After studying this chapter, you should be able to:
Describe how the sequential pattern of contraction and relaxation in the heart results in a normal pattern of blood flow.
Understand the pressure, volume, and flow changes that occur during the cardiac cycle.
Explain the basis of the arterial pulse, heart sounds, and murmurs.
Delineate the ways by which cardiac output can be up-regulated in the setting of specific physiologic demands for increased oxygen supply to the tissues, such as exercise.
Describe how the pumping action of the heart can be compromised in the setting of specific disease states.
Of course, the electrical activity of the heart discussed in the previous chapter is designed to subserve the heart’s primary physiological role—to pump blood through the lungs, where gas exchange can occur, and thence to the remainder of the body (Clinical Box 30–1). This is accomplished when the orderly depolarization process described in the previous chapter triggers a wave of contraction that spreads through the myocardium. In single muscle fibers, contraction starts just after depolarization and lasts until about 50 ms after repolarization is completed (see Figure 5–15). Atrial systole starts after the P wave of the electrocardiogram (ECG); ventricular systole starts near the end of the R wave and ends just after the T wave. In this chapter, we will consider how these changes in contraction produce sequential changes in pressures and flows in the heart chambers and blood vessels, and thereby propel blood appropriately as needed by whole body demands for oxygen and nutrients. As an aside, it should be noted that the term systolic pressure in the vascular system refers to the peak pressure reached during systole, not the mean pressure; similarly, the diastolic pressure refers to the lowest pressure during diastole.
CLINICAL BOX 30–1
Heart failure occurs when the heart is unable to put out an amount of blood that is adequate for the needs of the tissues. It can be acute and associated with sudden death, or chronic. The failure may involve primarily the right ventricle (cor pulmonale), but much more commonly it involves the larger, thicker left ventricle or both ventricles. Heart failure may also be systolic or diastolic. In systolic failure, stroke volume is reduced because ventricular contraction is weak. This causes an increase in the end-systolic ventricular volume, so that the ejection fraction falls from 65% to as low as 20%. The initial response to failure is activation of the genes that cause cardiac myocytes to hypertrophy, and thickening of the ventricular wall (cardiac remodeling). The incomplete filling of the arterial system leads to increased discharge of the sympathetic nervous system and increased secretion of renin and aldosterone, so Na+ and water are retained. These responses are initially compensatory, but eventually the failure worsens and the ventricles dilate.
In diastolic failure, the ejection fraction is initially maintained, but the elasticity of the myocardium is reduced so filling during diastole is reduced. This leads to inadequate stroke volume and the same cardiac remodeling and Na+and water retention that occur in systolic failure. It should be noted that the inadequate cardiac output in failure may be relative rather than absolute. When a large arteriovenous fistula is present, in thyrotoxicosis and in thiamine deficiency, cardiac output may be elevated in absolute terms but still be inadequate to meet the needs of the tissues (high-output failure).
Treatment of congestive heart failure is aimed at improving cardiac contractility, treating the symptoms, and decreasing the load on the heart. Currently, the most effective treatment in general use is inhibition of the production of angiotensin II with angiotensin-converting enzyme (ACE) inhibitors. Blockade of the effects of angiotensin II on AT1 receptors with nonpeptide antagonists is also of value. Blocking the production of angiotensin II or its effects also reduces the circulating aldosterone level and decreases blood pressure, reducing the afterload against which the heart pumps. The effects of aldosterone can be further reduced by administering aldosterone receptor blockers. Reducing venous tone with nitrates or hydralazine increases venous capacity so that the amount of blood returned to the heart is reduced, lowering the preload. Diuretics reduce the fluid overload. Drugs that block β-adrenergic receptors have been shown to decrease mortality and morbidity. Digitalis derivatives such as digoxin have classically been used to treat congestive heart failure because of their ability to increase stores of intracellular Ca2+ and hence exert a positive inotropic effect, but they are now used in a secondary role to treat systolic dysfunction and slow the ventricular rate in patients with atrial fibrillation.
MECHANICAL EVENTS OF THE CARDIAC CYCLE
EVENTS IN LATE DIASTOLE
Late in diastole, the mitral (bicuspid) and tricuspid valves between the atria and ventricles (atrioventricular [AV] valves) are open and the aortic and pulmonary valves are closed. Blood flows into the heart throughout diastole, filling the atria and ventricles. The rate of filling declines as the ventricles become distended, and, especially when the heart rate is low, the cusps of the AV valves drift toward the closed position (Figure 30–1). The pressure in the ventricles remains low. About 70% of the ventricular filling occurs passively during diastole.
FIGURE 30–1 Divisions of the cardiac cycle: A) systole and B) diastole. The phases of the cycle are identical in both halves of the heart. The direction in which the pressure difference favors flow is denoted by an arrow; note, however, that flow will not actually occur if avalve prevents it. AV, atrioventricular.
Contraction of the atria propels some additional blood into the ventricles. Contraction of the atrial muscle narrows the orifices of the superior and inferior vena cava and pulmonary veins, and the inertia of the blood moving toward the heart tends to keep blood in it. However, despite these inhibitory influences, there is some regurgitation of blood into the veins.
At the start of ventricular systole, the AV valves close. Ventricular muscle initially shortens relatively little, but intraventricular pressure rises sharply as the myocardium presses on the blood in the ventricle (Figure 30–2). This period of isovolumetric (isovolumic, isometric) ventricular contraction lasts about 0.05 s, until the pressures in the left and right ventricles exceed the pressures in the aorta (80 mm Hg; 10.6 kPa) and pulmonary artery (10 mm Hg) and the aortic and pulmonary valves open. During isovolumetric contraction, the AV valves bulge into the atria, causing a small but sharp rise in atrial pressure (Figure 30–3).
