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Unformatted text preview: Cardiac Function Cardiac Function - Introduction The primary function of the heart is to impart energy to blood in order to generate and sustain an arterial blood pressure necessary to provide adequate perfusion of organs. The heart achieves this by contracting its muscular walls around a closed chamber to generate sufficient pressure to propel blood from the cardiac chamber (e.g., left ventricle), through the aortic valve and into the aorta. Each time the heart beats, a volume of blood is ejected. This stroke volume (SV), times the number of beats per minute (heart rate, HR), equals the cardiac output (CO). CO = SV HR Stroke volume is expressed in ml/beat and heart rate in beats/minute. Therefore, cardiac output is in ml/minute. Cardiac output may also be expressed in liters/minute. Regulation of Stroke Volume Ventricular stroke volume (SV) is the difference between the ventricular end-diastolic volume (EDV) and the end-systolic volume (ESV). The EDV is the filled volume of the ventricle prior to contraction and the ESV is the residual volume of blood remaining in the ventricle after ejection. In a typical heart, the EDV is about 120 ml of blood and the ESV about 50 ml of blood. The difference in these two volumes, 70 ml, represents the SV. Therefore, any factor that alters either the EDV or the ESV will change SV. SV = EDV - ESV For example, an increase in EDV increases SV, whereas an increase in ESV decreases SV. There are three primary mechanisms that regulate EDV and ESV, and therefore SV. Preload Changes in preload affect the SV through the Frank-Starling mechanism. Briefly, an increase in venous return to the heart increases the filled volume (EDV) of the ventricle, which stretches the muscle fibers thereby increasing their preload. This leads to an increase in the force of ventricular contraction and enables the heart to eject the additional blood that was returned to it. Therefore, an increase in EDV results in an increase in SV. Conversely, a decrease in venous return and EDV leads to a decrease in SV by this mechanism. 1 Cardiac Function Afterload Afterload is related to the pressure that the ventricle must generate in order to eject blood into the aorta. Changes in afterload affect the ability of the ventricle to eject blood and thereby alter ESV and SV. For example, an increase in afterload (e.g., increased aortic pressure) decreases SV, and causes ESV to increase. Conversely, a decrease in afterload augments SV and decreases ESV. It is important to note, however, that the SV in a normal, non-diseased ventricle is not strongly influenced by afterload. In contrast, the SV of hearts that are failing are very sensitive to changes in afterload. Inotropy Changes in ventricular inotropy (contractility) alter the rate of ventricular pressure development, thereby affecting ESV and SV. For example, an increase in inotropy (e.g., produced by sympathetic activation of the heart) increases SV and decreases ESV. Conversely, a decrease in inotropy (e.g., heart failure) reduces SV and increases ESV. It is important to note that the effects of changes in EDV and ESV on SV are not independent. For example, an increase in ESV usually results in a compensatory increase in EDV. Furthermore, if SV is increased by increasing EDV, this can lead to a small increase in ESV because of the influence of increased afterload on ESV caused by an increase in aortic pressure. Therefore, while the primary effect of a change in preload, afterload or inotropy may be on either EDV or ESV, secondary changes can occur that can partially compensate for the initial change in SV. For a more detailed description of these interactions, see the web pages describing preload, afterload, or inotropy. 2 Cardiac Function Frank-Starling Mechanism As described elsewhere, cardiac output increases or decreases in response to changes in heart rate or stroke volume. When a person stands up, for example, cardiac output falls because of a fall in central venous pressure, which leads to a decrease in stroke volume. As another example, limb movement (muscle pump) during exercise enhances venous return to the heart, which causes an increase in stroke volume. What is the mechanism by which changes in venous return alters stroke volume? In the late19th century, Otto Frank found using isolated frog hearts that the strength of ventricular contraction was increased when the ventricle was stretched prior to contraction. This observation was extended by the elegant studies of Ernest Starling and colleagues in the 3 Cardiac Function early 20th century who found that increasing venous return, and therefore the filling pressure of the ventricle, led to increased stroke volume in dogs. These cardiac responses, which occur in isolated hearts as well as in intact animals and humans, are independent of neural and humoral influences on the heart. In honor of these two early pioneers, the ability of the heart to change its force of contraction and therefore stroke volume in response to changes in venous return is called the Frank-Starling mechanism (or Starling's Law of the heart). Increased venous return increases the ventricular filling (end-diastolic volume) and therefore preload, which is the initial stretching of the cardiac myocytes prior to contraction. Myocyte stretching increases the sarcomere length, which causes an increase in force generation. This mechanism enables the heart to eject the additional venous return, thereby increasing stroke volume. This phenomenon is described in mechanical terms by the length-tension and forcevelocity relationships for cardiac muscle. Increasing preload increases the active tension developed by the muscle fiber and increases the velocity of fiber shortening at a given afterload and inotropic state. One mechanism to explain how preload influences contractile force is that increasing the sarcomere length increases troponin C calcium sensitivity, which increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber (see Excitation-Contraction Coupling). The effect of increased sarcomere length on the contractile proteins is termed length-dependent activation. It has traditionally been taught that the Frank-Starling mechanism is due to changes in the number of overlapping actin and myosin units within the sarcomere as in skeletal muscle. According to this view, changes in the force of contraction do not result from a change in inotropy. Because we now know that changes in preload are associated with altered calcium handling and troponin C affinity for calcium, a sharp distinction cannot be made mechanistically between length-dependent (Frank-Starling mechanism) and length-independent changes (inotropic mechanisms) in contractile function. There is no single Frank-Starling curve on which the ventricle operates. There is actually a family of curves, each of which is defined by the afterload and inotropic state of the heart (Figure 2). For example, increasing afterload or decreasing inotropy shifts the curve down and to the right. Decreasing afterload and increasing inotropy shifts the curve up and to the left. To summarize, changes in venous return cause the ventricle to move along a single Frank-Starling curve that is defined by the existing conditions of afterload and inotropy. 