Cardiovascular Physiology: Mosby Physiology Monograph Series, 9e (Mosbys Physiology Monograph)

Objectives

The student knows the basic electrical and mechanical events of the cardiac cycle:

• Correlates the electrocardiographic events with the mechanical events during the cardiac cycle.
• Lists the major distinct phases of the cardiac cycle as delineated by valve opening and closure.
• Describes the pressure and volume changes in the atria, the ventricles, and the aorta during each phase of the cardiac cycle.
• Defines and states normal values for (1) ventricular end-diastolic volume, end-systolic volume, stroke volume, diastolic pressure, and peak systolic pressure, and (2) aortic diastolic pressure, systolic pressure, and pulse pressure.
• States similarities and differences between mechanical events in the left and right heart pump.
• States the origin of the heart sounds.
• Diagrams the relationship between left ventricular pressure and volume during the cardiac cycle.

The student understands the factors that determine cardiac output:

• Defines cardiac output and cardiac index.
• States the relationship between cardiac output, heart rate, and stroke volume.
• Identifies the major determinants of stroke volume.
  • States the Frank-Starling law of the heart.
  • Predicts the effect of altered ventricular preload on stroke volume and the ventricular pressure-volume relationship.
  • Predicts the effect of altered ventricular afterload on stroke volume and the ventricular pressure-volume relationship.
  • Predicts the effect of altered ventricular contractility (inotropic state) on stroke volume and the ventricular pressure-volume relationship.

• Draws a family of cardiac function curves describing the relationship between filling pressure and cardiac output under various levels of sympathetic tone.
• Given data, calculates cardiac output using the Fick principle.
• Defines ejection fraction and identifies methods to determine it.
• Describes the end-systolic pressure-volume relationship.

The Heart Pump: Introduction

The repetitive, synchronized contraction and relaxation of the cardiac muscle cells provide the forces necessary to pump blood through the systemic and pulmonary circulations. In this chapter, we shall describe (1) basic mechanical features of this cardiac pump, (2) factors that influence and/or regulate the cardiac output, and (3) various methods for estimating cardiac mechanical function.

Cardiac Cycle

Left Pump

The mechanical function of the heart can be described by the pressure, volume, and flow changes that occur within it during one cardiac cycle. A cardiac cycle is defined as one complete sequence of contraction and relaxation. The normal mechanical events of a cycle of the left heart pump are correlated in Figure 3 1. This important figure summarizes a great deal of information and should be studied carefully.

Ventricular Diastole

The diastolic phase¹ of the cardiac cycle begins with the opening of the atrioventricular (AV) valves. As shown in Figure 3 1, the mitral valve opens when left ventricular pressure falls below left atrial pressure and the period of ventricle filling begins. Blood that had previously accumulated in the atrium behind the closed mitral valve empties rapidly into the ventricle and this causes an initial drop in atrial pressure. Later, the pressures in both chambers slowly rise together as the atrium and ventricle continue passively filling in unison with blood returning to the heart through the veins.

Atrial contraction is initiated near the end of ventricular diastole by the depolarization of the atrial muscle cells, which causes the P wave of the electrocardiogram. As the atrial muscle cells develop tension and shorten, atrial pressure rises and an additional amount of blood is forced into the ventricle. At normal heart rates, atrial contraction is not essential for adequate ventricular filling. This is evident in Figure 3 1 from the fact that the ventricle has nearly reached its maximum or end-diastolic volume before atrial contraction begins. Atrial contraction plays an increasingly significant role in ventricular filling as heart rate increases because the time interval between beats for passive filling becomes progressively shorter with increased heart rate. Note that throughout diastole, atrial and ventricular pressures are nearly identical. This is because a normal open mitral valve has very little resistance to flow and thus only a very small atrial-ventricular pressure difference is necessary to produce ventricular filling.

¹ The atria and ventricles do not beat simultaneously. Usually, and unless otherwise noted, systole and diastole denote phases of ventricular operation.

Ventricular Systole

Ventricular systole begins when the action potential breaks through the AV node and sweeps over the ventricular muscle an event heralded by the QRS complex of the electrocardiogram. Contraction of the ventricular muscle cells causes intraventricular pressure to rise above that in the atrium, which causes abrupt closure of the AV valve.

Pressure in the left ventricle continues to rise sharply as the ventricular contraction intensifies. When the left ventricular pressure exceeds that in the aorta, the aortic valve opens. The period of time between mitral valve closure and aortic valve opening is referred to as the isovolumetric contraction phase because during this interval the ventricle is a closed chamber with a fixed volume. Ventricular ejection begins with the opening of the aortic valve. In early ejection, blood enters the aorta rapidly and causes the pressure there to rise. Pressure builds simultaneously in both the ventricle and the aorta as the ventricular muscle cells continue to contract in early systole. This period is often called the rapid ejection phase.

Left ventricular and aortic pressures ultimately reach a maximum called peak systolic pressure. At this point the strength of ventricular muscle contraction begins to wane. Muscle shortening and ejection continue, but at a reduced rate. Aortic pressure begins to fall because blood is leaving the aorta and large arteries faster than blood is entering from the left ventricle. Throughout ejection, very small pressure differences exist between the left ventricle and the aorta because the aortic valve orifice is so large that it presents very little resistance to flow.

