Ejection fraction is normally more than 55%. It is dependent on heart rate, preload, afterload, and contractility (all to be discussed below) and provides a nonspecific index of ventricular function. Still, it has proved to be valuable in predicting the severity of heart disease in individual patients.
A. Force of contraction
1. End-diastolic fiber length (Starling's law, preload)
a. End-diastolic pressure b. Ventricular diastolic compliance
2. Contractility a. Sympathetic stimulation via norepinephrine acting on p1 receptors b. Circulating epinephrine acting on p1 receptors (minor)
c. Intrinsic changes in contractility in response to changes in heart rate and afterload d. Drugs (positive inotropic drugs, e.g., digitalis, negative inotropic drugs, e.g., general anesthetics, toxins)
e. Disease (coronary artery disease, myocarditis, cardiomy-opathy, etc.)
1. Ventricular radius
2. Ventricular systolic pressure
Heart rate (and pattern of electrical excitation)
Stroke volume increases with increases in the force of contraction of ventricular muscle and decreases with increases in the afterload. The force of contraction is affected by end-diastolic fiber length, contractility, and hypertrophy. Afterload, the force against which the ventricle must contract to eject blood, is affected by the ventricular radius and ventricular systolic pressure. Because the pressure drop across the aortic valve is normally small, aortic pressure is often used as a substitute for ventricular pressure in such considerations.
Effect of End-Diastolic Fiber Length. The relationship between ventricular end-diastolic fiber length and stroke volume is known as Starling's law of the heart. Within limits, increases in the left ventricular end-diastolic fiber length augment the ventricular force of contraction, which increases the stroke volume. This reflects the relationship between the length of a muscle and the force of contraction (see Chapter 10). After reaching an optimal diastolic fiber length, stroke volume no longer increases with further stretching of the ventricle.
End-diastolic fiber length is determined by end-diastolic volume, which is dependent on end-diastolic pressure. End-diastolic pressure is the force that expands the ventricle to a particular volume. In Chapter 10, preload was defined as the passive force that establishes the muscle fiber length before contraction. For the intact heart, preload can be defined as end-diastolic pressure. For a given ventricular compliance (change in volume caused by a given change in pressure), a higher end-diastolic pressure (preload) increases both diastolic volume and fiber length. The end-di-astolic pressure depends on the degree of ventricular filling during ventricular diastole, which is influenced largely by atrial pressure.
In heart disease, ventricular compliance can decrease because of impaired ventricular muscle relaxation or a build up of connective tissue within the walls of the heart. In either case, the relationship between ventricular filling, end-diastolic pressure, and end-diastolic volume is altered. The effect is a decrease in end-diastolic fiber length and a resulting decrease in stroke volume.
The curve expressing the relationship between ventricular filling and ventricular contractile performance is called a Starling curve or a ventricular function curve (Fig. 14.2). This curve can be plotted with end-diastolic volume, end-diastolic pressure, or atrial pressure as the abscissa, as proxies for end-diastolic fiber length.
The ordinate on the plot of Starling's law (Fig. 14.2) can also be a variable other than stroke volume. For example, if heart rate remains constant, cardiac output can be substituted for stroke volume. The effect of arterial pressure on stroke volume can also be taken into account by plotting stroke work on the ordinate. Stroke work is stroke volume times mean arterial pressure. An increase in arterial pressure (after-load) decreases stroke volume by increasing the force that opposes the ejection of blood during systole. If stroke work is on the ordinate, any increase in the force of contraction that results in either increased arterial pressure or stroke volume shifts the stroke work curve upward and to the left. If stroke volume alone were the dependent variable, a change in the performance of the heart causing increased pressure would not be expressed by a change in the curve.
Starling's law explains the remarkable balancing of the output between the two ventricles. If the right heart were to pump 1% more blood than the left heart each minute without a compensatory mechanism, the entire blood volume of the body would be displaced into the pulmonary circulation in less than 2 hours. A similar error in the opposite direction would likewise displace all the blood volume into the systemic circuit. Fortunately, Starling's law prevents such an occurrence. If the right ventricle pumps slightly more blood than the left ventricle, left atrial filling (and pressure) will increase. As left atrial pressure increases,
A Starling (ventricular function) curve. Stroke "work increases with increased end-diastolic fiber length. Several other combinations of variables can be used to plot a Starling curve, depending on the assumptions made. For example, cardiac output can be substituted for stroke volume if heart rate is constant, and stroke volume can be substituted for stroke work if arterial pressure is constant. End-diastolic fiber length and volume are related by laws of geometry, and end-diastolic volume is related to end-diastolic pressure by ventricular compliance.
left ventricular pressure and left ventricular end-diastolic fiber length increase both the force of contraction and the stroke volume of the left ventricle. If the stroke volume rises too much, the left heart begins to pump more blood than the right heart and left atrial pressure drops,- this decreases left ventricular filling and reduces stroke volume. The process continues until left heart output is exactly equal to right heart output.