4 Cardiac Function Frank-Starling curves show how changes in ventricular preload lead to changes in stroke volume. This graphical representation, however, does not show how changes in venous return affect end-diastolic and end-systolic volume. In order to do this, it is necessary to describe ventricular function in terms of pressure-volume diagrams. When venous return is increased, there is increased filling of the ventricle along its passive pressure curve leading to an increase in end-diastolic volume (Figure 3). If the ventricle now contracts at this increased preload, and the afterload is held constant, the ventricle will empty to the same end-systolic volume, thereby increasing its stroke volume. The increased stroke volume is manifested by an increase in the width of the pressure-volume loop. The normal ventricle, therefore, is capable of increasing its stroke volume to match physiological increases in venous return. This is not, however, the case for ventricles that are in failure. 5 Cardiac Function Length-Tension Relationship for Cardiac Muscle (Effects of Preload) When the mechanical properties of isolated cardiac muscle are studied in the laboratory, we find that if the muscle is stimulated to contract at low resting lengths (low preloads), the amount of active tension developed is relatively small. If the same experiment is repeated with the muscle at a longer preload length, the active tension that is developed is greatly increased. If this experiment is done at several different preload lengths, and the active tension is plotted as a function of preload, we find the relationship shown in Figure 1. This plot is called the length-tension diagram. In summary, increases in preload lead to an increase in active tension. Furthermore, not only is the magnitude of active tension increased, but also the rate of active tension development. The changes in active tension caused by changes in preload are related to changes in the number of actin and myosin cross bridges formed, which depends on the sarcomere length. Changes in preload also affect active tension by altering the sensitivity of troponin C to calcium. The length-tension diagram shows that as preload increases, there is an increase in active tension up to a maximal limit. The maximal active tension corresponds in cardiac muscle to a sarcomere length of 2.2 microns. Cardiac muscle, unlike skeletal muscle, does not display a descending limb on the active tension curved because the greater stiffness of cardiac muscle normally prevents its sarcomeres from being stretched beyond 2.2 microns. 6 Cardiac Function There is no single, unique active tension curve in the length-tension relationship. The active tension curve depends upon the inotropic state of the muscle. If, for example, inotropy is increased by applying norepinephrine, the total tension curve shifts up and to the left as shown in Figure 2. This results in an increase in active tension development at any given preload length. The opposite occurs when inotropic state is reduced. The above discussion describes how changes in preload (and inotropy) affect the force generated by cardiac muscle fibers during isometric contractions (i.e., with no change in length). Cardiac muscle fibers, however, also undergo shortening when they contract (i.e., isotonic contractions). Changes in preload also affect the degree of shortening and the velocity of fiber shortening. 7 Cardiac Function Preload Preload can be defined as the initial stretching of the cardiac myocytes prior to contraction. Preload, therefore, is related to the sarcomere length. Because sarcomere length cannot be determined in the intact heart, other indices of preload are used such as ventricular end-diastolic volume or pressure. For example, when venous return is increased, the end-diastolic pressure and volume of the ventricle are increased, which stretches the sarcomeres (increases their preload). As another example, hypovolemia resulting from a loss of blood due to hemorrhage leads to less ventricular filling and therefore shorter sacromere lengths (reduced preload). Changes in ventricular preload dramatically affect ventricular stroke volume by what is called the Frank-Starling mechanism. Increased preload increases stroke volume, whereas decreased preload decreases stroke volume by altering the force of contraction of the cardiac muscle. The concept of preload can be applied to either the ventricles or atria. Regardless of the chamber, the preload is related to the chamber volume just prior to contraction. Ventricular filling and therefore preload is increased by: 1. Increased central venous pressure that can result from decreased venous compliance (e.g., caused by sympathetic venoconstriction) or increased thoracic blood volume. The latter can be increased by either increased total blood volume or by venous return augmented by increased respiratory activity, increased skeletal muscle pump activity, or gravity (e.g., head-down tilt). 2. Increased ventricular compliance, which results in a greater expansion of the chamber during filling at a given filling pressure. 8 Cardiac Function 3. Increased atrial force of contraction resulting from sympathetic stimulation of the atria or from increased filling of the atria and therefore increased atrial contractile force through the Frank-Starling mechanism. 4. Reduced heart rate, which increases ventricular filling time. 5. Increased aortic pressure, which increases the afterload on the ventricle, reduces stroke volume by increasing end-systolic volume, and leads to a secondary increase in preload. 6. Pathological conditions such as ventricular systolic failure and valve defects such as aortic stenosis, aortic regurgitation (pulmonary valve stenosis and regurgitation have similar effects on right ventricular preload). Ventricular preload is decreased by: 1. Decreased venous blood pressure, most commonly resulting from reduced blood volume (e.g., hemorrhage) or gravity causing blood to pool in the lower limbs when standing upright. 2. Impaired atrial contraction that can result from atrial arrhythmias such as atrial fibrillation. 3. Increased heart rate (e.g., atrial tachycardia), which reduces ventricular filling time. 4. Decreased ventricular afterload, which enhances forward flow (i.e., ejection) thereby reducing end-systolic volume and end-diastolic volume secondarily. 5. Ventricular diastolic failure (decreased ventricular compliance) caused, for example, by ventricular hypertrophy or impaired relaxation (lusitropy). 6. Inflow (mitral and tricuspid) valve stenosis, which reduces ventricular filling. 