NROSCI/BIOSC 1070 and MSNBIO 2070 September 18 & 20, 2017 Cardiovascular 3 & 4: Mechanical Actions of the Heart and Determinants of Cardiac Output

NROSCI/BIOSC 1070 and MSNBIO 2070 September 18 & 20, 2017 Cardiovascular 3 & 4: Mechanical Actions of the Heart and Determinants of Cardiac Output An essential component for the operation of the heart is the action of the valves. The valves insure that blood moves in only one direction. The opening and closing of the heart valves is controlled simply by the pressure gradients on the two sides of the valves. The two arteriovenous (AV) valves, the tricuspid and mitral valves, are comprised of flaps of connective tissue. On the ventricular side, the valves are attached to collagen cords called the cordae tendinae. The opposite ends of the cords are attached to the moundlike extensions of ventricular muscle called papillary muscles. The cordae tendinae prevent the flaps of the valve from getting stuck against the ventricular wall during ventricular filling and from being forced into the atria during ventricular systole. In contrast, the aortic and pulmonary semilunar valves have three cuplike leaflets that fill with blood, and which snap closed when backward pressure is placed on them. Special tethering such as the chordae tendinae are not required to insure that the semilunar valves close properly. The closing of the heart valves generates vibrations, which result in the heart sounds that physicians often monitor during examinations. The major heart sounds are commonly referred to as lub-dub. The softer lub is associated with closing of the tricuspid and mitral valves, and the dub comes from the closing of the semilunar valves. Careful assessment of the heart sounds can be done using a stethoscope; the procedure is referred to a auscultation. Through careful monitoring, two additional heart sounds are revealed. The third heart sound is associated with turbulent blood flow into the ventricle near the beginning of ventricular filling, and the fourth heart sound is produced by additional turbulent flow into the ventricle during atrial contraction. The heart sounds become abnormal if the valves are diseased. Two general types of abnormal heart sounds can be classified: a murmur and a gallop. Murmurs are heart sounds in addition to the four that are normally present, and gallops are augmented third or fourth heart sounds. Murmurs often occur when valves fail to close properly, producing regurgitation or movement of blood in the wrong direction. For example, if an AV valve does not close properly, blood will move from the ventricle into the atrium during systole. This turbulent movement of blood can be heard as an additional heart sound. Gallops often occur when the AV valves do not open properly or are narrowed (stenosed), resulting in excessive turbulence during movement of blood from the atria into the ventricles. Gallops can also occur when the ventricles are very stiff. 9/18/17 & 9/20/17 Page 1 Cardio 3-4

Clinical Notes: Echocardiography The beating heart can be imaged in real time using echocardiography. This technique employs ultrasound that is emitted from a piezoelectric crystal. The waves are reflected back to the crystal, and result in the production of electric impulses that are recorded. The characteristics of the reflected waves are dependent on the properties of the tissue that the waves pass through. A computer can interpret the electrical impulses generated by the vibrating pizoelectric crystal, and construct an image from these signals. There are three general placements for the echocardiograph transducer: Transthoracic echocardiogram (TTE), in which a transducer is moved over different locations on the chest or abdomen. Transesophageal echocardiogram (TEE), in which the transducer is passed down the esophagus to provide clearer pictures of the heart. Intracardiac echocardiogram, in which the transducer is inserted into the cardiac vessels. The following diagram shows two common planes imaged using transthoracic echocardiography: 9/18/17 & 9/20/17 Page 2 Cardio 3-4

