CHAPTER 18 Regulation of the Heart and Vasculature

REGULATION OF HEART RATE AND CONTRACTILITY

Cardiac output is defined as the quantity of blood pumped by the heart each minute. Cardiac output may be varied by changing the heart rate or the volume of blood ejected from either ventricle with each heartbeat; this volume is called the stroke volume. Mathematically, cardiac output (CO) can be expressed as the product of heart rate (HR) and stroke volume (SV):

Equation 18-1

Thus, understanding how cardiac activity is controlled can be gained by considering how the heart rate and stroke volume are regulated. Heart rate is regulated by the activity of the cardiac pacemaker, and stroke volume is directly related to myocardial performance. These two determinants are interdependent because a change in one determinant of cardiac output almost invariably alters the other determinant.

NERVOUS CONTROL OF THE HEART RATE

Although certain local factors, such as temperature changes and stretching of tissue, can affect the heart rate, the autonomic nervous system is the principal means by which the heart rate is controlled.

The average resting heart rate is about 70 beats/min in normal adults, and it is significantly greater in children. During sleep the heart rate decelerates by 10 to 20 beats/min, and during emotional excitement or muscular activity it may accelerate to rates well above 100. In well-trained athletes the resting rate is usually only about 50 beats/min.

Both divisions of the autonomic nervous system tonically influence the cardiac pacemaker, which is normally the sinoatrial (SA) node. The sympathetic system enhances automaticity, whereas the parasympathetic system inhibits it. Changes in heart rate usually involve a reciprocal action of these two divisions of the autonomic nervous system. Thus, the heart rate ordinarily increases with a combined decrease in parasympathetic activity and increase in sympathetic activity; the heart rate decreases with the opposite changes in autonomic neural activity.

Parasympathetic tone usually predominates in healthy, resting individuals. When a resting individual is given atropine, a muscarinic receptor antagonist that blocks parasympathetic effects, the heart rate generally increases substantially. If a resting individual is given propranolol, a β-adrenergic receptor antagonist that blocks sympathetic effects, the heart rate usually decreases only slightly (Fig. 18-1). When both divisions of the autonomic nervous system are blocked, the heart rate of young adults averages about 100 beats/min. The rate that prevails after complete autonomic blockade is called the intrinsic heart rate.

Figure 18-1 Effects of four equal doses of atropine (muscarinic receptor antagonist that blocks parasympathetic effects) and propranolol (β-adrenergic receptor antagonist that blocks sympathetic effects) on the heart rate of 10 healthy young men. In half of the trials, atropine was given first (top curve); in the other half, propranolol was given first (bottom curve).

(Redrawn from Katona PG et al: J Appl Physiol 52:1652, 1982.)

Parasympathetic Pathways

The cardiac parasympathetic fibers originate in the medulla oblongata, in cells that lie in the dorsal motor nucleus of the vagus or in the nucleus ambiguus (see Chapter 11). The precise location of the parasympathetic fibers varies among species. In humans, centrifugal vagal fibers pass inferiorly through the neck near the common carotid arteries and then through the mediastinum to synapse with postganglionic vagal cells. These cells are located either on the epicardial surface or within the walls of the heart. Most of the vagal ganglion cells are located in epicardial fat pads near the SA and atrioventicular (AV) nodes.

The right and left vagi are distributed to different cardiac structures. The right vagus nerve affects the SA node predominantly; stimulation of this nerve slows SA nodal firing and can even stop the firing for several seconds. The left vagus nerve mainly inhibits AV conduction tissue to produce various degrees of AV block (see Chapter 16). However, the distribution of the efferent vagal fibers is overlapping such that left vagal stimulation also depresses the SA node and right vagal stimulation impedes AV conduction.

The SA and AV nodes are rich in cholinesterase, an enzyme that rapidly hydrolyzes the neurotransmitter acetylcholine (ACh). The effects of a given vagal stimulus decay very quickly (Fig. 18-2, A) when vagal stimulation is discontinued because ACh is rapidly destroyed. In addition, vagal effects on SA and AV nodal function have a very short latency (≈50 to 100 msec) because the ACh released quickly activates special AChregulated K⁺ channels (K_ACh) in the cardiac cells. These channels open quickly because the muscarinic receptor is coupled directly to the K_ACh channel by a guanine nucleotide–binding protein (G_i). These two features of the vagus nerves—brief latency and rapid decay of the response—permit them to exert beat-by-beat control of SA and AV nodal function.