FIGURE 30–2 Normal pressure–volume loop of the left ventricle. During diastole, the ventricle fills and pressure increases from d to a. Pressure then rises sharply from a to b during isovolumetric contraction and from b to c during ventricular ejection. At c, the aortic valves close and pressure falls during isovolumetric relaxation from c back to d. (Reproduced with permission from McPhee SJ, Lingappa VR, Ganong WF [editors]: Pathophysiology of Disease, 6th ed. McGraw-Hill, 2010.)
FIGURE 30–3 Events of the cardiac cycle at a heart rate of 75 beats/min. The phases of the cardiac cycle identified by the numbers at the bottom are as follows: 1, atrial systole; 2, isovolumetric ventricular contraction; 3, ventricular ejection; 4, isovolumetric ventricular relaxation; 5, ventricular filling. Note that late in systole, aortic pressure actually exceeds left ventricular pressure. However, the momentum of the blood keeps it flowing out of the ventricle for a short period. The pressure relationships in the right ventricle and pulmonary artery are similar. Atr. syst., atrial systole; Ventric. syst., ventricular systole.
When the aortic and pulmonary valves open, the phase of ventricular ejection begins. Ejection is rapid at first, slowing down as systole progresses. The intraventricular pressure rises to a maximum and then declines somewhat before ventricular systole ends. Peak pressures in the left and right ventricles are about 120 and 25 mm Hg, respectively. Late in systole, pressure in the aorta actually exceeds that in the left ventricle, but for a short period momentum keeps the blood moving forward. The AV valves are pulled down by the contractions of the ventricular muscle, and atrial pressure drops. The amount of blood ejected by each ventricle per stroke at rest is 70–90 mL. The end-diastolic ventricular volume is about 130 mL. Thus, about 50 mL of blood remains in each ventricle at the end of systole (end-systolic ventricular volume), and the ejection fraction, the percentage of the end-diastolic ventricular volume that is ejected with each stroke, is about 65%. The ejection fraction is a valuable index of ventricular function. It can be measured by injecting radionuclide-labeled red blood cells and imaging the cardiac blood pool at the end of diastole and the end of systole (equilibrium radionuclide angiocardiography), or by computed tomography.
Once the ventricular muscle is fully contracted, the already falling ventricular pressures drop more rapidly. This is the period of protodiastole, which lasts about 0.04 s. It ends when the momentum of the ejected blood is overcome and the aortic and pulmonary valves close, setting up transient vibrations in the blood and blood vessel walls. After the valves are closed, pressure continues to drop rapidly during the period of isovolumetric ventricular relaxation.Isovolumetric relaxation ends when the ventricular pressure falls below the atrial pressure and the AV valves open, permitting the ventricles to fill. Filling is rapid at first, then slows as the next cardiac contraction approaches. Atrial pressure continues to rise after the end of ventricular systole until the AV valves open, then drops and slowly rises again until the next atrial systole.
Although events on the two sides of the heart are similar, they are somewhat asynchronous. Right atrial systole precedes left atrial systole, and contraction of the right ventricle starts after that of the left (see Chapter 29). However, since pulmonary arterial pressure is lower than aortic pressure, right ventricular ejection begins before that of the left. During expiration, the pulmonary and aortic valves close at the same time; but during inspiration, the aortic valve closes slightly before the pulmonary. The slower closure of the pulmonary valve is due to lower impedance of the pulmonary vascular tree. When measured over a period of minutes, the outputs of the two ventricles are, of course, equal, but transient differences in output during the respiratory cycle occur in normal individuals.
LENGTH OF SYSTOLE & DIASTOLE
Cardiac muscle has the unique property of contracting and repolarizing faster when the heart rate is high (see Chapter 5), and the duration of systole decreases from 0.27 s at a heart rate of 65 to–0.16 s at a rate of 200 beats/min (Table 30–1). The reduced time interval is mainly due to a decrease in the duration of systolic ejection. However, the duration of systole is much more fixed than that of diastole, and when the heart rate is increased, diastole is shortened to a much greater degree. For example, at a heart rate of 65, the duration of diastole is 0.62 s, whereas at a heart rate of 200, it is only 0.14 s. This fact has important physiologic and clinical implications. It is during diastole that the heart muscle rests, and coronary blood flow to the subendocardial portions of the left ventricle occurs only during diastole (see Chapter 33). Furthermore, most of the ventricular filling occurs in diastole. At heart rates up to about 180, filling is adequate as long as there is ample venous return, and cardiac output per minute is increased by an increase in rate. However, at very high heart rates, filling may be compromised to such a degree that cardiac output per minute falls.
TABLE 30–1 Variation in length of action potential and associated phenomena with cardiac rate.a
Because it has a prolonged action potential, cardiac muscle cannot contract in response to a second stimulus until near the end of the initial contraction (see Figure 5–15). Therefore, cardiac muscle cannot be tetanized like skeletal muscle. The highest rate at which the ventricles can contract is theoretically about 400/min, but in adults the AV node will not conduct more than about 230 impulses/min because of its long refractory period. A ventricular rate of more than 230 is seen only in paroxysmal ventricular tachycardia (see Chapter 29).