Another way of describing the cardiac cycle is through a pressure-volume graph. Between points A and B in this graph, the ventricles are filling with blood. The AV valves open when the pressure in the atria exceeds that in the ventricles. After the AV valves open, ventricular pressure increases slightly as volume increases. At the end of this part of the cardiac cycle, the atria contract and the ventricles contain the maximal amount of blood that they will have during the cardiac cycle (end diastolic volume, shown at point B). Note that although end diastolic volume is typically about 135 ml, it can be more or less under certain conditions. For example, when heart rate is very high (and filling time is low), end diastolic volume often drops. When cardiac return increases, EDV also increases. In the next phase of the cardiac cycle, the ventricles begin to contract. Very rapidly, pressure in the ventricles exceeds that in the atria and the AV valves close. Subsequently, ventricular pressure increases but ventricular volume stays constant (hence, an isovolumetric contraction). When pressure in the ventricles is great enough, the semilunar valves open and blood is ejected into the aorta and pulmonary arteries (point C). Ventricular pressure continues to increase while ventricular volume drops. Eventually, the ventricles begin to relax, and the semilunar valves close. Note that ventricular volume is not zero at this time, but instead end-systolic volume is about 65 ml. This volume is variable, however, and can decrease if ventricular contractility increases. The ventricle then relaxes, but because the ventricular pressure exceeds atrial pressure the AV valves are closed. This is the isovolumetric relaxation phase of the cardiac cycle. When ventricular pressure drops below atrial pressure, the AV valves open and ventricular filling starts again. Note that if MAP increases, more pressure is needed in the left ventricle to open the aortic valve. Ejection fraction (EF) is defined as the fraction of end diastolic volume that is ejected out of the ventricle during each contraction. EF = SV/EDV If SV=70ml and EDV=135ml Then EF=70/135 or 0.52 9/18/17 & 9/20/17 Page 3 Cardio 3-4

Yet another means of depicting the cardiac cycle is shown above. This diagram includes both electrical and mechanical events that occur in the heart. Such a diagram is called the Wiggers diagram after the physiologist who first published it (Carl Wiggers). We have not discussed one pressure tracing in the Wigger s diagram: a recording of pressure in the left atrium. Three waves are evident: the a, c, and v waves. The a wave is caused by atrial contraction. The c wave is caused by ventricular contraction, and is due to 1) the small backflow of blood from the ventricle to the atrium when the mitral valve closes and 2) the bulging of the closed mitral valve backward into the atrium when ventricle pressure increases. The v wave is due to blood flowing from the veins into the atrium during ventricular contraction, which cannot leave because the mitral valve is shut. When the mitral valve opens, atrial pressure drops, demarking the peak of the v wave. It is important for you to understand the relationships between MAP, aortic valve opening, and end systolic volume. If total peripheral resistance increases, then the pressure in the left ventricle must increase more to open the aortic valve (since MAP is higher [MAP=CO*TPR], and the pressure in the left ventricle must exceed that in the aorta for the valve to open). In addition, the valve closes earlier when the ventricle begins to relax. As a consequence, stroke volume diminishes. 9/18/17 & 9/20/17 Page 4 Cardio 3-4