Eventually, the strength of the ventricular contraction diminishes to the point where intraventricular pressure falls below aortic pressure. This causes abrupt closure of the aortic valve. A dip, called the incisura or dicrotic notch, appears in the aortic pressure trace because a small volume of aortic blood must flow backward to fill the aortic valve leaflets as they close. After aortic valve closure, intraventricular pressure falls rapidly as the ventricular muscle relaxes. For a brief interval, called the isovolumetric relaxation phase, the mitral valve is also closed. Ultimately, intraventricular pressure falls below atrial pressure, the AV valve opens, and a new cardiac cycle begins.

Note that atrial pressure progressively rises during ventricular systole because blood continues to return to the heart and fill the atrium. The elevated atrial pressure at the end of systole promotes rapid ventricular filling once the AV valve opens to begin the next heart cycle.

The ventricle has reached its minimum or end-systolic volume at the time of aortic valve closure. The amount of blood ejected from the ventricle during a single beat, the stroke volume, is equal to ventricular end-diastolic volume minus ventricular end-systolic volume.

The aorta distends or balloons out during systole because more blood enters the aorta than leaves it. During diastole, the arterial pressure is maintained by the elastic recoil of walls of the aorta and other large arteries. Nonetheless, aortic pressure gradually falls during diastole as the aorta supplies blood to the systemic vascular beds. The lowest aortic pressure, reached at the end of diastole, is called diastolic pressure. The difference between diastolic and peak systolic pressure in the aorta is called the arterial pulse pressure. Typical values for systolic and diastolic pressures in the aorta are 120 and 80 mmHg, respectively.

At a normal resting heart rate of about 70 beats per minute, the heart spends approximately two thirds of the cardiac cycle in diastole and one third in systole. When increases in heart rate occur, both diastolic and systolic intervals become shorter. Action potential durations are shortened and conduction velocity is increased. Contraction and relaxation rates are also enhanced. This shortening of the systolic interval tends to blunt the potential adverse effects of increases in heart rate on diastolic filling time.

Right Pump

Because the entire heart is served by a single electrical excitation system, similar mechanical events occur essentially simultaneously in both the left heart and the right heart. Both ventricles have synchronous systolic and diastolic periods and the valves of the right and left heart normally open and close nearly in unison. Because the two sides of the heart are arranged in series in the circulation, they must pump the same amount of blood and therefore must have identical stroke volumes.

The major difference between the right and left pumps is in the magnitude of the peak systolic pressure. The pressures developed by the right heart as shown in Figure 3 2 are considerably lower than those for the left heart (Figure 3 1). The lungs provide considerably less resistance to blood flow than that offered collectively by the systemic organs. Therefore, less arterial pressure is required to drive the cardiac output through the lungs than through the systemic organs. Typical pulmonary artery systolic and diastolic pressures are 24 and 8 mmHg, respectively.

The pressure pulsations that occur in the right atrium are transmitted in retrograde fashion to the large veins near the heart. These pulsations, shown on the atrial pressure trace of Figure 3 2, can be visualized in the neck over the jugular veins in a recumbent individual and can provide clinically useful information about the heart. Atrial contraction produces the first pressure peak called the a wave. The c wave, which follows shortly thereafter, coincides with the onset of ventricular systole and is caused by an initial bulging of the tricuspid valve into the right atrium. Right atrial pressure falls after the c wave because of atrial relaxation and a downward displacement of the tricuspid valve during ventricular emptying. Right atrial pressure then begins to increase toward a third peak, the v wave, as the central veins and right atrium fill behind a closed tricuspid valve with blood returning to the heart from the peripheral organs. With the opening of the tricuspid valve at the conclusion of ventricular systole, right atrial pressure again falls as blood moves into the relaxed right ventricle. Shortly afterward, right atrial pressure begins to rise once more toward the next a wave as returning blood fills the central veins, the right atrium, and right ventricle together during diastole.

Heart Sounds

A phonocardiographic record of the heart sounds, which occur in the cardiac cycle, is included in Figure 3 1. The first heart sound, S₁, occurs at the beginning of systole because of the abrupt closure of the AV valves, which produces vibrations of the cardiac structures and the blood in the ventricular chambers. S₁ can be heard most clearly by placing the stethoscope over the apex of the heart. Note that this sound occurs immediately after the QRS complex of the electrocardiogram.

The second heart sound, S₂, arises from the closure of the aortic and pulmonic valves at the beginning of the period of isovolumetric relaxation. This sound is heard at about the time of the T wave in the electrocardiogram. The pulmonic valve usually closes slightly after the aortic valve. Because this discrepancy is enhanced during the inspiratory phase of the respiratory cycle, inspiration causes what is referred to as the physiological splitting of the second heart sound. The discrepancy in valve closure during inspiration may range from 30 to 60 ms. One of the factors that leads to prolonged ejection of the right ventricle during inspiration is that the decreased intrathoracic pressure that accompanies inspiration transiently enhances venous return and diastolic filling of the right heart. For reasons that will be detailed later in this chapter, this extra filling volume will be ejected but a little extra time is required to do so.