Exact measurement of the duration of isovolumetric ventricular contraction is difficult in clinical situations, but it is relatively easy to measure the duration of total electromechanical systole (QS2), the preejection period (PEP),and the left ventricular ejection time (LVET) by recording the ECG, phonocardiogram, and carotid pulse simultaneously. QS2 is the period from the onset of the QRS complex to the closure of the aortic valves, as determined by the onset of the second heart sound. LVET is the period from the beginning of the carotid pressure rise to the dicrotic notch (see below). PEP is the difference between QS2 and LVET and represents the time for the electrical as well as the mechanical events that precede systolic ejection. The ratio PEP/LVET is normally about 0.35, and it increases without a change in QS2 when left ventricular performance is compromised in a variety of cardiac diseases.
The blood forced into the aorta during systole not only moves the blood in the vessels forward but also sets up a pressure wave that travels along the arteries. The pressure wave expands the arterial walls as it travels, and the expansion is palpable as the pulse. The rate at which the wave travels, which is independent of and much higher than the velocity of blood flow, is about 4 m/s in the aorta, 8 m/s in the large arteries, and 16 m/s in the small arteries of young adults. Consequently, the pulse is felt in the radial artery at the wrist about 0.1 s after the peak of systolic ejection into the aorta (Figure 30–3). With advancing age, the arteries become more rigid, and the pulse wave moves faster.
The strength of the pulse is determined by the pulse pressure and bears little relation to the mean pressure. The pulse is weak (“thready”) in shock. It is strong when stroke volume is large; for example, during exercise or after the administration of histamine. When the pulse pressure is high, the pulse waves may be large enough to be felt or even heard by the individual (palpitation, “pounding heart”). When the aortic valve is incompetent (aortic insufficiency), the pulse is particularly strong, and the force of systolic ejection may be sufficient to make the head nod with each heartbeat. The pulse in aortic insufficiency is called a collapsing, Corrigan, or water-hammer pulse.
The dicrotic notch, a small oscillation on the falling phase of the pulse wave caused by vibrations set up when the aortic valve snaps shut (Figure 30–3), is visible if the pressure wave is recorded but is not palpable at the wrist. The pulmonary artery pressure curve also has a dicrotic notch produced by the closure of the pulmonary valves.
ATRIAL PRESSURE CHANGES & THE JUGULAR PULSE
Atrial pressure rises during atrial systole and continues to rise during isovolumetric ventricular contraction when the AV valves bulge into the atria. When the AV valves are pulled down by the contracting ventricular muscle, pressure falls rapidly and then rises as blood flows into the atria until the AV valves open early in diastole. The return of the AV valves to their relaxed position also contributes to this pressure rise by reducing atrial capacity. The atrial pressure changes are transmitted to the great veins, producing three characteristic waves in the record of jugular pressure (Figure 30–3). The a wave is due to atrial systole. As noted above, some blood regurgitates into the great veins when the atria contract. In addition, venous inflow stops, and the resultant rise in venous pressure contributes to the a wave. The c wave is the transmitted manifestation of the rise in atrial pressure produced by the bulging of the tricuspid valve into the atria during isovolumetric ventricular contraction. The v wave mirrors the rise in atrial pressure before the tricuspid valve opens during diastole. The jugular pulse waves are superimposed on the respiratory fluctuations in venous pressure. Venous pressure falls during inspiration as a result of the increased negative intrathoracic pressure and rises again during expiration.
Two sounds are normally heard through a stethoscope during each cardiac cycle. The first is a low, slightly prolonged “lub” (first sound), caused by vibrations set up by the sudden closure of the AV valves at the start of ventricular systole (Figure 30–3). The second is a shorter, high-pitched “dup” (second sound), caused by vibrations associated with closure of the aortic and pulmonary valves just after the end of ventricular systole. A soft, low-pitched third sound is heard about one third of the way through diastole in many normal young individuals. It coincides with the period of rapid ventricular filling and is probably due to vibrations set up by the inrush of blood. A fourth soundcan sometimes be heard immediately before the first sound when atrial pressure is high or the ventricle is stiff in conditions such as ventricular hypertrophy. It is due to ventricular filling and is rarely heard in normal adults.
The first sound has a duration of about 0.15 s and a frequency of 25–45 Hz. It is soft when the heart rate is low, because the ventricles are well filled with blood and the leaflets of the AV valves float together before systole. The second sound lasts about 0.12 s, with a frequency of 50 Hz. It is loud and sharp when the diastolic pressure in the aorta or pulmonary artery is elevated, causing the respective valves to shut briskly at the end of systole. The interval between aortic and pulmonary valve closure during inspiration is frequently long enough for the second sound to be reduplicated (physiologic splitting of the second sound). Splitting also occurs in various diseases. The third sound, when present, has a duration of 0.1 s.
Murmurs, or bruits, are abnormal sounds heard in various parts of the vascular system. The two terms are used interchangeably, though “murmur” is more commonly used to denote noise heard over the heart than over blood vessels. As discussed in detail in Chapter 31, blood flow is laminar, nonturbulent, and silent up to a critical velocity; above this velocity (such as beyond an obstruction), blood flow is turbulent and creates sounds. Blood flow speeds up when an artery or a heart valve is narrowed.
Examples of vascular sounds outside the heart are the bruit heard over a large, highly vascular goiter, the bruit heard over a carotid artery when its lumen is narrowed and distorted by atherosclerosis, and the murmurs heard over an aneurysmal dilation of one of the large arteries, an arteriovenous (A-V) fistula, or a patent ductus arteriosus.