When stroke volume diminishes, there is more blood left in the ventricle at the end of systole (end systolic volume increases). This increased volume is added to the volume transferred from the left atrium to left ventricle after the mitral valve opens. As a consequence, end diastolic volume increases. Thus, the next ventricular contraction is stronger due to the Frank-Starling effect. In essence, if TPR is high, then the heart must work harder and use more ATP to maintain constant cardiac output. Cardiac output is the amount of blood pumped from the ventricles per unit time. As mentioned in the first lecture, cardiac output at rest is about 5 L/min. This value is derived through the following calculation. The resting heart beats at about 70 times/min, and each ventricular ejection is about 70 ml (EDV-ESV). Thus, 70 beats/min * 0.07 L/beat = 4.9 L/min. You should be familiar with the formula to compute cardiac output, and how cardiac output relates to mean arterial pressure. MAP = CO * TPR MAP=(SV*HR) * TPR SV= Stroke Volume HR=Heart Rate MAP=((EDV-ESV)*HR) * TPR Cardiac output can be changed tremendously during some conditions. For example, during exercise it can rise from 5 L/min to 35 L/min. Let us consider how this happens. Obviously, an increase in stroke volume or heart rate can increase cardiac output. During the last lecture, we noted that intrinsic heart rate is actually 90-100 beats/min, but is tonically suppressed to about 70 beats/minute by the parasympathetic nervous system. Thus, one way of increasing heart rate is by withdrawing parasympathetic drive on the heart. Heart rate can be increased further by the actions of the sympathetic nervous system. Recall that binding of NE or EPI to beta receptors on autorhythmic cells increases their firing rate, driving heart rate faster. Furthermore, the catecholamines enhance conduction through the AV node, bundle of His, and Purkinje fibers. However, there is an upward limit on heart rate. If the heart beats too rapidly, there is insufficient time for filling. This condition is called tachycardia. This begins to happen when heart rate exceeds ~170 beats/min. A limit on heart rate is imposed by the delay in conduction through the AV node as well as the long refractory period of myocardial cells. This limitation helps to insure that the heart will not beat too rapidly to effectively pump out blood. However, under certain pathological conditions tachycardia becomes so severe that circulatory collapse occurs. So, an increase in heart rate alone cannot explain the seven-fold increase in cardiac output that can occur during exercise. Stroke volume must also increase in order to amplify cardiac output. As noted in the last lecture, binding of catecholamines to beta-receptors on myocardial cells increases how powerfully they will contract. In other words, the sympathetic nervous system acts to enhance contractility. Obviously, increasing contractility tends to reduce end systolic volume, thereby increasing stroke volume. Any agent that increases cardiac contractility is called an inotropic agent. 9/18/17 & 9/20/17 Page 5 Cardio 3-4

Another way of enhancing stroke volume is to increase venous return (thereby increasing end diastolic volume). As noted previously, under physiological conditions the heart will pump out as much blood as it receives (the Frank-Starling Law of the Heart). This enhanced cardiac output during increased cardiac return is due to the fact that myocardial cells are stretched, which places their actin and myosin into a more efficient arrangement for contraction. In addition to mechanically affecting contraction strength by altering the relationship between the contractile proteins actin and myosin in cardiac muscle cells, stretch of a ventricle affects the sensitivity of the calcium-binding protein troponin for calcium. This heightened sensitivity increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber. These two adaptations result in a more intense ventricular contraction when the chamber s filling with blood increases. Thus, an increase in end diastolic volume insures that cardiac output will also increase. There are important limitations to consider in the relationships diagrammed above. When heart rate increases, there is a decrease in filling time for the ventricles, which tends to decrease stroke volume (Frank-Starling effect). However, this is offset by the Bowditch effect if increases in heart rate are only moderate. At heart rates > 140 bpm, filling time is so limited that cardiac output declines precipitously. There are also limits to ventricular filling. When the ventricle is full, pressure increases as more blood enters the ventricle. The pressure in the ventricle soon is equal to atrial pressure, such that there is no driving force for blood to enter the ventricle. 9/18/17 & 9/20/17 Page 6 Cardio 3-4

We previously noted for skeletal muscle that maximal tension is produced when the actin and myosin are in the optimal configuration for the myosin heads to interact with the actin active sites. If the skeletal muscle cell is crumpled too short or stretched too long, less tension is produced during contraction. A B C The length-tension relationship is even more pronounced in cardiac muscle than skeletal muscle. As noted in the graph to the right (brown line), small stretches of cardiac muscle cells results in a great increase in tension during contraction. An unfilled cardiac chamber is like example A above. Filling the chamber with blood stretches the myocytes so the arrangement of actin and myosin is like example B, which causes contractions to become stronger. In addition to mechanically affecting contraction strength by altering the relationship between the contractile proteins actin and myosin in cardiac muscle cells, stretch of a ventricle affects the sensitivity of the calcium-binding protein troponin for calcium. This heightened sensitivity increases the rate of cross-bridge attachment and detachment, and the amount of tension developed by the muscle fiber. As discussed in previous lectures, the parasympathetic nervous system has little affect on the contraction of ventricular cardiac muscle, although actions on atrial cardiac muscle have been demonstrated. The graph above also shows the changes in cardiac muscle tension during passive stretch (when the muscle is relaxed). Due to the presence of titin in cardiac muscle cells and collagen between the cells, as well as the interconnections between cells, tension is generated when cardiac muscle is stretched. This is important to remember when we discuss the stretch of a heart chamber and how that affects passive filling. Afterload is the mean tension produced by a chamber of the heart in order to eject blood. Another way of looking at afterload is the force that must be overcome to eject blood from the ventricle. A major factor contributing to afterload is aortic pressure: an increase in peripheral resistance increases afterload. As a consequence, the aortic valve closes earlier during the cardiac cycle, cardiac output is reduced, and end systolic volume increases. 9/18/17 & 9/20/17 Page 7 Cardio 3-4