The third and fourth heart sounds, shown in Figure 3 1, are not normally present. When they are present, however, they, along with S₁ and S₂, produce what are called gallop rhythms (resembling the sound of a galloping horse). When present, the third heart sound occurs shortly after S₂ during the period of rapid passive ventricular filling and, in combination with heart sounds S₁ and S₂, produces what is called ventricular gallop rhythm. Although S₃ may sometimes be detected in normal children, it is heard more commonly in patients with left ventricular failure. The fourth heart sound, which occasionally is heard shortly before S₁, is associated with atrial contraction and rapid active filling of the ventricle. Thus, the combination of S₁, S₂, and S₄ sounds produces what is called an atrial gallop rhythm. The presence of S₄ often indicates an increased ventricular diastolic stiffness, which can occur with several cardiac disease states.

Cardiac Cycle Pressure-Volume & Length-Tension Relationships

Intraventricular pressure and volume are intimately linked to the tension and length of the cardiac muscle cells in the ventricular wall through purely geometric and physical laws. Figures 3 3A and 3 3B show the correspondence between a ventricular pressure-volume loop and a cardiac muscle length-tension loop during one cardiac cycle. This fact makes it clear that cardiac muscle length-tension behavior is the underlying basis for ventricular function. Note that in Figure 3 3, each major phase of the ventricular cardiac cycle has a corresponding phase of cardiac muscle length and tension change. During diastolic ventricular filling, for example, the progressive increase in ventricular pressure causes a corresponding increase in muscle tension, which passively stretches the resting cardiac muscle to greater lengths along its resting length-tension curve. End-diastolic ventricular pressure is referred to as ventricular preload because it sets the end-diastolic ventricular volume and therefore the resting length of the cardiac muscle fibers at the end of diastole.

At the onset of systole, the ventricular muscle cells develop tension isometrically and intraventricular pressure rises accordingly. After the intraventricular pressure rises sufficiently to open the outlet valve, ventricular ejection begins as a consequence of ventricular muscle shortening. Systemic arterial pressure is often referred to as the ventricular afterload because it determines the tension that must be developed by cardiac muscle fibers before they can shorten.²

During cardiac ejection, cardiac muscle is simultaneously generating active tension and shortening (ie, an afterloaded isotonic contraction). The magnitude of ventricular volume change during ejection (ie, stroke volume) is determined simply by how far ventricular muscle cells are able to shorten during contraction. This, as already discussed, depends on the length-tension relationship of the cardiac muscle cells and the load against which they are shortening. Once shortening ceases and the output valve closes, the cardiac muscle cells relax isometrically. Ventricular wall tension and intraventricular pressure fall in unison during isovolumetric relaxation.

² This designation is somewhat misleading for at least two reasons. First, arterial pressure is more analogous to ventricular total load than to ventricular afterload. Second, because of the law of Laplace, the actual wall tension that needs to be generated to attain a given intraventricular pressure also depends on the ventricular radius (tension = pressure x radius). Thus, the larger the end-diastolic volume, the greater the tension required to develop sufficient intraventricular pressure to open the outflow valve. We choose, however, to ignore these complications.

Determinants of Cardiac Output

Cardiac output (liters of blood pumped by each of the ventricles per minute) is an extremely important cardiovascular variable that is continuously adjusted so that the cardiovascular system operates to meet the body's moment-to-moment transport needs. In going from rest to strenuous exercise, for example, the cardiac output of an average person will increase from approximately 5.5 to perhaps 15 L/min. The extra cardiac output provides the exercising skeletal muscles with the additional nutritional supply needed to sustain an increased metabolic rate. To understand the cardiovascular system's response not only to exercise but to all other physiological or pathological demands placed on it, we must understand what determines and therefore controls cardiac output.

As stated in Chapter 1, cardiac output is the product of heart rate and stroke volume (CO = HR x SV). Therefore, all changes in cardiac output must be produced by changes in heart rate and/or stroke volume.

Factors influencing heart rate do so by altering the characteristics of the diastolic depolarization of the pacemaker cells as discussed in Chapter 2 (Figure 2 6). Recall that variations in activity of the sympathetic and parasympathetic nerves leading to cells of the sinoatrial (SA) node constitute the most important regulators of heart rate. Increases in sympathetic activity increase heart rate whereas increases in parasympathetic activity decrease heart rate. These neural inputs have immediate effects (within one beat) and therefore can cause very rapid adjustments in cardiac output.

Influences on Stroke Volume

Effect of Changes in Ventricular Preload: Frank-Starling Law of the Heart

The volume of blood that the heart ejects with each beat can vary significantly. One of the most important factors responsible for these variations in stroke volume is the extent of cardiac filling during diastole. This concept was introduced in Chapter 1 (Figure 1 7) and is known as Starling's law of the heart. To review (and to reemphasize its importance), this law states that, with other factors equal, stroke volume increases as cardiac filling increases. As we will now show, this phenomenon is based on the intrinsic mechanical properties of myocardial muscle.