The descending limb of the ventricular function curve, analogous to the descending limb of the length-tension curve (see Chapter 10), is probably never reached in a living heart because the resistance to stretch increases as the end-diastolic volume reaches the limit for optimum stroke volume. Further enlargement of the ventricle would require end-diastolic pressures that do not occur. As a result of increased resistance to stretch or decreased compliance, the atrial pressures necessary to produce further filling of the ventricles are probably never reached. The limited compliance, therefore, prevents optimal sarcomere length from being exceeded. In heart failure, the ventricles can dilate beyond the normal limit because they exhibit increased compliance. Even under these conditions, optimal sarcom-ere length is not exceeded. Instead, the sarcomeres appear to realign so that there are more of them in series, allowing the ventricle to dilate without stretching sarcomeres beyond their optimal length.
Effect of Changes in Contractility. Factors other than end-diastolic fiber length can influence the force of ventricular contraction. Different conditions produce different relationships between stroke volume (or work) to end-diastolic fiber length. For example, increased sympathetic nerve activity causes release of norepinephrine (see Chapter 3). Norepi-nephrine increases the force of contraction for a given end-diastolic fiber length (Fig. 14.3). The increase in force of contraction causes more blood to be ejected against a given aortic pressure and, thus, raises stroke volume. A change in
End-diastolic fiber length End-diastolic ventricular pressure
Effect of norepinephrine and heart failure "on the ventricular function curve. Norepinephrine raises ventricular contractility (i.e., stroke volume and/or stroke work are elevated at a given end-diastolic fiber length). In heart failure, contractility is decreased, so that stroke volume and/or stroke work are decreased at a given end-diastolic fiber length. Digitalis raises the intracellular calcium ion concentration and restores the contractility of the failing ventricle.
the force of contraction at a constant end-diastolic fiber length reflects a change in the contractility of the heart. (The cellular mechanisms governing contractility are discussed in Chapter 10.) A shift in the ventricular function curve to the left indicates increased contractility (i.e., more force and/or shortening occurring at the same initial fiber length), and shifts to the right indicate decreased contractility. When an increase in contractility is accompanied by an increase in arterial pressure, the stroke volume may remain constant, and the increased contractility will not be evident by plotting the stroke volume against the end-diastolic fiber length. However, if stroke work is plotted, a leftward shift of the ventricular function curve is observed (see Fig. 14.3). A ventricular function curve with stroke volume on the ordinate can be used to indicate changes in contractility only when arterial pressure does not change.
During heart failure, the ventricular function curve is shifted to the right, causing a particular end-diastolic fiber length to be associated with less force of contraction and/or shortening and a smaller stroke volume. As described in Chapter 10, cardiac glycosides, such as digitalis, tend to normalize contractility,- that is, they shift the ventricular curve of the failing heart back to the left (see Fig. 14.3).
The collection of ventricular function curves reflecting changes in contractility in a particular heart is known as a family of ventricular function curves.
Effect of Hypertrophy. In the normal heart, the force of contraction is also increased by myocardial hypertrophy. Regular, intense exercise results in increased synthesis of contractile proteins and enlargement of cardiac myocytes. The latter is the result of increased numbers of parallel my-ofilaments, increasing the number of actomyosin cross-bridges that can be formed. As each cell enlarges, the ventricular wall thickens and is capable of greater force development. The ventricular lumen may also increase in size, and this is accompanied by an increase in stroke volume. The hearts of appropriately trained athletes are capable of producing much greater stroke volumes and cardiac outputs than those of sedentary individuals. These changes are reversed if the athlete stops training. Myocardial hypertrophy also occurs in heart disease. In heart disease, although myocardial hypertrophy initially has positive effects, it ultimately has negative effects on myocardial force development. A thorough discussion of pathological hypertrophy is beyond the scope of this book.
Effect of Afterload. The second determinant of stroke volume is afterload (see Table 14.1), the force against which the ventricular muscle fibers must shorten. In normal circumstances, afterload can be equated to the aortic pressure during systole. If arterial pressure is suddenly increased, a ventricular contraction (at a given level of contractility and end-diastolic fiber length) produces a lower stroke volume. This decrease can be predicted from the force-velocity relationship of cardiac muscle (see Chapter 10). The shortening velocity of ventricular muscle decreases with increasing load, which means that for a given duration of contraction (reflecting the duration of the action potential), the lower velocity results in less shortening and a decrease in stroke volume (Fig. 14.4).
Effect of aortic pressure on ventricular function. Ventricular pressure, ventricular volume, and the force-velocity relationship are shown for (A) normal and (B) elevated aortic pressure. Increased afterload slows the velocity of shortening, decreasing ventricular emptying, and stroke volume.