However, other factors can also contribute to afterload. For example, aortic valve stenosis also increase afterload. Note that increasing afterload produces a secondary increase in preload. The increased end systolic volume is added to normal venous return. 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 following a heart attack, where the left ventricle in damaged. Vasodilator drugs are used to augment stroke volume by decreasing afterload, and at the same time, reduce ventricular preload. When arterial pressure is reduced, the ventricle can eject blood more rapidly, which increases the stroke volume and thereby decreases the end-systolic volume. Determinants of Cardiac Output Because less blood remains in the ventricle after systole, the ventricle will not fill to the same enddiastolic volume found before the afterload reduction. As a consequence, higher stroke volumes can be sustained by weaker ventricular contractions, diminishing the risk of congestive heart failure. Cardiac output is influenced both by factors intrinsic to the heart (heart rate and contractility) and factors extrinsic to the heart (preload and afterload). If afterload increases, then cardiac output drops unless heart rate and contractility also increase. If preload increases then cardiac output increases without any changes in heart rate and contractility. Hence, cardiac output is dependent on the interactions between the cardiac and vascular components. Guyton and his colleagues conducted seminal experiments in the 1950s and 1960s to understand the interactions between the heart and the vasculature, and how they influence cardiac output. These interactions can be described through two equations that are plotted as the vascular function curve (sometimes called the venous return curve) and cardiac function curve. These curves consider the systemic circulation: a single pump and set of pipes. The vascular function curve determines how systemic venous pressure (P v ), which is the same as right atrial pressure, varies with changes in flow (Q) through the vasculature (or cardiac output). In other words, the vascular function curve considers how pressure in the circulation is affected by the vasculature. In contrast, the cardiac function curve considers how changes in systemic venous pressure (P v ) affects cardiac output. 9/18/17 & 9/20/17 Page 8 Cardio 3-4

This analysis is undoubtedly artificial, since it discounts the effects of factors such as gravity and skeletal muscle pumping on the cardiovascular system. However, it does provide some important insights, as noted below. The analysis makes the following assumptions: Q (R) Q Cardiac Output = Venous Return Central Venous Pressure = Right Atrial Pressure P v P a Using the model to understand differences in arterial and venous pressures As discussed in the first lecture, R = ΔP/Q (Ohm s Law) Thus, R=(P a P v )/Q (ΔP must be the difference between arterial and venous pressures) Assume that R = 20 mm Hg/L/min and Q = CO = 5 L/min Then, 20 mm Hg/L/min = (P a P v )/5 L/min 100 mm Hg = P a P v P a = 100 mm Hg + P v (in other words, P a is 100 mm Hg greater than P v ). Systemic Filling Pressure (P sf ) Normal Heart Stopped Q=5 L/min Q=0 L/min Pv=2 mm Hg Pa=102 mm Hg Pv=7 mm Hg Pa=7 mm Hg Guyton conducted experiments where the heart was transiently stopped in experimental animals. Immediately afterwards, pressures in the veins and arteries became equal. This pressure is known as systemic filling pressure (P sf ), which can be thought as the effective pressure head in the systemic circulation pushing the blood back into the heart. In mammals, P sf is approximately 7 mm Hg, which is much closer to normal venous pressure than to normal arterial pressure. Why is this the case? The answer relates to the fact that venous compliance is about 19 times higher than arterial compliance. The effects of vascular compliance on Psf can be determined quantitatively, as shown below. 9/18/17 & 9/20/17 Page 9 Cardio 3-4