9 Cardiac Function Afterload Afterload can be thought of as the "load" that the heart must eject blood against. In simple terms, the afterload is closely related to the aortic pressure. More precisely, afterload is related to ventricular wall stress (s ), where s (P r) / h (P, ventricular pressure; r, ventricular radius; h, wall thickness). This relationship is similar to the Law of LaPlace, which states that wall tension (T) is proportionate to the pressure (P) times radius (r) for thin-walled spheres or cylinders. Therefore, wall stress is wall tension divided by wall thickness. The exact equation depends on the geometry because of different constants for different shapes, and for this reason, the above relationship is expressed as a proportionality. The pressure that the ventricle generates during systolic ejection is very close to aortic pressure, unless aortic stenosis is present. At a given pressure, wall stress and therefore afterload are increased by an increase in ventricular inside radius (ventricular dilation). A hypertrophied ventricle (thickened wall) reduces wall stress and afterload. Hypertrophy can be thought of as a mechanism that permits more muscle fibers (actually, sarcomere units) to share in the wall tension that is determined at a give pressure and radius. The thicker the wall, the less tension experienced by each sarcomere unit. Afterload is increased when aortic pressure and systemic vascular resistance are increased, by aortic valve stenosis, and by ventricular dilation. When afterload increases, there is an increase in end-systolic volume and a decrease in stroke volume. As shown in Figure 1, an increase in afterload shifts the FrankStarling curve down and to the right (from A to B). The basis for this is found in the force-velocity relationship for cardiac myocytes. Briefly, an increase in afterload decreases the velocity of fiber shortening. Because the period of time available for ejection is finite (~200 10 Cardiac Function msec), a decrease in fiber shortening velocity reduces the rate of volume ejection so that more blood is left within the ventricle at the end of systole (increase end-systolic volume). A decrease in afterload shifts the Frank-Starling curve up and to the left (A to C). Afterload per se does not alter preload; however, preload changes secondarily to changes in afterload. As shown in Figure 1, increasing afterload not only reduces stroke volume, but it also increases left ventricular end-diastolic pressure (LVEDP) (i.e., increases preload). This occurs because the increase in end-systolic volume is added to the venous return into the ventricle and this increases end-diastolic volume. This increase in preload activates the Frank-Starling mechanism to partially compensate for the reduction in stroke volume caused by the increase in afterload. The interaction between afterload and preload is utilized in the treatment of heart failure, in which vasodilator drugs are used to augment stroke volume by decreasing afterload, and at the same time, reduce ventricular preload. This can be illustrated by seeing how ventricular volume changes in response to a decrease in arterial pressure (afterload) as shown in Figure 2. When arterial pressure is reduced, the ventricle can eject blood more rapidly, which increases the stroke volume and thereby decreases the end-systolic volume. Because less blood remains in the ventricle after systole, the ventricle will not fill to the same end-diastolic volume found before the afterload reduction. Therefore, in a sense, the end-diastolic volume (preload) is "pulled along" and reduced as endsystolic volume decreases. Stroke volume increases overall because the reduction in end-diastolic volume is less than the reduction in end-systolic volume. The effects of afterload on ventricular end-systolic and end-diastolic volumes can be illustrated using pressure-volume loops (Figure 2). If afterload is increased by increasing aortic diastolic pressure, the ventricle has to generate increased pressure before the aortic valve opens. The ejection velocity after the valve opens is reduced because increased afterload decreases the velocity of cardiac fibers shortening as described by the force-velocity relationship. Because there is only a finite time period for 11 Cardiac Function electrical and mechanical systole, less blood is ejected (decreased stroke volume), which increases the ventricular end-systolic volume as shown in the pressure-volume loop. Because end-systolic volume is increased, this extra blood within the ventricle is added to the venous return, which increases end-diastolic volume. Ordinarily, in the final steadystate (after several beats), the increase in end-systolic volume is greater than the increase in end-diastolic volume so that the difference between the two, the stroke volume, is decreased (i.e., the width of the pressure-volume loop is decreased). 12 Cardiac Function Inotropy (Contractility) Changes in stroke volume can be accomplished by changes in ventricular inotropy (contractility). Changes in inotropy are unique to cardiac muscle. Skeletal muscle, for example, cannot alter its intrinsic inotropic state. Changes in inotropy result in changes in force generation, which are independent of preload (i.e., sarcomere length). This is clearly demonstrated by use of length-tension diagrams in which an increase in inotropy results in an increase in active tension at a given preload. Furthermore, inotropy is displayed in the force-velocity relationship as a change in Vmax; that is, a change in the maximal velocity of fiber shortening at zero afterload. The increased velocity of fiber shortening that occurs with increased inotropy increases the rate of ventricular pressure development. During the phase of isovolumetric contraction, an increase in inotropy is manifested as an increase in maximal dP/dt (i.e., rate of pressure change). Changes in inotropy alter the rate of force and pressure development by the ventricle, and therefore change the rate of ejection (i.e., ejection velocity). For example, an increase in inotropy shifts the Frank-Starling curve up and to the left (point A to C in Figure 1). This causes a reduction in endsystolic volume and an increase in stroke volume as shown in the pressure-volume loops depicted in Figure 2. The increased stroke volume also causes a secondary reduction in ventricular end-diastolic volume and pressure because there is less end-systolic volume to be added to the incoming venous return. It should be noted that the active pressure curve that defines the limits of the end-systolic pressure-volume relationship (ESPVR) is shifted to the left and becomes steeper when inotropy is increased. The ESPVR is sometimes used as an index of ventricular inotropic state. It is analogous to the shift that occurs in the active tension curve in the length-tension relationship whenever there is a change in inotropy. 13 Cardiac Function Changes in inotropy produce significant changes in ejection fraction (EF, calculated as stroke volume divided by end-diastolic volume). Increasing inotropy leads to an increase in EF, while decreasing inotropy decreases EF. Therefore, EF is often used as a clinical index for evaluating the inotropic state of the heart. In heart failure, for example, there often is a decrease in inotropy that leads to a fall in stroke volume as well as an increase in preload, thereby decreasing EF. The increased preload, if it results in a left ventricular end-diastolic pressure greater than 20 mmHg, can lead to pulmonary congestion and edema. Treating a patient in heart failure with an inotropic drug (e.g., beta-adrenoceptor agonist or digoxin) will shift the depressed Frank-Starling curve up and to the left, thereby increasing stroke volume, decreasing preload, and increasing EF. Changes in inotropic state are particularly important during exercise. Increases in inotropic state help to maintain stroke volume at high heart rates. Increased heart rate alone decreases stroke volume because of reduced time for diastolic filling, which decreases end-diastolic volume. When the inotropic state increases at the same time, end-systolic volume decreases so that stroke volume can be maintained. Factors Regulating Inotropy The most important mechanism regulating inotropy is the autonomic nerves. Sympathetic nerves play a prominent role in ventricular and atrial inotropic regulation, while parasympathetic nerves (vagal efferents) have