Figure 3 4A illustrates how increasing muscle preload will increase the extent of shortening during a subsequent contraction with a fixed total load. Recall from the nature of the resting length-tension relationship that an increased preload is necessarily accompanied by increased initial muscle fiber length. As was described in Chapter 2, when a muscle starts from a greater length, it has more room to shorten before it reaches the length at which its tension-generating capability is no longer greater than the load upon it. The same behavior is exhibited by cardiac muscle cells when they are actually operating in the ventricular wall. Increases in ventricular preload increase both end-diastolic volume and stroke volume almost equally, as illustrated in Figure 3 4B.

The precise relationship between cardiac preload (cardiac filling pressure) and end-diastolic volume has especially important physiological and clinical consequences. Whereas the actual relationship is somewhat curvilinear, especially at very high filling pressures, it is nearly linear over the normal operating range of the heart. The low slope of this relationship indicates the incredible distensibility of the normal ventricle during diastole. (For example, a change in filling pressure of only 1 mmHg normally will change end-diastolic volume by about 25 mL!) As will be discussed in the final chapter of this book, one major form of cardiac failure is called "diastolic failure" and is characterized by a decidedly abnormal relationship between cardiac filling pressure and end-diastolic volume.

It should be noted in Figure 3 4A that increasing preload increases initial muscle length without significantly changing the final length to which the muscle shortens against a constant total load. Thus, increasing ventricular filling pressure increases stroke volume primarily by increasing end-diastolic volume. As shown in Figure 3 4B, this is not accompanied by a significant alteration in end-systolic volume.

Effect of Changes in Ventricular Afterload

As stated previously, systemic arterial pressure (ventricular afterload) is analogous to total load in isolated muscle experiments. A slight complication is that arterial pressure varies between a diastolic value and a systolic value during each cardiac ejection. Usually, however, we are interested in mean ventricular afterload and take this to be mean arterial pressure.

Figure 3 5A shows how increased afterload, at constant preload, has a negative effect on cardiac muscle shortening. Again, this is simply a consequence of the fact that muscle cannot shorten beyond the length at which its peak isometric tension-generating potential equals the total load upon it. Thus, shortening must stop at a greater muscle length when afterload is increased.

Normally, mean ventricular afterload is quite constant, because mean arterial pressure is held within tight limits by the cardiovascular control mechanisms described later. In many pathological situations such as hypertension and aortic valve obstruction, however, ventricular function is adversely influenced by abnormally high ventricular afterload. When this occurs, stroke volume is decreased as shown by the changes in the pressure-volume loop in Figure 3 5B. Under these conditions, note that stroke volume is decreased because end-systolic volume is increased.

The relationship between end-systolic pressure and end-systolic volume obtained at a constant preload but different afterloads is indicated by the dotted line in Figure 3 5B. In a normally functioning heart, the effect of changes in afterload on end-systolic volume (and therefore stroke volume) is quite small (about 0.5 mL/mmHg). However, in what is termed "systolic cardiac failure" the effect of afterload on end-systolic volume is greatly enhanced. Thus, the slope of this line can be used clinically to assess the systolic function of the heart.

Effect of Changes in Cardiac Muscle Contractility

Recall that activation of the sympathetic nervous system results in release of norepinephrine from cardiac sympathetic nerves which increases contractility of the individual cardiac muscle cells. This results in an upward shift of the peak isometric length-tension curve. As shown in Figure 3 6A, such a shift will result in an increase in the shortening of a muscle contracting with constant preload and total load. Thus, as shown in Figure 3 6B, the norepinephrine released by sympathetic nerve stimulation will increase ventricular stroke volume by decreasing the end-systolic volume without directly influencing the end-diastolic volume.

As previously discussed, the V_max value is commonly used as an index of the state of contractility of isolated cardiac muscle. Myocardial contractility cannot be directly measured in patients. However, several indirect methods are used to obtain clinically useful information about this important determinant of cardiac function. In one method, cardiac catheters are placed in the ventricle and the maximum rate of pressure development (dP/dt_max) during the isovolumetric contraction is measured. This may be used as an index of contractility on the grounds that, in isolated cardiac muscle preparations, changes in contractility and V_max cause changes in the rate of tension development in an isometric contraction. Decreases in left ventricular dP/dt_max below the normal values of 1500 to 2000 mmHg/s indicate that myocardial contractility is below normal. Other methods of assessing contractility that use information derived from cardiac imaging techniques are discussed at the end of this chapter.

Summary of Determinants of Cardiac Output

The major influences on cardiac output are summarized in Figure 3 7. Heart rate is controlled by chronotropic influences on the spontaneous electrical activity of SA nodal cells. Cardiac parasympathetic nerves have a negative chronotropic effect, and sympathetic nerves have a positive chronotropic effect on the SA node. Stroke volume is controlled by influences on the contractile performance of ventricular cardiac muscle in particular its degree of shortening in the afterloaded situation. The three distinct influences on stroke volume are contractility, preload, and afterload. Increased cardiac sympathetic nerve activity tends to increase stroke volume by increasing the contractility of cardiac muscle. Increased arterial pressure tends to decrease stroke volume by increasing the afterload on cardiac muscle fibers. Increased ventricular filling pressure increases end-diastolic volume, which tends to increase stroke volume through Starling's law.