During the first lecture, we learned that: ΔP = ΔV/C or C = ΔV/ΔP In the model: C a = ΔV a /ΔP a C v = ΔV v /ΔP v We also know that: C v =19C a or C v /C a = 19 When the heart is stopped, blood volume moves between the arterial and venous compartments, and the amount of blood moved is equal in the two compartments (the volume removed from one is placed in the other): ΔV a = ΔV v Hence: C a ΔP a = C v ΔP v C a ΔP a = 19C a ΔP v ΔP a = 19ΔP v In other words, the change in arterial pressure is much larger (19 times) than the change in venous pressure. The resulting pressure must be much closer to the original venous pressure. For example, if the original P a =102 mm Hg and the original P v =2 mm Hg, then: ΔP a = 102-X ΔP v = X-2 (102-X) = 19(X-2) (102-X)=19X-38 140-X=19X 140=20X 7=X = P sf The Vascular Function or Venous Return Curve The vascular function curve is derived based on the notion that the volumes of blood moving between the arterial and venous compartments is equal: ΔV a = ΔV v. We have previously noted that: C = ΔV/ΔP so C a = ΔV a /ΔP a and C v = ΔV v /ΔP v Applying algebra: C a * ΔP a = ΔV a and C v * ΔP v = ΔV v C a * ΔP a = C v * ΔP v ΔP v /ΔP a = C a /C v We have also previously noted that: ΔP a = P a P sf and ΔP v = P v P sf And Ohm s law stipulates that: R = (P a P v )/Q 9/18/17 & 9/20/17 Page 10 Cardio 3-4

Using this information and applying algebra, the equations underlying the vascular function curve can be derived: " P v = P sf R*C %! a $ 'Q P a = P sf + R*C $ v # &Q # C a + C v & " C a + C v % This equation provides the relationship between: Cardiac Factors P v, venous pressure (same as right atrial pressure) Q, flow through the vascular system (same as venous return or cardiac output) and Vascular Factors R (peripheral resistance), C a, C v, and P sf. The graphical depiction of this equation is called the vascular function curve or venous return curve. This curve relates venous return (or cardiac output) to right atrial pressure. As right atrial (venous) pressure increases, venous return (or cardiac output) decreases and vice versa. When right atrial pressure equals P sf, venous return (or cardiac output) is zero, since there is no pressure difference to drive blood flow. Note that there is little additional venous return between a right atrial pressure of 0 mmhg and -8 mmhg (or any negative right atrial pressure). This is because the negative right atrial pressure tends to suck together the walls of the large veins near the heart, which limits any further increase in blood flow. The major concept to learn from the vascular function curve is the following: Right atrial pressure decreases as flow through the cardiovascular system (either venous return or cardiac output) increases. This relationship is determined by vascular properties (R, C a, C v, and P sf ). Resistance to Vascular Return Resistance to vascular return is essentially the resistance to movement of blood through the vasculature (essentially the same as total peripheral resistance, with the additional consideration of compliance of the vasculature). This value can be calculated using the model as follows: 9/18/17 & 9/20/17 Page 11 Cardio 3-4

" P v = P sf R*C % " a $ 'Q so P sf P v = R*C % a $ 'Q # C a + C v & # C a + C v & and (P sf P v ) Q " = R*C % a $ ' # C a + C v &! RVR = R*C $ a # & " C a + C v % so (P sf P v ) Q = RVR Note that vascular compliance has a major impact on retarding return of blood flow to the heart. Note that the slope of the linear portion of the vascular function curve is 1/RVR. Thus, for typical physiological values of P sf = 7 mm Hg, P v = 2 mm Hg, and Q = 5 L/min: (P sf P v ) Q = RVR (7 2 mmhg) 5 L/min =1 mmhg min/l The slope of the linear portion of the vascular function curve is 1/RVR. Hence, as RVR increases, the slope decreases. This means that a given change in right atrial (venous) pressure causes a smaller change in cardiac output (or venous return) at higher RVR. In addition, maximal cardiac output (or venous return) is lower when RVR is high. 9/18/17 & 9/20/17 Page 12 Cardio 3-4

