the reasons stated in relation to C.

In a system of rigid U tubes, gravitational effects do not alter the rate of fluid flow. However, experience shows that gravity does affect the cardiovascular system. The reason is that the vessels are distensible rather than rigid. To explain the gravitational effects, the pressures in a set of U tubes with distensible components (at the bends in the tubes of Figure 10-24) are examined. In tubes A and B in Figure 10-24, the pressure distributions resemble those in tubes A and C, respectively, in Figure 10-23. In Figure 10-24, because the pressure is higher at the bend of tube B than at the bend of tube A, and because the segments are distensible in this region, the distention at the bend in tube B exceeds that at the bend in tube A. The extent of the distention depends on the compliance of these tube segments. Because flow varies directly with the tube diameter, the flow through tube B exceeds the flow through tube A for a given pressure difference applied at the ends.

Orienting a U tube with its bend downward actually increases, rather than diminishes, the flow. How then is the observed impairment of cardiovascular function explained when the body is similarly oriented? The explanation is that the cardiovascular system is a closed circuit of constant fluid (blood) volume, whereas the U tube is an open conduit that is supplied by a fluid source of unlimited volume. In the dependent regions of the cardiovascular system, the distention occurs more on the venous than on the arterial side of the circuit, because the venous compliance is so much greater than the arterial compliance. Such venous distention is readily observed on the back of the hands when the arms are allowed to hang down. The hemodynamic effects of such venous distention (venous pooling) resemble those caused by the hemorrhage of an equivalent volume of blood from the body. When an adult person shifts from a supine position to a relaxed standing position, 300 to 800 mL of blood is pooled in the legs. This change may reduce cardiac output by about 2 L/min.

The compensatory adjustments to the erect position are similar to the adjustments to blood loss. For example, the diminished baroreceptor excitation reflexly speeds the heart, strengthens the cardiac contraction, and constricts the arterioles and veins. The baroreceptor reflex has a greater effect on the resistance vessels than on the capacitance vessels. Warm, ambient temperatures interfere with the compensatory vasomotor reactions, and the absence of muscular activity exaggerates the effects.

When the U tube is rotated so that the bend is directed upward (Figure 10-24, tube C), the effects are opposite to those that take place in tube B. The pressure at the bend of tube C would tend to be −30 mm Hg, just as in tube D in Figure 10-23. However, the distensible segment of tube C collapses because the ambient pressure exceeds the internal pressure. Flow then ceases, and therefore the pressure decrease associated with viscous flow does not occur. In U tube C, when flow stops, the pressure at the top of each limb is 80 mm Hg less than at the bottom (the hydrostatic pressure difference). Hence, in the left (or inflow) limb, the pressure begins to rise rapidly from a negative value. If the tube remained collapsed at the bend, the pressure to the left of the collapsed segment would rapidly approach 20 mm Hg. However, as soon as this pressure exceeds the ambient pressure (0 mm Hg), the collapsed tubing is forced open, and flow begins. With the onset of flow, however, pressure at the bend again drops below the ambient pressure. Thus, the tubing at the bend flutters; that is, it fluctuates between the open and closed states.

When an arm is raised, the cutaneous veins in the hand and forearm collapse, for the reasons described previously. Fluttering does not occur, because the deeper veins are protected from collapse by being tethered to surrounding structures. This protection allows these deeper veins to accommodate the flow that is ordinarily carried by the collapsed superficial veins. The analogy would be to add a rigid tube (which represents the deeper veins) in parallel with the collapsible tube (which represents the superficial veins) at the bend of tube C in Figure 10-24. The collapsible tube would no longer flutter but it would remain closed. All flow would occur through the rigid tube, just as in tube D in Figure 10-23.

Muscular Activity and Venous Valves

When a person who is recumbent stands but remains at rest, the pressure rises in the veins in the dependent regions of the body. The venous pressure in the legs increases gradually, and it does not reach an equilibrium value until almost 1 minute after standing. The slowness of this rise in P_v is attributable to the venous valves, which permit flow only toward the heart. When the person stands, the valves prevent blood in the veins from actually falling toward the feet. Hence the column of venous blood is supported at numerous levels by these valves; temporarily, the venous column consists of many discontinuous segments. However, blood continues to enter the column from many venules and small tributary veins, and the pressure continues to rise. As soon as the pressure in one segment exceeds that in the segment just above it, the intervening valve is forced to open. Ultimately, all the valves are open and the column is continuous. This state resembles that in the outflow limbs of the U tubes shown in Figures 10-23 and 10-24.

Precise measurement reveals that the final level of P_v in the feet during quiet standing is only slightly greater than that in a static column of blood extending from the right atrium to the feet. This finding indicates that the pressure drop caused by blood flow from the foot veins to the right atrium is very small. This very low resistance justifies regarding all the veins as a common venous compliance in the circulatory system model illustrated in Figure 10-8.