Figure 18-2 Changes in heart rate evoked by stimulation (horizontal bars) of the vagus (A) and sympathetic nerves (B).

(Modified from Warner HR, Cox A: J Appl Physiol 17:349, 1962.)

Parasympathetic influences usually predominate over sympathetic effects at the SA node, as shown in Figure 18-3. When the frequency of sympathetic stimulation increases from 0 to 4 Hz, the heart rate increases by about 80 beats/min in the absence of vagal stimulation (Vag = 0 Hz). However, when the vagi are stimulated at 8 Hz, increasing the sympathetic stimulation frequency from 0 to 4 Hz has only a negligible influence on heart rate.

Figure 18-3 Changes in heart rate when the vagus and cardiac sympathetic nerves are stimulated simultaneously. The sympathetic nerves are stimulated at 0, 2, and 4 Hz and the vagus nerves at 0, 4, and 8 Hz.

(Modified from Levy MN, Zieske H: J Appl Physiol 27:465, 1969.)

Sympathetic Pathways

The cardiac sympathetic fibers originate in the intermediolateral columns of the upper five or six thoracic and lower one or two cervical segments of the spinal cord (see Chapter 11). These fibers emerge from the spinal column through the white communicating branches and enter the paravertebral chains of ganglia. The preganglionic and postganglionic neurons synapse mainly in the stellate or middle cervical ganglia, depending on the species. In the mediastinum, the postganglionic and preganglionic parasympathetic fibers join to form a complicated plexus of mixed efferent nerves to the heart.

The postganglionic cardiac sympathetic fibers in this plexus approach the base of the heart along the adventitial surface of the great vessels. From the base of the heart, these fibers are distributed to the various chambers as an extensive epicardial plexus. They then penetrate the myocardium, usually accompanying the coronary vessels.

In contrast to abrupt termination of the response after vagal activity, the effects of sympathetic stimulation decay gradually after stimulation is stopped (Fig. 18-2, B). Nerve terminals take up to 70% of the norepinephrine released during sympathetic stimulation; much of the remainder is carried away by the bloodstream. These processes are slow. Furthermore, the facilitatory effects of sympathetic stimulation on the heart attain steady-state values much more slowly than do the inhibitory effects of vagal stimulation. The onset of the cardiac response to sympathetic stimulation begins slowly for two main reasons. First, norepinephrine appears to be released slowly from the sympathetic nerve terminals. Second, the cardiac effects of the neurally released norepinephrine are mediated mainly by a relatively slow second messenger system involving cAMP (see Chapter 3). Hence, sympathetic activity alters the heart rate and AV conduction much more slowly than vagal activity does. Although vagal activity can exert beat-by-beat control of cardiac function, sympathetic activity cannot.

Control by Higher Centers

Stimulation of various brain regions can have significant effects on cardiac rate, rhythm, and contractility (see Chapter 11). In the cerebral cortex, centers that regulate cardiac function are located in the anterior half of the brain, principally in the frontal lobe, the orbital cortex, the motor and premotor cortex, the anterior portion of the temporal lobe, the insula, and the cingulate gyrus. Stimulation of the midline, ventral, and medial nuclei of the thalamus elicits tachycardia. Stimulation of the posterior and posterolateral regions of the hypothalamus can also change the heart rate. Stimuli applied to the H2 fields of Forel in the diencephalon evoke various cardiovascular responses, including tachycardia; these changes resemble those observed during muscular exercise. Undoubtedly, the cortical and diencephalic centers initiate the cardiac reactions that occur during excitement, anxiety, and other emotional states. The hypothalamic centers also initiate the cardiac response to alterations in environmental temperature. Experimentally induced temperature changes in the preoptic anterior hypothalamus alter the heart rate and peripheral resistance.

Stimulation of the parahypoglossal area of the medulla reciprocally activates cardiac sympathetic pathways and inhibits cardiac parasympathetic pathways. In certain dorsal regions of the medulla, distinct cardiac accelerator (increase the heart rate) and augmentor (increase cardiac contractility) sites have been detected in animals with transected vagi. The accelerator regions are more abundant on the right side, whereas the augmentor sites are more prevalent on the left. A similar distribution also exists in the hypothalamus. Therefore, the sympathetic fibers mainly descend ipsilaterally through the brainstem.