The relative compliance of the venous and arterial vessels has a major impact on relative pressures in the two types of vessels, as illustrated in the graph to the left for different cardiac outputs. As we have discussed, C a ΔP a = C v ΔP v Let us assume that C v = 19C a, so C a ΔP a = 19C a ΔP v ΔP a = 19ΔP v At Q = 0, P v = P a = P sf = 7 mm Hg At Q = 5 L/min, P v = 2 mm Hg thus ΔP v = 5 mm Hg (= 7 2) A small change in circulatory blood volume results in a huge change in P sf, as reflected in the sharp steepness of the curve relating the two parameters. At a circulatory blood volume of 4 L, P sf is 0; this is the unstressed volume, which is insufficient to contribute to pressure because there is insufficient stretch of the vessel walls. Any additional volume inside the cardiovascular system above the unstressed volume is called the stressed volume. At a circulatory blood volume of 5 L, P sf = 7 mm Hg. If blood volume increases by 10%, P sf doubles! Changes in P sf produced by alterations in circulatory volume have a huge impact on cardiac output and venous return, as illustrated in the graph to the left. An increase in P sf causes the vascular function curve to shift upwards and to the right. Consequently, at a particular right atrial pressure, cardiac output and venous return are much larger. In other words, when circulatory blood volume increases, it is much easier for the heart to fill with blood, and cardiac output increases. 9/18/17 & 9/20/17 Page 13 Cardio 3-4

Cardiac Function Curve Now we will look at the effects of manipulating right atrial pressure on cardiac output. In essence, this approach measures the effects of changing preload on cardiac output and blood pressure, and produces the cardiac function curve. In the experiments we will be discussing, cardiac contractile state and heart rate are maintained constant, as is arterial pressure (afterload). The cardiac function curve is illustrated to the left. When right atrial pressure is low, cardiac output is 0, since there is too little blood in the cardiac chambers to generate pressure during systole. When right atrial pressure increases above ~4 mm Hg, cardiac output is maximum. This is because the ventricle fulls maximally, and thus cannot accommodate more blood (the factors that limit ventricle filling are discussed below). The cardiac function curves to the left show the effect of increasing heart rate on cardiac output. Modest increases in heart rate facilitate cardiac output, despite a shorter ventricular filling time, due to the Bowditch effect. However, large increases in heart rate shorten filling time so much that cardiac output plummets. 9/18/17 & 9/20/17 Page 14 Cardio 3-4

The cardiac output produced by a particular right atrial pressure is altered if the ventricle is hypereffective or hypoeffective. A hypereffective ventricle is present when sympathetic activity is high, or the ventricle is hypertrophied (the muscle mass has increased due to factors such as chronic exercise). In addition, the ventricle is hypereffective when afterload is low. A hypoeffective ventricle is present when there is no sympathetic stimulation, the ventricle is damaged, or afterload increases. It is possible to plot the vascular function and cardiac function curves on the same axes, as shown to the left. The two curves intersect at one point, called the equilibrium point. This point indicates the cardiac output, venous return, and right atrial pressure under this particular physiological condition. In the adjacent graph, point A shows the normal equilibrium point, when right atrial pressure is near 0 and cardiac output and venous return are near 5 L/min. The dashed line indicates the effect of increasing blood volume by 20%. The vascular function curve shifts but the cardiac function curve doesn t. Note that P sf increases to about 16 mm Hg, right atrial pressure is near 8 mm Hg, and cardiac output is ~13 L/min. Under most conditions, both the cardiac output and vascular function curves shift during a manipulation. For example, sympathetic nervous system activity causes the cardiac function curve to shift upwards and a bit to the left, while the vascular function curve shifts upwards and to the right, as illustrated below. These effects are due to the following actions of the sympathetic nervous system: 1) Increased cardiac contractility 2) Increased heart rate 3) Decreased venous compliance 4) Increased total peripheral resistance. Note that afterload increases during sympathetic stimulation, and this opposes a shift in the vascular function curve. Consequently, cardiac output just rises to 10 L/min during maximal sympathetic stimulation. 9/18/17 & 9/20/17 Page 15 Cardio 3-4