It is important to recognize at this point that both heart rate and stroke volume are subject to more than one influence. Thus, the fact that increased contractility tends to increase stroke volume should not be taken to mean that, in the intact cardiovascular system, stroke volume is always high when contractility is high. Following blood loss caused by hemorrhage, for example, stroke volume may be low in spite of a high level of sympathetic nerve activity and increased contractility. The only other possible causes for low stroke volume are high arterial pressure and low cardiac filling pressure. Because arterial pressure is normal or low following hemorrhage, the low stroke volume associated with severe blood loss must be (and is) the result of low cardiac filling pressure.

Cardiac Function Curves

One very useful way to summarize the influences on cardiac function and the interactions between them is by cardiac function curves such as those shown in Figure 3 8.

In this case, cardiac output is treated as the dependent variable and is plotted on the vertical axis in Figure 3 8, while cardiac filling pressure is plotted on the horizontal axis.³

Different curves are used to show the influence of alterations in sympathetic nerve activity. Thus, Figure 3 8 shows how the cardiac filling pressure and the activity level of cardiac sympathetic nerves interact to determine cardiac output. When cardiac filling pressure is 2 mmHg and the activity of cardiac sympathetic nerves is normal, the heart will operate at point A and will have a cardiac output of 5 L/min. Each single curve in Figure 3 8 shows how cardiac output would be changed by changes in cardiac filling pressure if cardiac sympathetic nerve activity were held at a fixed level. For example, if cardiac sympathetic nerve activity remained normal, increasing cardiac filling pressure from 2 to 4 mmHg would cause the heart to shift its operation from point A to point B on the cardiac function diagram. In this case, cardiac output would increase from 5 to 7 L/min solely as a result of the increased filling pressure (Starling's law). If, on the other hand, cardiac filling pressure were fixed at 2 mmHg while the activity of cardiac sympathetic nerves was moderately increased from normal, the heart would change from operating at point A to operating at point C. Cardiac output would again increase from 5 to 7 L/min. In this instance, however, cardiac output does not increase through the length-dependent mechanism because cardiac filling pressure did not change. Cardiac output increases at constant filling pressure with an increase in cardiac sympathetic activity for two reasons. First, increased cardiac sympathetic nerve activity increases heart rate. Second, but just as important, increased sympathetic nerve activity increases stroke volume by increasing cardiac contractility.

Cardiac function graphs thus consolidate knowledge of many mechanisms of cardiac control, and are most helpful in describing how the heart interacts with other elements in the cardiovascular system. Furthermore, these graphs reemphasize the important point that a change in cardiac filling pressure alone will have a very potent effect on cardiac output at any level of sympathetic activity.

³ Other variables may appear on the axes of these curves. The vertical axis may be designated as stroke volume or stroke work whereas the horizontal axis may be designated as central venous pressure, right (or left) atrial pressure, or ventricular end-diastolic volume (or pressure). In all cases, the curves describe the relationship between preload and cardiac function.

Summary of Sympathetic Neural Influences on Cardiac Function

Because of its importance in overall control of cardiac function, it is appropriate at this point to summarize the major direct effects that the sympathetic nervous system exerts upon electrical and mechanical properties of cardiac muscle and thus upon cardiac pumping ability. These effects are initiated by norepinephrine interaction with ₁-adrenergic receptors on cardiac muscle cells resulting in an increase in cytosolic cyclic adenosine monophosphate (cAMP). Various intracellular signaling pathways are then triggered, which evoke improvements in pumping capabilities of the heart. These improvements include the following:

1. An increase in heart rate (positive chronotropic effect);

2. A decrease in cardiac action potential duration, which minimizes the detrimental effect of high heart rates on diastolic filling time;

3. An increase in rate of action potential conduction, particularly evident in the AV node (positive dromotropic effect);

4. An increase in cardiac contractility (positive inotropic effect), which increases the contractile ability of cardiac muscle at any given preload; and

5. An increase in rate of cardiac relaxation (positive lusitropic effect), which also helps minimize the detrimental effect of high heart rates on diastolic filling time.^4,5

As we will see in subsequent chapters, increases in sympathetic activity can have indirect influences on cardiac function that are a consequence of sympathetic-induced alterations in arteriolar and venous tone (ie, alterations in afterload and preload, respectively).

⁴ Most catecholamine effects on the heart are a result of increases in sympathetic neural activity. Although circulating catecholamines of adrenal origin can potentially evoke similar effects, their concentrations are normally so low that their contributions are negligible.

⁵ All of the effects of catecholamines on cardiac muscle can be blocked by specific drugs called -adrenergic receptor blockers. The drugs may be useful in the treatment of coronary artery disease to thwart increased metabolic demands placed on the heart by activity of sympathetic nerves.