Baroreceptor Reflex

Sudden changes in arterial blood pressure initiate a reflex that evokes an inverse change in heart rate (Fig. 18-4). Baroreceptors located in the aortic arch and carotid sinuses are responsible for this reflex. The inverse relationship between heart rate and arterial blood pressure is generally most pronounced over an intermediate range of arterial blood pressure. Below this intermediate range, the heart rate maintains a constant, high value; above this pressure range, the heart rate maintains a constant, low value.

Figure 18-4 Heart rate as a function of mean arterial pressure.

The effects of these changes in carotid sinus pressure on activity in the cardiac autonomic nerves are presented in Figure 18-5, which shows that over an intermediate range of carotid sinus pressure (100 to 180 mm Hg), reciprocal changes are evoked in efferent vagal and sympathetic neural activity. Below this range of carotid sinus pressure, sympathetic activity is intense and vagal activity is virtually absent. Conversely, above the intermediate range of carotid sinus pressure, vagal activity is intense and sympathetic activity is minimal.

Figure 18-5 Effects of changes in pressure in isolated carotid sinuses on neural activity in cardiac vagal and sympathetic efferent nerve fibers.

(Adapted from Kollai M, Koizumi K: Pflügers Arch 413:365, 1989.)

Bainbridge Reflex, Atrial Receptors, and Atrial Natriuretic Peptide

In 1915, Bainbridge reported that infusing blood or saline into dogs accelerated their heart rate. This increase did not seem to be tied to arterial blood pressure because the heart rate rose regardless of whether arterial blood pressure did or did not change. However, Bainbridge also noted that the heart rate increased whenever central venous pressure rose sufficiently to distend the right side of the heart. Bilateral transection of the vagi abolished this response. This is termed the Bainbridge reflex.

Many investigators have confirmed Bainbridge’s observations and have noted that the magnitude and direction of the response depend on the prevailing heart rate. When the heart rate is slow, intravenous infusions usually accelerate the heart. At more rapid heart rates, however, infusions ordinarily slow the heart. What accounts for these different responses? Increases in blood volume not only evoke the so-called Bainbridge reflex but also activate other reflexes (notably the baroreceptor reflex). These other reflexes tend to elicit opposite changes in heart rate. Therefore, changes in heart rate evoked by an alteration in blood volume are the result of these antagonistic reflex effects (Fig. 18-6). Evidently, the Bainbridge reflex predominates over the baroreceptor reflex when blood volume rises, but the baroreceptor reflex prevails over the Bainbridge reflex when blood volume diminishes.

Figure 18-6 Intravenous infusions of blood or electrolyte solutions tend to increase the heart rate via the Bainbridge reflex and to decrease the heart rate via the baroreceptor reflex. The actual change in heart rate induced by such infusions is the result of these two opposing effects.

Both atria have receptors that are affected by changes in blood volume and that influence the heart rate. These receptors are located principally in the venoatrial junctions: in the right atrium at its junctions with the venae cavae and in the left atrium at its junctions with the pulmonary veins. Distention of these atrial receptors sends afferent impulses to the brainstem in the vagi. The efferent impulses are carried from the brainstem to the SA node by fibers from both autonomic divisions.

The cardiac response to these changes in autonomic neural activity is highly selective. Even when the reflex increase in heart rate is large, changes in ventricular contractility are generally negligible. Furthermore, the neurally induced increase in heart rate is not usually accompanied by an increase in sympathetic activity in the peripheral arterioles.

Stimulation of the atrial receptors increases not only the heart rate but also urine volume. Reduced activity in the renal sympathetic nerve fibers may partially account for this diuresis. However, the principal mechanism appears to be a neurally mediated reduction in vasopressin (antidiuretic hormone) secretion by the posterior pituitary gland (see Chapters 34 and 40). Stretch of the atrial walls also releases atrial natriuretic peptide (ANP) from the atria.^* ANP, a 28–amino acid peptide, exerts potent diuretic and natriuretic effects on the kidneys (see also Chapter 34) and vasodilator effects on the resistance and capacitance vessels. Thus, ANP is an important regulator of blood volume and blood pressure.