a significant negative inotropic 14 Cardiac Function effect in the atria but only a small effect in the ventricles. Under certain conditions, high levels of circulating epinephrine augment sympathetic adrenergic effects. In the human heart, an abrupt increase in afterload can cause a small increase in inotropy (Anrep effect) by a mechanism that is not fully understood. An increase in heart rate also stimulates inotropy (Bowditch effect; treppe; frequency-dependent inotropy). This latter phenomenon is probably due to an inability of the Na+/K+-ATPase to keep up with the sodium influx at higher heart rates, which leads to an accumulation of intracellular calcium via the sodium-calcium exchanger. Systolic failure that results from cardiomyopathy, ischemia, valve disease, arrhythmias, and other conditions is characterized by a loss of intrinsic inotropy. In addition to these physiological mechanisms, a variety of inotropic drugs are used clinically to stimulate the heart, particularly in acute and chronic heart failure. These drugs include digoxin (inhibits sarcolemmal Na+/K+-ATPase), beta-adrenoceptor agonists (e.g., dopamine, dobutamine, epinephrine, isoproterenol), and phosphodiesterase inhibitors (e.g., milrinone). Mechanisms of Inotropy Most of the signal transduction pathways that stimulate inotropy ultimately involve Ca++, either by increasing Ca++ influx (via Ca++ channels) during the action potential (primarily during phase 2), by increasing the release of Ca++ by the sacroplasmic reticulum, or by sensitizing troponin-C (TN-C) to Ca++. 15 Cardiac Function Ejection Fraction Ejection Fraction (EF) is the fraction of blood ejected by the ventricle relative to its enddiastolic volume. Therefore, EF is calculated from: EF = (SV / EDV) 100 where SV = stroke volume, EDV = end-diastolic volume Ejection fraction is most commonly measured using echocardiography. This noninvasive technique provides good estimates of end-diastolic (EDV) and end-systolic volumes (ESV), and stroke volume (SV = EDV-ESV). Normally, EF is >60%. For example, if the SV is 75 ml and the EDV is 120 ml, then the EF is 63%. During exercise in highly conditioned individuals, the increased stroke volume (caused primarily by increased inotropy), can result in the EF exceeding 90%. In heart failure, particularly in dilated cardiomyopathy, EF can become very small as SV decreases and EDV increases. In severe heart failure, EF may be 20% or less. EF is often used as a clinical index to evaluate the the inotropic status of the heart. However, it is important to note that there are circumstances in which EF can be normal, yet the ventricle is in failure. One example is diastolic dysfunction caused by hypertrophy in which filling is impaired because of low ventricular compliance and stroke volume is therefore reduced. In this case, both SV and EDV can be reduced such that EF does not change appreciably. For this reason, low ejection fractions are generally associated with systolic dysfunction rather than diastolic dysfunction. 16 Cardiac Function Compliance The term compliance is used to describe how easily a chamber of the heart or the lumen of a blood vessels expands expands when it is filled with a volume of blood. Physically, compliance (C) is defined as the change in volume (DV) divided by the change in pressure (DP). C = DV / DP For example, if a volume of blood is used to fill a cardiac chamber, the pressure within the chamber will increase, and it is the ratio of the change in volume to the change in pressure that represents the compliance of the chambers. The compliance of a biological tissue is not constant, meaning that at greater volumes there will be a disproportionate increase in pressure (i.e., compliance decreases as the chamber or blood vessel expands) as shown in the figure. Another way to view this is that the "stiffness" of the chamber or vessel wall increases at higher volumes and pressures. Compliance is a fundamental property of a tissue; however, the compliance can be modified histological changes in the tissue (e.g., as occurs in cardiac and vascular disease) or by external influences that alter the mechanical properties of the tissue. Examples of this would be activation of smooth muscle in a blood vessel wall that decreases the compliance, or impaired relaxation of the ventricular chamber as it fills with blood. 17 Cardiac Function Ventricular Compliance As the ventricle fills with blood, the pressure and volume that result from filling are determined by the compliance of the ventricle. Normally, compliance curves are plotted as the change in volume (DV) over the change in pressure (DP). For the ventricle, however, it is common to plot DP versus DV (see Figure). Therefore, the slope of the relationship is the reciprocal of the compliance, which is sometimes referred to as ventricular "stiffness." The compliance of the ventricular is determined by the physical properties of the cardiac muscle and other tissues making up the ventricular wall as well as by the state of ventricular contraction and relaxation. For example, in ventricular hypertrophy the ventricular compliance is decreased (i.e., the ventricle is "stiffer"), therefore, ventricular end-diastolic pressure (EDP) is higher at any given end-diastolic volume (EDV) (see Figure). Alternatively, at a given EDP, a less compliant ventricle would have a smaller EDV (i.e., filling will be impaired). If ventricular relaxation is impaired (as occurs in some forms of heart failure), the functional ventricular compliance is also reduced (because of residual active tension), which will also impair ventricular filling. In a disease state such as dilated cardiomyopathy, the ventricle becomes very dilated without appreciable thickening of the wall. This dilated ventricle will have increased compliance as shown in the figure; therefore, although the EDV may be very high, the EDP may not be greatly elevated. 18 Cardiac Function Venous Return - Hemodynamics Venous return (VR) is the flow of blood back to the heart. Under steady-state conditions, venous return must equal cardiac output (CO) when averaged over time because the cardiovascular system is essentially a closed loop (see figure at right). Otherwise, blood would accumulate in either the systemic or pulmonary circulations. Although cardiac output and venous return are interdependent, each can be independently regulated. The circulatory system is made up of two circulations (pulmonary and systemic) situated in series between the right ventricle (RV) and left ventricle (LV) as depicted in the figure to the right. Balance is achieved, in large part, by the Frank-Starling mechanism. For example, if systemic venous return is suddenly increased (e.g., changing from upright to supine position), right ventricular preload increases leading to an increase in stroke volume and pulmonary blood flow. The left ventricle experiences an increase in pulmonary venous return, which in turn increases left ventricular preload and stroke volume by the Frank-Starling mechanism. In this way, an increase in venous return can lead to a matched increase in cardiac output. Hemodynamically, venous return (VR) to the heart from the venous vascular beds is determined by a pressure gradient (venous pressure, PV, minus right atrial pressure, PRA) and venous resistance (RV) as shown to the right. Therefore, increases in venous pressure or decreases in right atrial pressure or venous resistance will lead to an increase in venous return, except when changes are brought about altered body posture (see below). Although the above 19 Cardiac Function relationship is true for the hemodynamic factors that determine the flow of blood from the veins back to the heart, it is important not to lose site of the fact that blood flow through the entire systemic circulation represents both the cardiac output and the venous return, which are equal in the steady-state because the circulatory system is closed. Therefore, one could just as well say that venous return is determined by the mean aortic pressure minus the mean right atrial pressure, divided by the resistance of the entire systemic circulation (i.e., the systemic vascular resistance). Venous return is influenced by several factors. 