Fortunately, the heart can compensate for the decrease in left ventricular stroke volume produced by increased afterload. Although a sudden rise in systemic arterial pressure causes the left ventricle to eject less blood per beat, the output from the right heart remains constant. Left ventricular filling subsequently exceeds its output. As the end-diastolic volume and fiber length of the left ventricle increase, the ventricular force of contraction is enhanced. A new steady state is quickly reached in which the end-diastolic fiber length is increased and the previous stroke volume is maintained. Within limits, an additional compensation also occurs. During the next 30 seconds, the end-diastolic fiber length returns toward the control level, and the stroke volume is maintained despite the increase in aortic pressure. If arterial pressure times stroke volume (stroke work) is plotted against end-diastolic fiber length, it is apparent that stroke work has increased for a given end-diastolic fiber length. This leftward shift of the ventricular function curve indicates an increase in contractility.
Effect of the Ventricular Radius. The ventricular radius influences stroke volume because of the relationship between ventricular pressures (Pv) and ventricular wall tension (T). For a hollow structure, such as a ventricle, Laplace's law states that
where r and r2 are the radii of curvature for the ventricular wall. Figure 14.5 shows this relationship for a simpler structure, in which curvature occurs in only one dimension (i.e., a cylinder). In this case, r2 approaches infinity. Therefore:
The internal pressure expands the cylinder until it is exactly balanced by the wall tension. The larger the radius, the larger the tension needed to balance a particular pressure. For example, in a long balloon that has an inflated part with a large radius and an uninflated parted with a much smaller radius, the pressure inside the balloon is the same everywhere, yet the tension in the wall is much higher in the inflated part because the radius is much greater (Fig. 14.6). This general principle also applies to noncylin-drical objects, such as the heart and tapering blood vessels.
When the ventricular chamber enlarges, the wall tension required to balance a given intraventricular pressure increases. As a result, the force resisting ventricular wall shortening (afterload) likewise increases with ventricular size. Despite the effect of increased radius on afterload, an increase in ventricular size (within physiological limits) raises both wall tension and stroke volume. This occurs because the positive effects of adjustment in sarcomere length overcompensate for the negative effects of increasing ventricular radius. However, if a ventricle becomes pathologically dilated, the myocardial fibers may be unable to generate enough tension to raise pressure to the normal systolic level, and the stroke volume may fall.
Effect of Diastolic Compliance. Several diseases—including hypertension, myocardial ischemia, and cardiomyopa-thy—cause the left ventricle to be less compliant during diastole. In the presence of decreased diastolic compliance, a normal end-diastolic pressure stretches the ventricle less. Reduced stretch of the ventricle results in lowered stroke vol-
Pressure and tension in a cylindrical blood vessel. The tension tends to open an imaginary slit along the length of the blood vessel. The Laplace law relates pressure (P), radius, and tension (T), as described in the text.
Tension = Pressure x radius
Effect of the radius of a cylinder on tension. The pressure inside an inflated balloon is the same everywhere. With the same inside pressure, the tension in the wall is proportional to the radius. The tension is lower in the portion of the balloon with the smaller radius.
ume. In this situation, compensatory events increase central blood volume and end-diastolic pressure (see Chapter 18). A higher end-diastolic pressure stretches the stiffer ventricle and helps restore the stroke volume to normal. The physiological price for this compensation is higher left atrial and pulmonary pressures. Several pathological consequences, including pulmonary congestion and edema, can result.
Pressure-Volume Loops Provide Information Regarding Ventricular Performance
Figure 14.7A shows a plot of left ventricular pressure as a function of left ventricular volume. One cardiac cycle is represented by one counterclockwise circuit of the loop. At point 1, the mitral valve opens and the volume of the ventricle begins to increase. As it does, diastolic ventricular pressure rises a little, depending on given ventricular dias-tolic compliance. (Remember that compliance is AV/AP.) The less the pressure rises with the filling of the ventricle, the greater the compliance. The volume increase between point 1 and point 2 occurs during rapid and reduced ventricular filling and atrial systole (see Fig. 14.1). At point 2, the ventricle begins to contract and pressure rises rapidly. Because the mitral valve closes at this point and the aortic valve has not yet opened, the volume of the ventricle cannot change (isovolumetric contraction). At point 3, the aortic valve opens. As blood is ejected from the ventricle, ventricular volume falls. At first, ventricular pressure continues to rise because the ventricle continues to contract and build up pressure—this is the period of rapid ejection in Figure 14.1. Later, pressure begins to fall—this is the period of reduced ejection in Figure 14.1. The reduction in ventricular volume between points 3 and 4 is the difference between end-diastolic volume (3) and end-systolic volume (4) and equals stroke volume.
At point 4, ventricular pressure drops enough below aortic pressure to cause the aortic valve to close. The ventricle continues to relax after closure of the aortic valve, and this is reflected by the drop in ventricular pressure. Because the mitral valve has not yet opened, ventricular volume cannot change (isovolumetric relaxation). The loop returns to point 1 when the mitral valve opens and, once more, the ventricle begins to fill.
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