When an individual who has been standing quietly begins to walk, the venous pressure in the legs decreases appreciably (Figure 10-25). Blood is forced from the veins toward the heart because of the intermittent venous compression exerted by the contracting leg muscles and because of the presence of the venous valves (see Figure 12-2). Hence, muscular contraction lowers the mean venous pressure in the legs, and it serves as an auxiliary pump. Furthermore, it prevents venous pooling and lowers capillary hydrostatic pressure, thereby reducing the tendency for edema fluid to collect in the feet during standing.

FIGURE 10-25 Mean pressures (± 95% confidence intervals) in the foot veins of 18 people during quiet standing, walking, and running.

(From Stick C, Jaeger H, Witzleb E: Measurements of volume changes and venous pressure in the human lower leg during walking and running. J Appl Physiol 72:2063, 1992.)

Respiratory Activity

The normal, periodic activity of the respiratory muscles causes rhythmic variations in vena caval blood flow. Thus, respiration constitutes an auxiliary pump to promote venous return. Coughing, straining at stool, and other activities that require respiratory muscle exertion may affect cardiac output substantially.

The changes in blood flow in the superior vena cava during the normal respiratory cycle are shown in Figure 10-26. During normal respiration, the reduction in intrathoracic pressure is transmitted to the lumina of the intrathoracic blood vessels. Central venous pressure is reduced during inspiration, increasing the pressure gradient between extrathoracic and intrathoracic veins. The consequent acceleration of venous return to the right atrium is displayed in Figure 10-26 as an increase in superior vena caval blood flow, from 5.2 mL/second (s) during expiration to 11 mL/s during inspiration.

FIGURE 10-26 During a normal inspiration, intrathoracic (ITP), right atrial (RAP), and jugular venous (JVP) pressures decrease, and flow in the superior vena cava (SVCF) increases (from 5.2 to 11 mL/second [s]). All pressures are in millimeters of water, except for femoral arterial pressure (FAP), which is in millimeters of mercury.

(Modified from Brecher GA: Venous return, New York, 1956, Grune & Stratton.)

An exaggerated reduction in intrathoracic pressure achieved by a strong inspiratory effort against a closed glottis (called Müller maneuver) does not increase venous return proportionately. The extrathoracic veins collapse near their entry into the chest when their internal pressures fall below the ambient level. As the veins collapse, flow into the chest momentarily stops. The cessation of flow raises pressure upstream, thereby forcing the collapsed segment to open again. The process is repetitive; the venous segments adjacent to the chest alternately open and close.

During normal expiration, flow into the central veins decelerates. However, the mean rate of venous return during normal respiration exceeds the flow during a brief period of apnea (cessation of respiration). Hence normal inspiration apparently facilitates venous return more than normal expiration impedes it. This effect must be partly attributable to the valves in the veins of the extremities and neck. These valves prevent any reversal of flow during expiration. Thus, the respiratory muscles and venous valves constitute an auxiliary pump for venous return.

Sustained expiratory efforts increase intrathoracic pressure and thereby impede venous return. Straining against a closed glottis (termed Valsalva maneuver) regularly occurs during coughing, defecation, and heavy lifting. Intrathoracic pressures in excess of 100 mm Hg have been recorded in trumpet players, and pressures over 400 mm Hg have been observed during paroxysms of coughing. Such pressure increases are transmitted directly to the lumina of the intrathoracic arteries. After coughing ceases, the arterial blood pressure may fall precipitously because of the preceding impediment to venous return.

Artificial Respiration

In most forms of artificial respiration (mouth-to-mouth resuscitation, mechanical respiration), lung inflation is achieved by applying endotracheal pressures above atmospheric pressure, and expiration occurs by passive recoil of the thoracic cage. Thus, lung inflation is accompanied by an appreciable rise in intrathoracic pressure. Vena caval flow decreases sharply during the phase of positive-pressure lung inflation (indicated by the progressive rise in endotracheal pressure in the central portion of Figure 10-27). When negative endotracheal pressure (indicated by the abrupt decrease in endotracheal pressure in the right side of Figure 10-27) is used to facilitate deflation, vena caval flow accelerates more than when the lungs are allowed to deflate passively (near the left border of Figure 10-27).

FIGURE 10-27 During intermittent positive-pressure respiration, the flow in the superior vena cava is approximately 30% greater when the lungs are deflated actively by application of negative endotracheal pressure (right side) than when they are allowed to deflate passively against atmospheric pressure (left side).

(Modified from Brecher GA: Venous return, New York, 1956, Grune & Stratton.)