1. Muscle contraction. Rhythmical contraction of limb muscles as occurs during normal locomotory activity (walking, running, swimming) promotes venous return by the muscle pump mechanism. 2. Decreased venous compliance. Sympathetic activation of veins decreases venous compliance, increases central venous pressure and promotes venous return indirectly by augmenting cardiac output through the Frank-Starling mechanism, which increases the total blood flow through the circulatory system. 3. Respiratory activity. During respiratory inspiration, the venous return increases because of a decrease in right atrial pressure. 4. Vena cava compression. An increase in the resistance of the vena cava, as occurs when the thoracic vena cava becomes compressed during a Valsalva maneuver or during late pregnancy, decreases return. 5. Gravity. The effects of gravity on venous return seem paradoxical because when a person stands up hydrostatic forces cause the right atrial pressure to decrease and the venous pressure in the dependent limbs to increase. This increases the pressure gradient for venous return from the dependent limbs to the right atrium; however, venous return actually decreases. The reason for this is when a person initially stands, cardiac output and arterial pressure decrease (because right atrial pressure falls). The flow through the entire systemic circulation falls because arterial pressure falls more than right atrial pressure, therefore the pressure gradient driving flow throughout the entire circulatory system is decreased. 20 Cardiac Function Effects of Gravity on Venous Return Gravitational forces significantly affect venous return and therefore cardiac output, and arterial and venous pressures. To illustrate this, consider a person who is lying down and then suddenly stands up. As the person stands, gravity acts on the vascular volume so that blood accumulates in the lower extremities. (Compare the size of veins in the top of your feet while lying down and standing.) Because venous compliance is high and the veins readily expand with blood, most of the blood volume shift occurs in the veins. Therefore, venous volume and pressure becomes very high in the feet and lower limbs when standing. This shift in blood volume decreases thoracic venous blood volume and therefore central venous pressure decreases. This decreases right ventricular filling pressure (preload), leading to a decline in stroke volume by the Frank-Starling mechanism. Left ventricular stroke volume also falls because of reduced pulmonary venous return (decreased left ventricular preload). This causes cardiac output and arterial blood pressure to fall. If arterial pressure falls appreciably upon standing, this is termed orthostatic or postural hypotension. Normally, baroreceptor reflexes are activated to restore arterial pressure by causing peripheral vasoconstriction and cardiac stimulation. Without the operation of important compensatory mechanisms, standing upright would lead to significant edema in the feet and lower legs in addition to orthostatic hypotension. Venous pooling and reduced venous return are rapidly compensated in a normal individual by myogenic and neurogenic vasoconstriction of veins, the functioning of venous valves, by muscle pump activity, and by the abdominothoracic pump. When these mechanisms are operating, capillary and venous pressures in the feet will only be elevated by 10-20 mmHg, mean aortic pressure will be maintained, and central venous pressure will be only slightly reduced. Despite the operation of compensatory mechanisms, changes in posture still affect cardiovascular balance. Therefore, a person who is standing upright has increased systemic vascular resistance (sympathetic mediated), decreased venous compliance (due to sympathetic activation of veins), decreased stroke volume and cardiac output (due to decreased preload), and increased heart rate (baroreceptor-mediated tachycardia). These changes help to maintain normal mean aortic pressure when a person stands. 21 Cardiac Function Factors Promoting Venous Return Skeletal Muscle Pump A major mechanism promoting venous return during normal locomotory activity (e.g., walking, running) is the muscle pump system. Peripheral veins, particularly in the legs and arms, have one-way valves that direct flow away from the limb and toward the heart. Veins physically located within large muscle groups undergo compression as the muscles surrounding them contract, and they become decompressed as the muscles relax. Therefore, with normal cycles of contraction and relaxation, the veins are alternately compressed and decompressed (i.e., "pumped"). As illustrated in the animated figure, muscle contraction propels blood forward through the open distal valves (upper valves in figure) and impedes flow into the muscle as the proximal valves close during contraction (lower valves in figure). During muscle relaxation, the proximal valves open and blood flows into and fills the venous segment. Initially during relaxation, the distal valves close, but then they open as the volume of blood and pressure increases in the venous segment. The net effect is that the cycle of compression and relaxation propels the blood in the direction of the heart. Venous valves prevent the blood from flowing backwards, thereby permitting unidirectional flow that enhances venous return. When a person is standing, postural muscles in the legs alternately contract and relax to keep the body in balance. This muscle activity promotes venous return and helps to maintain central venous pressure and venous return, and to lower venous and capillary pressures in the feet and lower limbs. Respiratory Activity (Abdominothoracic or Respiratory Pump) Respiratory activity influences venous return to the heart. Briefly, increasing the rate and depth of respiration promotes venous return and therefore enhances cardiac output. Non-typical respiratory activity such as being on positive pressure ventilation or doing a force expiration against a closed glottis (Valsalva maneuver) impedes and therefore reduces venous return and cardiac output. 