During exercise, the shift in the venous return curve is considerably different than during sympathetic stimulation. Why? First, afterload decreases as arterioles in skeletal muscle dilate (the mechanisms involved will be discussed in subsequent lectures). In addition, skeletal muscle pumping contributes to an increase in venous return. Cumulatively, these factors in addition to the actions of the sympathetic nervous system cause cardiac output to increase to ~20 L/min. Using the Pressure Volume Relationship to Understand Cardiac Dynamics We previously considered the functional pressure-volume curve, as shown on the left. Such curves can be used to determine a number of parameters regarding the cardiovascular system, and even to diagnose diseases. As such, it is important to understand these curves and the principles they reveal. The functional pressure-volume curve is shown in the area labeled by EW in the curve to the left (EW stands for external work, as discussed later in this lecture). The pressure-volume curves can also be used to describe all physiological events in the heart. The diastolic pressure curve is determined by filling the heart with progressively greater volumes of blood and then measuring the diastolic pressure immediately before ventricular contraction occurs, which is the end-diastolic pressure of the ventricle. Thus curve is often called the end diastolic pressure-volume relationship (EDPVR). 9/18/17 & 9/20/17 Page 16 Cardio 3-4

Until the volume of the noncontracting ventricle rises above about 150 ml, the diastolic pressure does not increase greatly. Therefore, up to this volume, blood can flow easily into the ventricle from the atrium. Above 150 ml, the ventricular diastolic pressure increases rapidly, partly because of fibrous tissue in the heart that will stretch no more and partly because the pericardium that surrounds the heart becomes filled nearly to its limit. The systolic pressure curve represents the maximal pressure that can be developed at a particular filling volume of the ventricle. During ventricular contraction, the systolic pressure increases even at low ventricular volumes and reaches a maximum at a ventricular volume of 150 to 170 ml. Then, as the volume increases still further, the systolic pressure actually decreases: at these great volumes, the actin and myosin filaments of the cardiac muscle fibers are pulled apart far enough that the strength of each cardiac fiber contraction becomes less than optimal. The systolic pressure curve is usually referred to as the end systolic pressure-volume relationship (ESPVR). Under physiological conditions, ESPVR is a line that intersects the upper left corner of the functional pressure volume curve. It is common for pressure-volume loops to be constructed from data collected from either experimental animals or human patients. In patients, a device that measures flow rates and pressures can be inserted via the femoral artery into the aorta and then the left ventricle to obtain the necessary data. It is also possible to obtain the volume of blood in the ventricle via echocardiography (although pressure must be measured invasively). As venous return varies spontaneously, many curves can be generated and plotted on the same axes. A line is then drawn connecting the upper left corner of each curve, which is ESPVR. The upper left corner of the functional pressure-volume curve represents aortic valve closure. Interestingly, the pressure at this point is generally near mean arterial pressure. Thus, ESPVR shows the mean arterial pressure generated at different ventricular volumes. The slope of ESPVR is dependent on the contractility of the ventricle. Under sympathetic stimulation, the slope becomes steeper, such that a particular ventricular volume the pressure is greater. By comparing a normal pressure-volume loop with one generated at the same end diastolic volume but under sympathetic stimulation, the changes in stroke volume resulting from the manipulation can be determined. 9/18/17 & 9/20/17 Page 17 Cardio 3-4