Cardiac Energetics

Energy Sources

In order for the heart to operate properly, it must have an adequate supply of chemical energy in the form of adenosine triphosphate (ATP). The relatively low ATP content of cardiac tissue combined with a relatively high rate of ATP hydrolysis at rest suggests that the myocardial ATP pool will completely turn over every 10 seconds. The substrates from which ATP is formed by the heart depend partly on which are in the greatest supply at a particular instant. For example, after a high carbohydrate meal, the heart will take up and metabolize glucose and pyruvate, whereas between meals, the heart can switch to metabolize free fatty acids, triglycerides, and ketones. In addition, the choice of substrate also depends on the metabolic phenotype of the cardiac muscle. Fetal and newborn hearts derive most of their ATP from metabolism of glucose and lactate, whereas, within a few weeks of birth, a switch toward fatty acid oxidation occurs so that by adulthood, 60 to 90% of cardiac ATP is derived from fatty acids. A switch back toward the fetal phenotype accompanies severe heart failure. Glycogen is stored in myocardial cells as a reserve energy supply and can be mobilized via the glycolytic pathway to provide extra substrate under conditions of increased sympathetic stimulation.⁶ The end-product of metabolism of glycogen, glucose, fatty acids, triglycerides, pyruvate, and lactate is acetyl CoA, which enters the citric acid (Krebs) cycle in the mitochondria, where, by a process of oxidative phosphorylation, the molecules are degraded to carbon dioxide and water and the energy is converted to ATP. (The student is encouraged to consult a biochemistry textbook for further details of these important metabolic pathways.)

The anaerobic sources of energy in the heart (eg, glycolysis, creatine phosphate) are not adequate to sustain the metabolic demand for more than a few minutes. The heavy (nearly total) reliance of the heart on the aerobic pathways for ATP production is evident by (1) the high number of mitochondria and (2) the presence of high concentrations of the oxygen-binding protein myoglobin within the cardiac muscle cells. Myoglobin can release its oxygen to the mitochondrial cytochrome oxidase system when intracellular oxygen levels are lowered. In these regards, cardiac muscle resembles "red" skeletal muscle that is adapted for sustained contractile activity as opposed to "white" skeletal muscle that is adapted for high-intensity, short-duration contractile activity.

⁶ Catecholamines interacting with membrane receptors increase intracellular cyclic adenosine monophosphate (cAMP), which then activates phosphorylase b to stimulate glycogen metabolism.

Determinants of Myocardial Oxygen Consumption

In many pathological situations, such as obstructive coronary artery disease, the oxygen requirements of the myocardial tissue may exceed the capacity of coronary blood flow to deliver oxygen to the heart muscle. It is important, therefore, to understand what factors determine the myocardial oxygen consumption rate because reduction of the oxygen demand may be of significant clinical benefit to the patient.

Because the heart derives its energy almost entirely from aerobic metabolism, myocardial oxygen consumption is directly related to myocardial energy use (ie, ATP splitting). Understanding the determinants of myocardial oxygen consumption essentially means understanding the myocardial processes that require ATP.

The basal metabolism of the heart tissue normally accounts for about 25% of myocardial ATP use and therefore myocardial oxygen consumption in a resting individual. Because basal metabolism represents the energy consumed in cellular processes other than contraction (eg, energy-dependent ion pumping), little can be done to reduce it.

The processes associated with muscle contraction account for about 75% of myocardial energy use. Primarily this reflects ATP splitting associated with cross-bridge cycling during the isovolumetric contraction and ejection phases of the cardiac cycle. Some ATP is also used for Ca²⁺ sequestration at the termination of each contraction.

The energy expended during the isovolumetric contraction phase of the cardiac cycle accounts for the largest portion (50%) of total myocardial oxygen consumption despite the fact that the heart does no external work during this period. The energy needed for isovolumetric contraction depends heavily on the intraventricular pressure that must develop during this time, ie, on the cardiac afterload. Cardiac afterload then is a major determinant of myocardial oxygen consumption. Reductions in cardiac afterload can produce clinically significant reductions in myocardial energy requirements and therefore myocardial oxygen consumption.

Energy utilization during isovolumetric contraction is actually more directly related to isometric wall tension development than to intraventricular pressure development. Recall that wall tension is related to intraventricular pressure and ventricular radius through the law of Laplace (T = P x r). Consequently, reductions in cardiac preload (ie, end-diastolic volume, radius) will also tend to reduce the energy required for isovolumetric contraction.

It is during the ejection phase of the cardiac cycle that the heart actually performs external work and the energy the heart expends during ejection depends on how much external work it is doing. In a fluid system, work (force x distance) is equal to pressure (force/distance²) x volume (distance³). The external physical work done by the left ventricle in one beat, called stroke work, is equal to the area enclosed by the left ventricular pressure-volume loop (see Figure 3 3). Stroke work is increased either by an increase in stroke volume (increased "volume" work) or by an increase in afterload (increased "pressure" work). In terms of ATP utilization and oxygen consumption, increases in the pressure work of the heart are more costly than increases in volume work. Thus, reductions in afterload are especially helpful in reducing the myocardial oxygen requirements for doing external work.

Changes in myocardial contractility can have important consequences on the oxygen requirement for basal metabolism, isovolumic wall tension generation, and external work. Heart muscle cells use more energy in rapidly developing a given tension and shortening by a given amount than in doing the same thing more slowly. Also, with increased contractility, more energy is expended in active Ca²⁺ transport. The net result of these influences is often referred to as the "energy wasting" effect of increased contractility.