22 Cardiac Function Respiratory activity affects venous return through changes in right atrial pressure, which is an important component of the pressure gradient for venous return. Increasing right atrial pressure impedes venous return, while lowering this pressure facilitates venous return. Respiratory activity can also affect the diameter of the thoracic vena cava and cardiac chambers, which either directly (e.g., vena cava compression) or indirectly (by changing cardiac preload) affect venous return. Pressures in the right atrium and thoracic vena cava are very dependent on intrapleural pressure (Ppl ), which is the pressure within the thoracic space between the organs (lungs, heart, vena cava) and the chest wall. During inspiration, the chest wall expands and the diaphragm descends (see animated figure). This makes the Ppl become more negative, which leads to expansion of the lungs, cardiac chambers (right atrium [RA] and right ventricle [RV]), and the thoracic superior and inferior vena cava (SVC and IVC, respectively). This expansion causes the intravascular and intracardiac pressures (e.g., right atrial pressure) to fall. Because the pressure inside the cardiac chambers falls less than the Ppl, the transmural pressure (pressure inside the heart chamber minus the Ppl) increases, which leads to cardiac chamber expansion and an increase in cardiac preload and stroke volume through the Frank-Starling mechanism. Furthermore, as right atrial pressure falls during inspiration, the pressure gradient for venous return to the right ventricle increases. During expiration, the opposite occurs although the dynamics are such that the net effect of respiration is that increasing the rate and depth of ventilation facilitates venous return and ventricular stroke volume. 23 Cardiac Function Stroke Work and Cardiac Work In physics, work is the product of force times distance. Therefore, considering a solid object of a given mass, the work done to move the object is the force applied to the object times the distance that the objects moves. In the case of the work done to move a volume of fluid, work is defined as the product of the volume of fluid and the pressure required to move the fluid. Stroke work (SW) refers to the work done by the ventricle to eject a volume of blood (i.e., stroke volume) into the aorta. The force that is applied to the volume of blood is the intraventricular pressure. Therefore, ventricular stroke work can be estimated as the product of stroke volume and mean aortic pressure during ejection. The use of aortic pressure instead of intraventricular pressure assumes that kinetic energy is negligible, which is generally true at resting cardiac outputs. Sometimes this is simplified to stroke volume (SV) times mean aortic pressure (MAP), although this will further underestimate the stroke work. SW @ SV MAP Stroke work is best depicted by the use of ventricular pressurevolume diagrams, in which stroke work is the area within the pressure-volume loop. This area represents the external work done by the ventricle to eject blood into the aorta. Stroke work is sometimes used to assess ventricular function. If stroke work is plotted against ventricular preload, the resulting ventricular function curve will appear qualitatively similar to a Frank-Starling curve. Like the Frank-Starling relationship, there will be a family of curves depending upon the inotropic state of the ventricle. Cardiac work is the product of stroke work and heart rate, which is the equivalent of the triple produce of stroke volume, mean aortic pressure and heart rate. 24 Cardiac Function Measurement of Cardiac Output Several direct and indirect techniques for measurement of cardiac output are available. The thermodilution technique uses a special thermistor-tipped catheter (Swan-Ganz catheter) that is inserted from a peripheral vein into the pulmonary artery. A cold saline solution of known temperature and volume is injected into the right atrium from a proximal catheter port. The injectate mixes with the blood as it passes through the ventricle and into the pulmonary artery, thus cooling the blood. The blood temperature is measured by a thermistor at the catheter tip, which lies within the pulmonary artery, and a computer is used to acquire the thermodilution profile; that is, the computer quantifies the change in blood temperature as it flows over the thermistor surface. The cardiac output computer then calculates flow (cardiac output from the right ventricle) using the blood temperature information, and the temperature and volume of the injectate. The injection is normally repeated a few times and the cardiac output averaged. Because cardiac output changes with respiration, it is important inject the saline at a consistent time point during the respiratory cycle. In normal practice this is done at the end of expiration. Echocardiographic techniques and radionuclide imaging techniques can be used to estimate real-time changes in ventricular dimensions, thus computing stroke volume, which when multiplied by heart rate, gives cardiac output. An old technique based on the Fick Principle can be used to compute cardiac output (CO) indirectly from whole body oxygen consumption (VO2) and the mixed venous (O2ven) and arterial oxygen contents (O2art); however, this technique is seldom used. The CO is calculated as follows: CO = VO2/(O2art O2ven) To calculate CO, the oxygen contents of arterial and venous blood samples are measured, and at the same time, whole body oxygen consumption is measured by analyzing expired air. The blood contents of oxygen are expressed as ml O2/ml blood, and the VO2 is expressed in units of ml O2/min. If O2art and O2ven contents are 0.2 ml and 0.15 ml O2/ml blood, respectively, and VO2 is 250 ml O2/minute, then CO = 5000 ml/ min, or 5 L/min. Ventricular stroke volume would simply be the cardiac output divided by the heart rate. 25 Cardiac Function Ventricular Pressure-Volume Relationship Left ventricular pressure-volume (PV) loops are derived from pressure and volume information found in the cardiac cycle diagram (see left panel of figure below). To generate a PV loop for the left ventricle, the left ventricular pressure (LVP) is plotted against left ventricular (LV) volume at multiple time points during a complete cardiac cycle. When this is done, a PV loop is generated (right panel of figure and animated figure). To illustrate the pressure-volume relationship for a single cardiac cycle, the cycle can be divided into four basic phases: ventricular filling (phase a; diastole), isovolumetric contraction (phase b) , ejection (phase c) , and isovolumetric relaxation (phase d) . Point 1 on the PV loop is the pressure and volume at the end of ventricular filling (diastole), and therefore represents the end-diastolic pressure and end-diastolic volume (EDV) for the ventricle. As the ventricle begins to contract isovolumetrically (phase b), the LVP increases but the LV volume remains the same, therefore resulting in a vertical line (all valves are closed). Once LVP exceeds aortic diastolic pressure, the aortic valve opens (point 2) and ejection (phase c) begins. During this phase the LV volume decreases as LVP increases to a peak value (peak systolic pressure) and then decreases as the ventricle begins to relax. When the aortic valve closes (point 3), ejection ceases and the ventricle relaxes isovolumetrically - that is, the LVP falls but the LV volume remains unchanged, therefore the line is vertical (all valves are closed). The LV volume at this time is the end-systolic (i.e., residual) volume (ESV). When the LVP falls below left atrial pressure, the mitral valve opens (point 4) and the ventricle begins to fill. Initially, the LVP continues to fall as the ventricle fills because the ventricle is still relaxing. However, once the ventricle is fully relaxed, the LVP gradually increases as the LV volume 26 Cardiac Function increases. The width of the loop represents the difference between EDV and ESV, which is by definition the stroke volume (SV). The area within the loop is the ventricular stroke work. The filling phase moves along the end-diastolic pressure-volume relationship (EDPVR), or passive filling curve for the ventricle. The slope of the EDPVR is the reciprocal of ventricular compliance. The maximal pressure that can be developed by the ventricle at any given left ventricular volume is defined by the end-systolic pressure-volume relationship (ESPVR), which represents the inotropic state of the ventricle. The pressure-volume loop, therefore, cannot cross over the ESPVR, because that relationship defines the maximal pressure that can be generated under a given inotropic state. The end-diastolic and endsystolic pressure-volume relationships are analogous to the passive and total tension curves used to analyze muscle function. The PV loop changes when the preload, afterload and inotropic state of the heart change. 