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’s method and the indicator dilution method.
The Fick’s 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.
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 30–3Effect of various conditions on cardiac output. ||Download (.pdf) TABLE 30–3 Effect of various conditions on cardiac output.
| ||Condition or Factora |
|No change ||Sleep |
| ||Moderate changes in environmental temperature |
|Increase ||Anxiety and excitement (50–100%) |
| ||Eating (30%) |
| ||Exercise (up to 700%) |
| ||High environmental temperature |
| ||Pregnancy |
| ||Epinephrine |
|Decrease ||Sitting or standing from lying position (20–30%) |
| ||Rapid arrhythmias |
| ||Heart disease |
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.
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.
Model for contraction of afterloaded muscles. The figure depicts isotonic and afterloaded contractions within the constraints of the cardiac muscle length–tension diagram. The numbered points on the diagram correspond to the various conditions shown in the upper part. (Adapted with permission from Mohrman DE, Heller LJ: Cardiovascular Physiology, 8th ed. New York, NY: McGraw-Hill; 2014.)
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 5–10); 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 (ie, 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.
The effects of systolic and diastolic dysfunction on the pressure-volume loop of the left ventricle are summarized in 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. New York, NY: 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.
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; Oct 12; 277(15):794–800.)
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.
CLINICAL BOX 30–2 Shock
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 kidney injury). 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. THERAPUETIC HIGHLIGHTS
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.
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 30–4Changes 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. ||Download (.pdf) 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.
|Work (kg-m/min) ||O2 Usage (mL/min) ||Pulse Rate (per min) ||Cardiac Output (L/min) ||Stroke Volume (mL) ||A-V O2 Difference (mL/dL) |
|Rest ||267 ||64 ||6.4 ||100 ||4.3 |
|288 ||910 ||104 ||13.1 ||126 ||7.0 |
|540 ||1430 ||122 ||15.2 ||125 ||9.4 |
|900 ||2143 ||161 ||17.8 ||110 ||12.3 |
|1260 ||3007 ||173 ||20.9 ||120 ||14.5 |
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; Nov7; 291(19):1017–1021.)
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 regurgitation. In aortic stenosis, intraventricular pressure must be increased to force blood through the stenotic valve, whereas in aortic regurgitation, an increase in stroke volume with little change in aortic impedance occurs.
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 (V·O2max) that can be produced by exercise in an individual. V·O2max 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. V·O2max 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.
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.