An increase in contractility has a complex effect on cardiac output. This is because mean arterial pressure (and thus afterload) increases along with the increase in cardiac output. Hence, an increase in contractility both facilitates and opposes an increase in cardiac output. As a result, the increase in cardiac output is relatively modest. Increased Afterload The graph to the left shows the effect of a selective increase in afterload (e.g., resulting from the administration of an alpha-receptor agonist) on cardiac output. Note that ventricular pressure must become much higher before the aortic valve opens, and the valve closes much earlier. Consequently, stroke volume is reduced appreciably. Increased Contractility Increased Afterload However, the effects of increased afterload on stroke volume are ameliorated when contractility increases along with the afterload, as shown in the graph to the left. In this example, stroke volume is identical in the normal state and in the state with combined increases in contractility and afterload. 9/18/17 & 9/20/17 Page 18 Cardio 3-4

Increased Preload An increase in preload results in more filling of the ventricle during diastole. Consequently, stroke volume increases in accordance with the additional filling, due to the Frank-Starling Law of the Heart. As noted in previous lectures, a variety of factors can contribute to an increase in preload. They include: 1. Decreased venous compliance (venoconstriction) 2. Decreased resistance to venous return (RVR) 3. Increased blood volume 4. Negative intrathoracic pressure 5. Decreased heart rate 6. Decreased ventricular stiffness 7. Supine posture 8. Increased skeletal muscle pumping Diagnosing Cardiovascular Disease Using the Pressure-Volume Relationship As noted earlier, the structural features of cardiac muscle (collagen, titin, interconnections of myocytes) cause tension (and thus pressure) to build in a ventricle as it fills with blood. The ventricle continues to fill as long as pressure in this chamber is lower than that in the connected atrium. Thus, changing the length-tension relationship (stiffness) for a ventricle can affect how much blood enters the chamber during diastole, and thus cardiac output. A number of medical conditions can result in restrictive cardiomyopathy, or scarring and stiffening of the left ventricle without a loss of contractility. This condition results in the EDPVR curve shifting upwards (dashed line is normal, solid line is during the disease state). As a result, pressure inside the ventricle increases quickly as fluid enters the chamber, and thus filling is limited before intraventricular pressure matches atrial pressure. Consequently, end-diastolic volume is reduced and stroke volume decreases. 9/18/17 & 9/20/17 Page 19 Cardio 3-4

The situation is even worse in many patients following a myocardial infarction. Damage to the cardiac muscle can result in both scarring of the ventricular wall and loss of contractility. As a result, stroke volume decreases appreciably (compare the dashed [normal] curve with the solid [disease state] curve in the diagram to the left. Energetics of cardiac contraction in the chamber. The area encompassed by the pressurevolume loop is defined as external work or stroke work, or the work performed by the ventricle to eject the stroke volume into the aorta. Stroke work can be estimated by the product of stroke volume and mean aortic pressure (SW = SV * MAP). In the graph to the left, the stroke work is the area labeled EW. The graph to the left also indicates the area that represents potential energy (PE). Potential energy is defined as the energy stored as a result of deformation of an elastic object. In the heart, the potential energy is the energy absorbed by the ventricular wall that does not result in a change in the pressure of the fluid The term pressure-volume area (PVA) refers to the sum of potential energy and external work. There is a highly linear correlation between the PVA and cardiac oxygen consumption per beat. This relationship holds true under a variety of loading and contractile conditions. This estimation of myocardial oxygen consumption (MVO 2 ) is used to study the coupling of mechanical work and the energy requirement of the heart in various disease states, such as diabetes, ventricular hypertrophy and heart failure. MVO 2 is also used in the calculation of cardiac efficiency, which is the ratio of cardiac stroke work to MVO 2 (Cardiac Efficiency = SW/MVO 2 ). 9/18/17 & 9/20/17 Page 20 Cardio 3-4