Heart rate is also one of the more important determinants of myocardial oxygen consumption because the energy costs per minute must equal the energy cost per beat times the number of beats per minute. In general, it has been found that it is more efficient (less oxygen is required) to achieve a given cardiac output with low heart rate and high stroke volume than with high heart rate and low stroke volume. This again appears to be related to the relatively high energy cost of the pressure development phase of the cardiac cycle. The less pressure (wall tension) developed and the less often pressure development occurs, the better.

Many attempts have been made to develop clinically practical methods for estimating myocardial oxygen requirements from routinely measured cardiovascular variables. While none of these take into account all the factors that can influence myocardial oxygen consumption and therefore do not give 100% accurate predictions in all situations, many methods have proved to be of some usefulness. Perhaps the simplest "index" of the energy demands of the heart is obtained by multiplying peak systolic arterial pressure times heart rate. This pressure-rate product takes into account two of the most important factors in cardiac energy use (the magnitude and frequency of pressure development) and requires no invasive measures. Another formula, the tension-time index, is defined as summed areas under the systolic portions of a ventricular pressure recording for 1 minute. A continuous high-fidelity recording of intraventricular pressure such as that obtained during cardiac catheterization is required to calculate the tension-time index. It is debatable whether the tension-time index predicts myocardial oxygen consumption with any more certainty than the simple pressure-rate product. The quest for a reliable index of myocardial oxygen consumption continues as cardiac imaging techniques (described near the end of this chapter) make cardiac volume and dimension information more routinely available. For example, this additional information makes it possible to construct ventricular pressure-volume loops whose area accurately indicates external cardiac work. As yet, however, no simple method has been found for assessing all the factors that affect myocardial energy use and using them to predict myocardial oxygen consumption.

Measurement of Cardiac Function

Cardiac Output/Cardiac Index

Establishing the absolute value of a patient's cardiac output is a relatively difficult task. It is, however, possible to estimate the relative change in a patient's cardiac output between two situations from the changes in heart rate (HR) and arterial pressure that occur. Recall (from Figure 3 1) that arterial pulse pressure (P_p) is defined as the difference between the arterial systolic (P_s) and diastolic (P_d) pressures. For reasons that will be explained in Chapter 6, acute changes in pulse pressure occur primarily because of changes in stroke volume (SV). If one assumes a linear relationship between changes in stroke volume and pulse pressure, then one can reason that since CO = HR x SV, the fractional change in CO that occurs in going from situation 1 to situation 2 is approximately equal to the product of the fractional changes in HR and P_p between these situations. For example, if heart rate increased by 10% and pulse pressure increased by 10%, one would estimate that cardiac output increased by 21% (1.1 x 1.1 = 1.21).

One of the most accurate methods of measuring cardiac output makes use of the Fick principle, which is discussed in detail in Chapter 6. Briefly, this principle states that the amount of a substance consumed by the tissues, X_tc, is equal to what goes in minus what goes out [which is the arterial-venous concentration difference in the substance ([X]_a [X]_v) times the blood flow rate, ]. This relationship can be algebraically arranged to solve for blood flow:

A common method of determining cardiac output is to use the Fick principle to calculate the collective flow through the systemic organs from (1) the whole body oxygen consumption rate (_tc), (2) the oxygen concentration in arterial blood ([X]_a), and (3) the concentration of oxygen in mixed venous blood ([X]_v). Of the values required for this calculation, the oxygen content of mixed venous blood is the most difficult to obtain. Generally, the sample for venous blood oxygen measurement must be taken from venous catheters positioned in the right ventricle or pulmonary artery to ensure that it is a mixed sample of venous blood from all systemic organs.

The calculation of cardiac output from the Fick principle is best illustrated by an example. Suppose a patient is consuming 250 mL of O₂ per minute when his or her systemic arterial blood contains 200 mL of O₂ per liter and the right ventricular blood contains 150 mL of O₂ per liter. This means that, on the average, each liter of blood loses 50 mL of O₂ as it passes through the systemic organs. In order for 250 mL of O₂ to be consumed per minute, 5 L of blood must pass through the systemic circulation each minute:

Dye dilution and thermal dilution (dilution of heat) are other clinical techniques commonly employed for estimating cardiac output. Usually a known quantity of indicator (dye or heat) is rapidly injected into the blood as it enters the right heart and appropriate detectors are arranged to continuously record the concentration of the indicator in blood as it leaves the left heart. It is possible to estimate the cardiac output from the quantity of indicator injected and the time record of indicator concentration in the blood that leaves the left heart.

The normal cardiac output for an individual is obviously dependent on his or her size. For example, the cardiac output of 50-kg woman will be significantly lower than that of a 90-kg man. It has been found, however, that cardiac output correlates better with body surface area than with body weight. Therefore, it is common to express the cardiac output per square meter of surface area. This value is called the cardiac index; at rest it is normally approximately 3 (L/min)/m².

Cardiac Contractility Estimates

Imaging Techniques

It is often important to assess an individual s cardiac function without using major invasive procedures. Advances in several techniques have made it possible to obtain two- and three-dimensional images of the heart throughout the cardiac cycle. Visual or computer-aided analysis of such images provides information useful in clinically evaluating cardiac function. These techniques are especially suited for detecting abnormal operation of cardiac valves or contractile function in portions of the heart walls. They also can provide estimates of heart chamber volumes at different times in the cardiac cycle which, as described later, are used in a number of ways to assess cardiac function.