The major—but certainly not the only—cause of cardiac murmurs is disease of the heart valves. When the orifice of a valve is narrowed (stenosis), blood flow through it is accelerated and turbulent. When a valve is incompetent, blood flows through it backward (regurgitation or insufficiency), again through a narrow orifice that accelerates flow. The timing (systolic or diastolic) of a murmur due to any particular valve (Table 30–2) can be predicted from a knowledge of the mechanical events of the cardiac cycle. Murmurs due to disease of a particular valve can generally be heard best when the stethoscope is directly over the valve. There are also other aspects of the duration, character, accentuation, and transmission of the sound that help to locate its origin in one valve or another. One of the loudest murmurs is that produced when blood flows backward in diastole through a hole in a cusp of the aortic valve. Most murmurs can be heard only with the aid of the stethoscope, but this high-pitched musical diastolic murmur is sometimes audible to the unaided ear several feet from the patient.
TABLE 30–2 Heart murmurs.
In patients with congenital interventricular septal defects, flow from the left to the right ventricle causes a systolic murmur. Soft murmurs may also be heard in patients with interatrial septal defects, although they are not a constant finding.
Soft systolic murmurs are also common in individuals, especially children, who have no cardiac disease. Systolic murmurs are also heard in anemic patients as a result of the low viscosity of the blood and associated rapid flow (see Chapter 31).
Wall movement and other aspects of cardiac function can be evaluated by the noninvasive technique of echocardiography. Pulses of ultrasonic waves are emitted from a transducer that also functions as a receiver to detect waves reflected back from various parts of the heart. Reflections occur wherever acoustic impedance changes, and a recording of the echoes displayed against time on an oscilloscope provides a record of the movements of the ventricular wall, septum, and valves during the cardiac cycle. When combined with Doppler techniques, echocardiography can be used to measure velocity and volume of flow through valves. It has considerable clinical usefulness, particularly in evaluating and planning therapy in patients with valvular lesions.
METHODS OF MEASUREMENT
In experimental animals, cardiac output can be measured with an electromagnetic flow meter placed on the ascending aorta. Two methods of measuring output that are applicable to humans, in addition to Doppler combined with echocardiography, are the direct Fick method and the indicator dilution method.
The Fick principle states that the amount of a substance taken up by an organ (or by the whole body) per unit of time is equal to the arterial level of the substance minus the venous level (A-V difference) times the blood flow. This principle can be applied, of course, only in situations in which the arterial blood is the sole source of the substance taken up. The principle can be used to determine cardiac output by measuring the amount of O2 consumed by the body in a given period and dividing this value by the A-V difference across the lungs. Because systemic arterial blood has effectively the same O2 content in all parts of the body, the arterial O2 content can be measured in a sample obtained from any convenient artery. A sample of venous blood in the pulmonary artery is obtained by means of a cardiac catheter. It has now become commonplace to insert a long catheter through a forearm vein and to guide its tip into the heart with the aid of a fluoroscope. The procedure is generally benign. Catheters can be inserted through the right atrium and ventricle into the small branches of the pulmonary artery. An example of the calculation of cardiac output using a typical set of values is as follows:
In the indicator dilution technique, a known amount of a substance such as a dye or, more commonly, a radioactive isotope is injected into an arm vein and the concentration of the indicator in serial samples of arterial blood is determined. The output of the heart is equal to the amount of indicator injected divided by its average concentration in arterial blood after a single circulation through the heart (Figure 30–4). The indicator must, of course, be a substance that stays in the bloodstream during the test and has no harmful or hemodynamic effects. In practice, the log of the indicator concentration in the serial arterial samples is plotted against time as the concentration rises, falls, and then rises again as the indicator recirculates. The initial decline in concentration, linear on a semilog plot, is extrapolated to the abscissa, giving the time for first passage of the indicator through the circulation. The cardiac output for that period is calculated (Figure 30–4) and then converted to output per minute.
FIGURE 30–4 Determination of cardiac output by indicator (dye) dilution. Two examples are shown—at rest and during exercise.
A popular indicator dilution technique is thermodilution, in which the indicator used is cold saline. The saline is injected into the right atrium through one channel of a double-lumen catheter, and the temperature change in the blood is recorded in the pulmonary artery, using a thermistor in the other, longer side of the catheter. The temperature change is inversely proportional to the amount of blood flowing through the pulmonary artery; that is, to the extent that the cold saline is diluted by blood. This technique has two important advantages: (1) the saline is completely innocuous; and (2) the cold is dissipated in the tissues so recirculation is not a problem, and it is easy to make repeated determinations.
CARDIAC OUTPUT IN VARIOUS CONDITIONS
The amount of blood pumped out of the heart per beat, the stroke volume, is about 70 mL from each ventricle in a resting man of average size in the supine position. The output of the heart per unit of time is the cardiac output. In a resting, supine man, it averages about 5.0 L/min (70 mL × 72 beats/min). There is a correlation between resting cardiac output and body surface area. The output per minute per square meter of body surface (the cardiac index) averages 3.2 L. The effects of various conditions on cardiac output are summarized in Table 30–3.
TABLE 30–3 Effect of various conditions on cardiac output.
FACTORS CONTROLLING CARDIAC OUTPUT
Predictably, changes in cardiac output that are called for by physiologic conditions can be produced by changes in cardiac rate, or stroke volume, or both (Figure 30–5). The cardiac rate is controlled primarily by the autonomic nerves, with sympathetic stimulation increasing the rate and parasympathetic stimulation decreasing it (see Chapter 29). Stroke volume is also determined in part by neural input, with sympathetic stimuli making the myocardial muscle fibers contract with greater strength at any given length and parasympathetic stimuli having the opposite effect. When the strength of contraction increases without an increase in fiber length, more of the blood that normally remains in the ventricles is expelled; that is, the ejection fraction increases. The cardiac accelerator action of the catecholamines liberated by sympathetic stimulation is referred to as their chronotropic action, whereas their effect on the strength of cardiac contraction is called their inotropic action.