27 Cardiac Function Effects of Preload, Afterload and Inotropy on Ventricular Pressure-Volume Loops Ventricular pressure-volume (PV) loops an are excellent tool for visualizing changes in ventricular function in response to changes in preload, afterload and inotropy. These ventricular changes can be complex because preload, afterload and inotropy are interdependent variables, meaning that when one variable is changed, the other variables change. Therefore, it is first important to understand the independent effects of each of these variables on ventricular function when the other variables are held constant. The next step is then to see how changing a variable leads to changes in the other variables in a more intact system. Independent Effects of Preload To examine the independent effects of preload, assume that aortic diastolic pressure (afterload) and inotropy are held constant. If preload is increased by increasing the enddiastolic volume (this occurs with increased venous pressure), then as the ventricle contracts it will develop greater pressure and eject blood more rapidly because the Frank-Starling mechanism will be activated by the increased preload. The ventricle will eject blood to the same end-systolic volume. The net effect will be an increase in stroke volume, shown by an increase in the width of the PV loop. Ejection fraction (EF) will increase slightly. This ability to contract to the same end-systolic volume is a property of cardiac muscle that can be demonstrated using isolated cardiac muscle and studying isotonic (shortening) contractions under the condition of constant afterload. When muscle preload length is increased, the contracting muscle shortens to the same minimal length as found before the preload was increased. If preload is decreased (e.g., this occurs when central venous pressure decreases), opposite changes occur; namely, stroke volume is decreased, but the end-systolic volume is unchanged. The independent effects of preload on the left ventricular PV loop are shown below: 28 Cardiac Function Independent Effects of Afterload If afterload is increased by increasing aortic diastolic pressure, and if the preload (enddiastolic volume) and inotropy are held constant, this will result in less stroke volume and an increase in end-systolic volume. Stroke volume is reduced because the increased afterload reduces the velocity of muscle fiber shortening and the velocity by which the blood is ejected (see force-velocity relationship). The reduced stroke volume at the same end-diastolic volume reduces the ejection fraction. If afterload is reduced by decreasing aortic diastolic pressure), the opposite occurs - stroke volume and ejection fraction increase, and end-systolic volume decreases. These changes are illustrated below: 29 Cardiac Function Independent Effects of Inotropy Increasing inotropy increases the velocity of fiber shortening at any given preload and afterload (see force-velocity relationship). This enables the ventricle to increase the rate of pressure development and ejection velocity, which leads to an increase in stroke volume and ejection fraction, and a decrease in end-systolic volume. In PV loop diagrams, increased inotropy increases the slope and shifts the end-systolic pressurevolume relationship (ESPVR) to the left, which permits the ventricle to generate more pressure at a given LV volume. Decreasing inotropy has the opposite effects; namely, increased end-systolic volume and decreased stroke volume and ejection fraction. The effects of inotropy on PV loops are shown below: Interdependent Effects of Preload, Afterload and Inotropy In the intact heart, preload, afterload and inotropy are not held constant. To further complicate matters, changing any one of these variables usually changes the other two variables. Therefore, the above PV loops, although they illustrate the independent effects of these three variables, they do not represent what happens when the heart is in the body. However, if one understands the independent effects of these variables, then it is relatively easy combine the loops to illustrate what occurs when multiple variables change. 30 Cardiac Function Interdependent Effects of Preload, Afterload and Inotropy on Ventricular Pressure-Volume Loops In the intact organism, changes in preload, afterload and inotropy are interdependent, meaning that when one variable is changed, it usually alters the other two variables. The independent effects of preload, afterload and inotropy are described elsewhere (CLICK HERE). The following discussion illustrates the interdependent changes that can occur as preload, afterload and inotropy are altered. These interdependent effects are illustrated using left ventricular pressure-volume loops. Interactions between Preload and Afterload at Constant Inotropy An increase in preload (end-diastolic volume) leads to an increase in stroke volume because of the Frank-Starling mechanism. If afterload and inotropy do not change, then the end-systolic volume will not change. The heart simply ejects all of the extra blood that filled it. However, if the increased stroke volume leads to an increase in cardiac output and arterial pressure, then the afterload on the ventricle increases, which partially offsets the increased stroke volume by increasing the end-systolic volume. The reason for this is that the increased afterload reduces the velocity of fiber shortening and therefore the ejection velocity (see force-velocity relationship). Conversely, a decrease in preload reduces stroke volume, but this reduction is partially offset by the decreased afterload (reduced aortic pressure) so that the end-systolic volume decreases slightly. The effects of changes in preload when arterial pressure changes are shown below: Interdependent Effects of Changes in Afterload If afterload is increased (e.g., increasing aortic diastolic pressure by increasing systemic vascular resistance), the stroke volume is reduced and the end-systolic volume 31 Cardiac Function increased. The increased end-systolic volume, however, leads to a secondary increase in end-diastolic volume because more blood is left inside the ventricle following ejection and this extra blood is added to the venous return, thereby increasing ventricular filling. This secondary increase in preload, through the operation of the Frank-Starling mechanism, partially offsets the reduction in stroke volume caused by the initial increase in afterload. Consequently, in a normal heart, changes in aortic pressure have little effect on stroke volume. However, in heart failure