Echocardiography is the most widely used of the three cardiac imaging techniques currently available. This noninvasive technique is based on the fact that sound waves reflect back toward the source when encountering abrupt changes in the density of the medium through which they travel. A transducer, placed at specified locations on the chest, generates pulses of ultrasonic waves and detects reflected waves that bounce off the cardiac tissue interfaces. The longer the time between the transmission of the wave and the arrival of the reflection, the deeper the structure is in the thorax. Such information can be reconstructed by computer in various ways to produce a continuous image of the heart and its chambers throughout the cardiac cycle. Cardiac angiography involves the placement of catheters into the right or left ventricle and injection of radiopaque contrast medium during high speed x-ray filming (cineradiography). Radionuclide ventriculography involves the intravenous injection of a radioactive isotope that stays in the vascular space (usually technitium that binds to red blood cells) and the measurement of the changes in intensity of radiation detected over the ventricles during the cardiac cycle.

Information derived from these various imaging techniques can be used to evaluate myocardial contractility, a critically important component of cardiac function that is somewhat difficult to measure in a clinical setting.

Ejection Fraction

Ejection fraction (EF) is an extremely useful clinical measurement. It is defined as the ratio of stroke volume (SV) to end-diastolic volume (EDV):

Ejection fraction is commonly expressed as a percentage and normally ranges from 55% to 80% (mean 67%) under resting conditions. Ejection fractions of less than 55% indicate depressed myocardial contractility.

End-Systolic Pressure-Volume Relationship

This relationship was first described in Figure 3 5B. End-systolic volume for a given cardiac cycle is estimated by one of the imaging techniques described above while end-systolic pressure for that cardiac cycle is obtained from the arterial pressure record at the point of the closure of the aortic valve (the incisura). Values for several different cardiac cycles are obtained during infusion of a vasoconstrictor (which increases afterload), and the data are plotted. As shown in Figure 3 9, increases in myocardial contractility are associated with a leftward shift in this relationship. Decreases in contractility (as may be caused by heart disease) are associated with a downward shift of the line and will be discussed further in Chapter 11. This method of assessing cardiac function is particularly important because it provides an estimate of contractility that is independent of the end-diastolic volume (preload). Recall from Figure 3 4 and from the pressure-volume loop described by the dotted line in Figure 3 9 that increases in preload cause increases in stroke volume without changing the end-systolic volume. Thus only alterations in contractility will cause shifts in the end-systolic pressure-volume relationship.

Key Concepts

Effective cardiac pumping of blood requires coordinated filling of the chambers, excitation and contraction of the cardiac muscle cells, pressure generation within the chambers, opening and closing of cardiac valves, and one-way movement of blood through the chambers into the aorta or pulmonary artery.

Except for lower ejection pressures, events of the right side of the heart are identical to those of the left side.

Heart sounds associated with valve movements and detected upon auscultation can be used to identify the beginnings of diastolic and systolic phases of the cardiac cycle.

The events of a single ventricular cardiac cycle can be displayed as a record against time or as a record of volume against pressure.

Cardiac output is defined as the amount of blood pumped by either of the ventricles per minute and is determined by the product of heart rate and stroke volume.

Stroke volume can be altered by changes in ventricular preload (filling), ventricular afterload (arterial pressure), and/or cardiac muscle contractility.

A cardiac function curve describes the relationship between ventricular filling and cardiac output and can be shifted up (left) or down (right) by changes in sympathetic activity to the heart or by changes in cardiac muscle contractility.

Energy for cardiac muscle contraction is derived primarily from aerobic metabolic pathways such that cardiac work is tightly related to myocardial oxygen consumption.

A variety of methods are available for measuring various aspects of cardiac function (cardiac output, cardiac index, ejection fraction). These methods are based on the Fick principle, dye-dilution techniques, and various imaging techniques.

Study Questions

3 1. If pulmonary artery pressure is 24/8 mmHg (systolic/diastolic), what are the respective systolic and diastolic pressures of the right ventricle?

3 2. Because pulmonary artery pressure is so much lower than aortic pressure, the right ventricle has a larger stroke volume than the left ventricle. True or false?

3 3. Which of the following interventions will increase cardiac stroke volume?

   a. Increased ventricular filling pressure

   b. Decreased arterial pressure

   c. Increased activity of cardiac sympathetic nerves

   d. Increased circulating catecholamine levels

3 4. Given the following information, calculate cardiac output:

   Systemic arterial blood oxygen concentration, [O₂]_SA = 200 mL/L

   Pulmonary arterial blood oxygen concentration, [O₂]_PA = 140 mL/L

   Total body oxygen consumption, O₂ = 600 mL/min

3 5. In which direction will cardiac output change if central venous pressure is lowered while cardiac sympathetic tone is increased?

3 6. Increases in sympathetic neural activity to the heart will result in an increase in stroke volume by causing a decrease in end-systolic volume for any given end-diastolic volume. True or false?

See answers.

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