FIGURE 30–5 Interactions between the components that regulate cardiac output and arterial pressure. Solid arrows indicate increases, and the dashed arrow indicates a decrease.
The force of contraction of cardiac muscle depends on its preloading and its afterloading. These factors are illustrated in Figure 30–6, in which a muscle strip is stretched by a load (the preload) that rests on a platform. The initial phase of the contraction is isometric; the elastic component in series with the contractile element is stretched, and tension increases until it is sufficient to lift the load. The tension at which the load is lifted is the afterload. The muscle then contracts isotonically without developing further tension. In vivo, the preload is the degree to which the myocardium is stretched before it contracts and the afterload is the resistance against which blood is expelled.
FIGURE 30–6 Model for contraction of afterloaded muscles. A) Rest. B) Partial contraction of the contractile element of the muscle (CE), with stretching of the series elastic element (SE) but no shortening. C) Complete contraction, with shortening. (Reproduced with permission from Sonnenblick EH: The Myocardial Cell: Structure, Function and Modification. Briller SA, Conn HL [editors]. University Pennsylvania Press, 1966.)
RELATION OF TENSION TO LENGTH IN CARDIAC MUSCLE
The length–tension relationship in cardiac muscle (see Figure 5–17) is similar to that in skeletal muscle (see Figure 5–11); when the muscle is stretched, the developed tension increases to a maximum and then declines as stretch becomes more extreme. Starling pointed this out when he stated that the “energy of contraction is proportional to the initial length of the cardiac muscle fiber” (Starling’s law of the heart or the Frank–Starling law). For the heart, the length of the muscle fibers (ie, the extent of the preload) is proportional to the end-diastolic volume. The relation between ventricular stroke volume and end-diastolic volume is called the Frank–Starling curve.
When cardiac output is regulated by changes in cardiac muscle fiber length, this is referred to as heterometric regulation. Conversely, regulation due to changes in contractility independent of length is sometimes called homometric regulation.
FACTORS AFFECTING END-DIASTOLIC VOLUME
Alterations in systolic and diastolic function have different effects on the heart. When systolic contractions are reduced, there is a primary reduction in stroke volume. Diastolic function also affects stroke volume, but in a different way.
The myocardium is covered by a fibrous layer known as the epicardium. This, in turn, is surrounded by the pericardium, which separates the heart from the rest of the thoracic viscera. The space between the epicardium and pericardium (the pericardial sac) normally contains 5–30 mL of clear fluid, which lubricates the heart and permits it to contract with minimal friction.
An increase in intrapericardial pressure (eg, as a result of infection or pressure from a tumor) limits the extent to which the ventricle can fill, as does a decrease in ventricular compliance; that is, an increase in ventricular stiffness produced by myocardial infarction, infiltrative disease, and other abnormalities. Atrial contractions aid ventricular filling. Factors affecting the amount of blood returning to the heart likewise influence the degree of cardiac filling during diastole. An increase in total blood volume increases venous return (Clinical Box 30–2). Constriction of the veins reduces the size of the venous reservoirs, decreasing venous pooling and thus increasing venous return. An increase in the normal negative intrathoracic pressure increases the pressure gradient along which blood flows to the heart, whereas a decrease impedes venous return. Standing decreases venous return, and muscular activity increases it as a result of the pumping action of skeletal muscle.
CLINICAL BOX 30–2
Circulatory shock comprises a collection of different entities that share certain common features; however, the feature that is common to all the entities is inadequate tissue perfusion with a relatively or absolutely inadequate cardiac output. The cardiac output may be inadequate because the amount of fluid in the vascular system is inadequate to fill it (hypovolemic shock). Alternatively, it may be inadequate in the relative sense because the size of the vascular system is increased by vasodilation even though the blood volume is normal (distributive, vasogenic, or low-resistance shock). Shock may also be caused by inadequate pumping action of the heart as a result of myocardial abnormalities (cardiogenic shock), and by inadequate cardiac output as a result of obstruction of blood flow in the lungs or heart (obstructive shock).
Hypovolemic shock is also called “cold shock.” It is characterized by hypotension; a rapid, thready pulse; cold, pale, clammy skin; intense thirst; rapid respiration; and restlessness or, alternatively, torpor. None of these findings, however, are invariably present. Hypovolemic shock is commonly subdivided into categories on the basis of cause. Of these, it is useful to consider the effects of hemorrhage in some detail because of the multiple compensatory reactions that come into play to defend extracellular fluid (ECF) volume. Thus, the decline in blood volume produced by bleeding decreases venous return, and cardiac output falls. The heart rate is increased, and with severe hemorrhage, a fall in blood pressure always occurs. With moderate hemorrhage (5–15 mL/kg body weight), pulse pressure is reduced but mean arterial pressure may be normal. The blood pressure changes vary from individual to individual, even when exactly the same amount of blood is lost. The skin is cool and pale and may have a grayish tinge because of stasis in the capillaries and a small amount of cyanosis. Inadequate perfusion of the tissues leads to increased anaerobic glycolysis, with the production of large amounts of lactic acid. In severe cases, the blood lactate level rises from the normal value of about 1 mmol/L to 9 mmol/L or more. The resulting lactic acidosis depresses the myocardium, decreases peripheral vascular responsiveness to catecholamines, and may be severe enough to cause coma. When blood volume is reduced and venous return is decreased, moreover, stimulation of arterial baroreceptors is reduced, increasing sympathetic output. Even if there is no drop in mean arterial pressure, the decrease in pulse pressure decreases the rate of discharge in the arterial baroreceptors, and reflex tachycardia and vasoconstriction result.