patients in which the end-diastolic volume is already maximal, an increase in aortic pressure can significantly reduce stroke volume. If afterload (aortic pressure) is reduced, the opposite changes occur stroke volume increases due to the decrease in end-systolic volume, accompanied by a smaller reduction in end-diastolic volume. This is the basis for giving an arterial dilator to enhance cardiac output in heart failure patients. Stroke volume can be significantly enhanced in heart failure patients by reducing afterload. These effects of afterload on stroke volume and preload are shown below: Interdependent Effects of Changes in Inotropy Increased inotropy increases the slope and shifts the end-systolic pressure-volume relationship (ESPVR) to the left, which permits the ventricle to generate more pressure at a given LV volume. Increased inotropy also increases the rate of pressure development and ejection velocity, which increases stroke volume and ejection fraction, and decreases end-systolic volume. With less blood remaining in the ventricle after ejection, the ventricle fills to a smaller end-diastolic volume during diastole. A patient in acute heart failure due to a loss of inotropy may be given a positive inotropic drug to increase stroke volume and to reduce ventricular preload, both of with are beneficial (CLICK HERE for more information). Decreasing inotropy has the opposite effects; namely, it increases end-systolic volume and decreases stroke volume and ejection fraction, accompanied by a small secondary increase in end-diastolic volume. The effects of inotropy on PV loops are shown below: 32 Cardiac Function 33 Cardiac Function Cardiac and Systemic Vascular Function Curves Guyton and colleagues in the 1950s and 1960s conducted extensive animal experimentation studying the interrelationships between cardiac function and systemic vascular function. These elegant studies led to a model of these relationships that could be graphically represented by plotting both cardiac function and systemic vascular function curves on the same graph. This analysis is very helpful in understanding how changes in cardiac function affect venous pressures, and how changes in arterial and venous resistance, and blood volume affect venous pressure and cardiac output. To examine these interactions, the two component curves will first be described individually, then they will be combined to show how changes in one affects the other. Cardiac Function Curves Cardiac function curves (sometimes called cardiac output curves) are essentially Frank-Starling curves, but differ in that cardiac output instead of ventricular stroke volume is plotted against changes in venous pressure (usually right atrial pressure, PRA). If in a controlled experimental model right atrial pressure is varied (independent variable) and the cardiac output measured (dependent variable), one will find that as PRA is increased, the cardiac output (CO) increases. When the mean PRA is about 0 mmHg (note that PRA normally fluctuates with atrial contraction and respiration), the cardiac output in an adult human is about 5 L/min. Because of the steepness of the cardiac function curve, very small changes in PRA (just a few mmHg) can lead to large changes in CO. Similar to Frank-Starling curves, there is no single cardiac function curve. Instead, there is a family of curves that can shift upward when cardiac performance is enhanced or shift downward when cardiac performance is depressed. Performance is enhanced by increased inotropy, increased heart rate, and reduced afterload. Performance is depressed by decreased inotropy, decreased heart rate, and by increased afterload. 34 Cardiac Function Systemic Vascular Function Curves Systemic vascular function curves (sometimes called venous return curves) are generated by measuring PRA (dependent variable) as CO (independent variable) changes. Note that the independent and dependent variables are reversed for these curves compared to the cardiac function curves. Experimentally, if cardiac output is stopped, aortic pressure falls and PRA increases to a common value of about 8 mmHg (if the baroreceptor reflex is blocked). This pressure, which is recorded shortly after the heart is stopped, is called the mean circulatory filling pressure (Pmc). If the heart is restarted, then PRA decreases as the CO increases. As the PRA starts to fall below zero, the CO begins to level off because the vena cava collapses, thus limiting venous return to the heart. There is no single systemic vascular function curve, but instead there is a family of curves that are determined by the blood volume (Vol), venous compliance (CV; inverse of venous tone) and systemic vascular resistance (SVR; primarily arterial resistance). If, for example, blood volume is increased due to renal retention of sodium and water, or venous compliance is decreased due to sympathetic activation of the veins (Panel A), there is a parallel shift to the right in the vascular function curve, which leads to an increase in the Pmc when the heart is stopped. The opposite shift occurs with decreased blood volume or decreased venous compliance. If SVR is increased (Panel B) by administering an arterial vasoconstrictor drug, the slope of the systemic vascular function curve decreases, but there is little or no change in the Pmc. The opposite occurs with a decrease in SVR. If, for example, both arteries and veins are constricted during sympathetic activation, then the curve will shift to the right as shown in Panel C (increased Pmc due to decreased CV) and the slope will decrease due to the increase in SVR. 35 Cardiac Function Coupling of Cardiac and Vascular Function When the cardiac and vascular function curves are plotted together in the same graph, there is a unique intercept between the two curves (see point A in top panel of figure at right). This intercept represents the steady-state operating point that defines the cardiac output and right atrial pressure for these particular physiological conditions. In this example, the CO is 5 L/min at a PRA of 0 mmHg. If the heart were stimulated, the cardiac function curve would shift up and to the left; however, there would only be a very small increase in CO because decreasing the PRA below zero causes venous collapse, which impedes venous return and hence filling of the ventricle. If cardiac function is depressed (e.g., by decreasing inotropy) as shown in the bottom panel of the figure, the cardiac function curve shifts down and to the right, and the intercept will change from Point A to B. This shows that depressing the heart leads to an increase in PRA and venous pressures along with the decrease in 36 Cardiac Function CO. If this depressed cardiac function is also accompanied by an increase in blood volume, venous constriction (decreased venous compliance, CV) and arterial constriction (increased SVR), the systemic function curve will shift to the right and have a reduced slope. The new operating point (C) represents this condition. Notice that these systemic vascular function changes help to partially restore CO despite the depressed cardiac function curve, although at the expense of a further increase in PRA and venous pressures. 37 ...
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This note was uploaded on 04/18/2008 for the course BIOC 1010 taught by Professor Zhang during the Fall '07 term at New York Medical College.

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