With more severe blood loss, tachycardia is replaced by bradycardia; this occurs while shock is still reversible. The bradycardia is presumably due to unmasking a vagally mediated depressor reflex, and the response may have evolved as a mechanism for stopping further blood loss. With even greater hemorrhage, the heart rate rises again. Vasoconstriction is generalized, sparing only the vessels of the brain and heart. A widespread reflex venoconstriction also helps maintain the filling pressure of the heart. In the kidneys, both afferent and efferent arterioles are constricted, but the efferent vessels are constricted to a greater degree. The glomerular filtration rate is depressed, but renal plasma flow is decreased to a greater extent, so that the filtration fraction increases. Na+ retention is marked, and the nitrogenous products of metabolism are retained in the blood (azotemia or uremia). If the hypotension is prolonged, renal tubular damage may be severe (acute renal failure). After a moderate hemorrhage, the circulating plasma volume is restored in 12–72 h. Preformed albumin also enters rapidly from extravascular stores, but most of the tissue fluids that are mobilized are protein-free. After the initial influx of preformed albumin, the rest of the plasma protein losses are replaced, presumably by hepatic synthesis, over a period of 3–4 days. Erythropoietin appears in the circulation, and the reticulocyte count increases, reaching a peak in 10 days. The red cell mass is restored to normal in 4–8 weeks.
The treatment of shock is aimed at correcting the cause and helping the physiologic compensatory mechanisms to restore an adequate level of tissue perfusion. If the primary cause of the shock is blood loss, the treatment should include early and rapid transfusion of adequate amounts of compatible whole blood. In shock due to burns and other conditions in which there is hemoconcentration, plasma is the treatment of choice to restore the fundamental defect, the loss of plasma. Concentrated human serum albumin and other hypertonic solutions expand the blood volume by drawing fluid out of the interstitial spaces. They are valuable in emergency treatment but have the disadvantage of further dehydrating the tissues of an already dehydrated patient.
The effects of systolic and diastolic dysfunction on the pressure–volume loop of the left ventricle are summarized in Figure 30–7.
FIGURE 30–7 Effect of systolic and diastolic dysfunction on the pressure–volume loop of the left ventricle. In both panels, the solid lines represents the normal pressure–volume loop (equivalent to that shown in Figure 30–2 and the dashed lines show how the loop is shifted by the disease process represented. Left: Systolic dysfunction shifts the isovolumic pressure–volume curve to the right, decreasing the stroke volume from b–c to b’–c’. Right: Diastolic dysfunction increases end-diastolic volume and shifts the diastolic pressure–volume relationship upward and to the left. This reduces the stroke volume from b–c to b’–c’. (Reproduced with permission from McPhee SJ, Lingappa VR, Ganong WF [editors]: Pathophysiology of Disease, 6th ed. McGraw-Hill, 2010.)
The contractility of the myocardium exerts a major influence on stroke volume. When the sympathetic nerves to the heart are stimulated, the whole length–tension curve shifts upward and to the left (Figure 30–8). The positive inotropic effect of norepinephrine liberated at the nerve endings is augmented by circulating norepinephrine, and epinephrine has a similar effect. Conversely, there is a negative inotropic effect of vagal stimulation on both atrial and (to a lesser extent) ventricular muscle.
FIGURE 30–8 Effect of changes in myocardial contractility on the Frank–Starling curve. The curve shifts downward and to the right as contractility is decreased. The major factors influencing contractility are summarized on the right. The dashed lines indicate portions of the ventricular function curves where maximum contractility has been exceeded; that is, they identify points on the “descending limb” of the Frank–Starling curve. EDV, end-diastolic volume. (Reproduced with permission from Braunwald E, Ross J, Sonnenblick EH: Mechanisms of contraction of the normal and failing heart. N Engl J Med 1967;277:794.)
Changes in cardiac rate and rhythm also affect myocardial contractility (known as the force–frequency relation, Figure 30–8). Ventricular extrasystoles condition the myocardium in such a way that the next succeeding contraction is stronger than the preceding normal contraction. This postextrasystolic potentiation is independent of ventricular filling, since it occurs in isolated cardiac muscle and is due to increased availability of intracellular Ca2+. A sustained increment in contractility can be produced therapeutically by delivering paired electrical stimuli to the heart in such a way that the second stimulus is delivered shortly after the refractory period of the first. It has also been shown that myocardial contractility increases as the heart rate increases, although this effect is relatively small.
Catecholamines exert their inotropic effect via an action on cardiac β1-adrenergic receptors and Gs, with resultant activation of adenylyl cyclase and increased intracellular cyclic adenosine 3′,5′-monophosphate (cAMP). Xanthines such as caffeine and theophylline that inhibit the breakdown of cAMP are predictably positively inotropic. The positively inotropic effect of digitalis and related drugs (Figure 30–8), on the other hand, is due to their inhibitory effect on the Na+–K ATPase in the myocardium, and a subsequent decrease in calcium removal from the cytosol by Na+/Ca2+ exchange (see Chapter 5). Hypercapnia, hypoxia, acidosis, and drugs such as quinidine, procainamide, and barbiturates depress myocardial contractility. The contractility of the myocardium is also reduced in heart failure (intrinsic depression). The causes of this depression are not fully understood, but may reflect down-regulation of β-adrenergic receptors and associated signaling pathways and impaired calcium liberation from the sarcoplasmic reticulum. In acute heart failure, such as that associated with sepsis, this response could be considered an appropriate adaptation (so-called “myocardial hibernation”) to a situation where energy supply to the heart is limited, thereby reducing energy expenditure and avoiding cell death.
INTEGRATED CONTROL OF CARDIAC OUTPUT
The mechanisms listed above operate in an integrated way to maintain cardiac output. For example, during muscular exercise, there is increased sympathetic discharge, so that myocardial contractility is increased and the heart rate rises. The increase in heart rate is particularly prominent in normal individuals, and there is only a modest increase in stroke volume (see Table 30–4 and Clinical Box 30–3). However, patients with transplanted hearts are able to increase their cardiac output during exercise in the absence of cardiac innervation through the operation of the Frank–Starling mechanism (Figure 30–9). Circulating catecholamines also contribute. If venous return increases and there is no change in sympathetic tone, venous pressure rises, diastolic inflow is greater, ventricular end-diastolic pressure increases, and the heart muscle contracts more forcefully. During muscular exercise, venous return is increased by the pumping action of the muscles and the increase in respiration (see Chapter 32). In addition, because of vasodilation in the contracting muscles, peripheral resistance and, consequently, afterload are decreased. The end result in both normal and transplanted hearts is thus a prompt and marked increase in cardiac output.
TABLE 30–4 Changes in cardiac function with exercise. Note that stroke volume levels off, then falls somewhat (as a result of the shortening of diastole) when the heart rate rises to high values.
CLINICAL BOX 30–3
Circulatory Changes during Exercise
The blood flow of resting skeletal muscle is low (2–4 mL/100 g/min). When a muscle contracts, it compresses the vessels in it if it develops more than 10% of its maximal tension; when it develops more than 70% of its maximal tension, blood flow is completely stopped. Between contractions, however, flow is so greatly increased that blood flow per unit of time in a rhythmically contracting muscle is increased as much as 30-fold. Local mechanisms maintaining a high blood flow in exercising muscle include a fall in tissue PO2, a rise in tissue PCO2, and accumulation of K+ and other vasodilator metabolites. The temperature rises in active muscle, and this further dilates the vessels. Dilation of the arterioles and precapillary sphincters causes a 10- to 100-fold increase in the number of open capillaries. The average distance between the blood and the active cells—and the distance O2 and metabolic products must diffuse—is thus greatly decreased. The dilation increases the cross-sectional area of the vascular bed, and the velocity of flow therefore decreases.
The systemic cardiovascular response to exercise that provides for the additional blood flow to contracting muscle depends on whether the muscle contractions are primarily isometric or primarily isotonic with the performance of external work. With the start of an isometric muscle contraction, the heart rate rises, probably as a result of psychic stimuli acting on the medulla oblongata. The increase is largely due to decreased vagal tone, although increased discharge of the cardiac sympathetic nerves plays some role. Within a few seconds of the onset of an isometric muscle contraction, systolic and diastolic blood pressures rise sharply. Stroke volume changes relatively little, and blood flow to the steadily contracting muscles is reduced as a result of compression of their blood vessels. The response to exercise involving isotonic muscle contraction is similar in that there is a prompt increase in heart rate, but different in that a marked increase in stroke volume occurs. In addition, there is a net fall in total peripheral resistance due to vasodilation in exercising muscles. Consequently, systolic blood pressure rises only moderately, whereas diastolic pressure usually remains unchanged or falls.
The difference in response to isometric and isotonic exercise is explained in part by the fact that the active muscles are tonically contracted during isometric exercise and consequently contribute to increased total peripheral resistance. Cardiac output is increased during isotonic exercise to values that may exceed 35 L/min, the amount being proportional to the increase in O2 consumption. The maximal heart rate achieved during exercise decreases with age. In children, it rises to 200 or more beats/min; in adults it rarely exceeds 195 beats/min, and in elderly individuals the rise is even smaller. Both at rest and at any given level of exercise, trained athletes have a larger stroke volume and lower heart rate than untrained individuals and they tend to have larger hearts. Training increases the maximal oxygen consumption (VO2max) that can be produced by exercise in an individual. VO2max averages about 38 mL/kg/min in active healthy men and about 29 mL/kg/min in active healthy women. It is lower in sedentary individuals. VO2max is the product of maximal cardiac output and maximal O2 extraction by the tissues, and both increase with training.
A great increase in venous return also takes place with exercise, although the increase in venous return is not the primary cause of the increase in cardiac output. Venous return is increased by the activity of the muscle and thoracic pumps; by mobilization of blood from the viscera; by increased pressure transmitted through the dilated arterioles to the veins; and by noradrenergically mediated venoconstriction, which decreases the volume of blood in the veins. Blood mobilized from the splanchnic area and other reservoirs may increase the amount of blood in the arterial portion of the circulation by as much as 30% during strenuous exercise. After exercise, the blood pressure may transiently drop to subnormal levels, presumably because accumulated metabolites keep the muscle vessels dilated for a short period. However, the blood pressure soon returns to the preexercise level. The heart rate returns to normal more slowly.
FIGURE 30–9 Cardiac responses to moderate supine exercise in normal humans and patients with transplanted and hence denervated hearts. Note that the transplanted heart, without the benefit of neural input, relies primarily on an increase in stroke volume rather than heart rate to raise cardiac output in the setting of exercise. (Reproduced with permission from Kent KM, Cooper T: The denervated heart. N Engl J Med 1974;291:1017.)
One of the differences between untrained individuals and trained athletes is that the athletes have lower heart rates, greater end-systolic ventricular volumes, and greater stroke volumes at rest. Therefore, they can potentially achieve a given increase in cardiac output by further increases in stroke volume without increasing their heart rate to as great a degree as an untrained individual.
OXYGEN CONSUMPTION BY THE HEART
Basal O2 consumption by the myocardium is about 2 mL/100 g/min. This value is considerably higher than that of resting skeletal muscle. O2 consumption by the beating heart is about 9 mL/100 g/min at rest. Increases occur during exercise and in a number of different states. Cardiac venous O2 tension is low, and little additional O2 can be extracted from the blood in the coronaries, so increases in O2 consumption require increases in coronary blood flow. The regulation of coronary flow is discussed in Chapter 33.
O2 consumption by the heart is determined primarily by the intramyocardial tension, the contractile state of the myocardium, and the heart rate. Ventricular work per beat correlates with O2 consumption. The work is the product of stroke volume and mean arterial pressure in the pulmonary artery or the aorta (for the right and left ventricle, respectively). Because aortic pressure is seven times greater than pulmonary artery pressure, the stroke work of the left ventricle is approximately seven times the stroke work of the right. In theory, a 25% increase in stroke volume without a change in arterial pressure should produce the same increase in O2 consumption as a 25% increase in arterial pressure without a change in stroke volume. However, for reasons that are incompletely understood, pressure work produces a greater increase in O2 consumption than volume work. In other words, an increase in afterload causes a greater increase in cardiac O2 consumption than does an increase in preload. This is why angina pectoris due to deficient delivery of O2 to the myocardium is more common in aortic stenosis than in aortic insufficiency. In aortic stenosis, intraventricular pressure must be increased to force blood through the stenotic valve, whereas in aortic insufficiency, regurgitation of blood produces an increase in stroke volume with little change in aortic impedance.
It is worth noting that the increase in O2 consumption produced by increased stroke volume when the myocardial fibers are stretched is an example of the operation of the law of Laplace. This law, which is discussed in detail in Chapter 31, states that the tension developed in the wall of a hollow viscus is proportional to the radius of the viscus. When the heart is dilated, its radius is increased. O2 consumption per unit time increases when the heart rate is increased by sympathetic stimulation because of the increased number of beats and the increased velocity and strength of each contraction. However, this is somewhat offset by the decrease in end-systolic volume and hence in the radius of the heart.
Blood flows into the atria and then the ventricles of the heart during diastole and atrial systole, and is ejected during systole when the ventricles contract and pressure exceeds the pressures in the pulmonary artery and aorta.
Careful timing of the opening and closing of the atrioventricular (AV), pulmonary, and aortic valves allows blood to move in an appropriate direction through the heart with minimal regurgitation.
The proportion of blood leaving the ventricles in each cardiac cycle is called the ejection fraction and is a sensitive indicator of cardiac health.
The arterial pulse represents a pressure wave set up when blood is forced into the aorta; it travels much faster than the blood itself.
Heart sounds reflect the normal vibrations set up by abrupt valve closures; heart murmurs can arise from abnormal flow often (although not exclusively) caused by diseased valves.
Changes in cardiac output reflect variations in heart rate, stroke volume, or both; these are controlled, in turn, by neural and hormonal input to cardiac myocytes.
Cardiac output is strikingly increased during exercise.
In heart failure, the ejection fraction of the heart is reduced due to impaired contractility in systole or reduced filling during diastole; this results in inadequate blood supplies to meet the body’s needs. Initially, this is manifested only during exercise, but eventually the heart will not be able to supply sufficient blood flow even at rest.
For all questions, select the single best answer unless otherwise directed.
1. The second heart sound is caused by
A. closure of the aortic and pulmonary valves.
B. vibrations in the ventricular wall during systole.
C. ventricular filling.
D. closure of the mitral and tricuspid valves.
E. retrograde flow in the vena cava.
2. The fourth heart sound is caused by
A. closure of the aortic and pulmonary valves.
B. vibrations in the ventricular wall during systole.
C. ventricular filling.
D. closure of the mitral and tricuspid valves.
E. retrograde flow in the vena cava.
3. The dicrotic notch on the aortic pressure curve is caused by
A. closure of the mitral valve.
B. closure of the tricuspid valve.
C. closure of the aortic valve.
D. closure of the pulmonary valve.
E. rapid filling of the left ventricle.
4. During exercise, a man consumes 1.8 L of oxygen per minute. His arterial O2 content is 190 mL/L, and the O2 content of his mixed venous blood is 134 mL/L. His cardiac output is approximately
A. 3.2 L/min.
B. 16 L/min.
C. 32 L/min.
D. 54 L/min.
E. 160 mL/min.
5. The work performed by the left ventricle is substantially greater than that performed by the right ventricle, because in the left ventricle
A. the contraction is slower.
B. the wall is thicker.
C. the stroke volume is greater.
D. the preload is greater.
E. the afterload is greater.
6. Starling’s law of the heart
A. does not operate in the failing heart.
B. does not operate during exercise.
C. explains the increase in heart rate produced by exercise.
D. explains the increase in cardiac output that occurs when venous return is increased.
E. explains the increase in cardiac output when the sympathetic nerves supplying the heart are stimulated.
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