IN THE CLINIC

In congestive heart failure, NaCl and water are retained, mainly because stimulation by the renin-angiotensin system increases the release of aldosterone from the adrenal cortex. The plasma level of ANP is also increased in congestive heart failure. By enhancing the renal excretion of NaCl and water, this peptide gradually reduces fluid retention and the consequent elevations in central venous pressure and cardiac preload.

Respiratory Sinus Arrhythmia

Rhythmic variations in heart rate, occurring at the frequency of respiration, are detectable in most individuals and tend to be more pronounced in children. The heart rate typically accelerates during inspiration and decelerates during expiration (Fig. 18-7).

Figure 18-7 Respiratory sinus arrhythmia. Note that the heart rate increases during inspiration and decreases during expiration

(Modified from Warner MR et al. Am J Physiol 251:H1134, 1986).

Recordings from cardiac autonomic nerves reveal that neural activity increases in the sympathetic fibers during inspiration and increases in the vagal fibers during expiration. The heart rate response to cessation of vagal stimulation is very quick because as already noted, the ACh released from the vagus nerves is rapidly hydrolyzed by cholinesterase. This short latency permits the heart rate to vary rhythmically at the respiratory frequency. Conversely, the norepinephrine released periodically at the sympathetic endings is removed very slowly. Therefore, the rhythmic variations in sympathetic activity that accompany inspiration do not induce any appreciable oscillatory changes in heart rate. Thus, respiratory sinus arrhythmia is almost entirely brought about by changes in vagal activity. In fact, respiratory sinus arrhythmia is exaggerated when vagal tone is enhanced.

Both reflex and central factors help initiate respiratory sinus arrhythmia (Fig. 18-8). Stretch receptors in the lungs are stimulated during inspiration, and this action leads to a reflex increase in heart rate. The afferent and efferent limbs of this reflex are located in the vagus nerves. Intrathoracic pressure also decreases during inspiration and thereby increases venous return to the right side of the heart (see Chapter 19). The consequent stretch of the right atrium elicits the Bainbridge reflex. After the time delay required for the increased venous return to reach the left side of the heart, left ventricular output increases and raises arterial blood pressure. This rise in blood pressure in turn reduces the heart rate through the baroreceptor reflex.

Figure 18-8 Respiratory sinus arrhythmia is generated by a direct interaction between the respiratory and cardiac centers in the medulla, as well as by reflexes that originate from stretch receptors in the lungs, stretch receptors in the right atrium (the Bainbridge reflex), and baroreceptors in the carotid sinuses and aortic arch.

Central factors are also responsible for respiratory cardiac arrhythmia. The respiratory center in the medulla directly influences the cardiac autonomic centers (Fig. 18-8). In heart-lung bypass experiments, the chest is open, the lungs are collapsed, venous return is diverted to a pump-oxygenator, and arterial blood pressure is maintained at a constant level. In such experiments, rhythmic movement of the rib cage attests to the activity of the medullary respiratory centers. Such movement of the rib cage is often accompanied by rhythmic changes in heart rate at the respiratory frequency. This respiratory cardiac arrhythmia is almost certainly induced by a direct interaction between the respiratory and cardiac centers in the medulla.

Chemoreceptor Reflex

The cardiac response to peripheral chemoreceptor stimulation illustrates the complex interactions that may ensue when one stimulus excites two organ systems simultaneously. In intact animals, stimulation of the carotid chemoreceptors consistently increases ventilatory rate and depth (see Chapter 24), but ordinarily it changes the heart rate only slightly. The magnitude of the ventilatory response determines whether the heart rate increases or decreases as a result of carotid chemoreceptor stimulation. Mild chemoreceptor-induced stimulation of respiration decreases the heart rate moderately; more pronounced stimulation increases the heart rate only slightly. If the pulmonary response to chemoreceptor stimulation is blocked, the heart rate response may be greatly exaggerated, as described later.

The cardiac response to peripheral chemoreceptor stimulation is the result of primary and secondary reflex mechanisms (Fig. 18-9). The principal effect of the primary reflex stimulation is to excite the medullary vagal center and thereby decrease the heart rate. The respiratory system mediates secondary reflex effects. The respiratory stimulation by arterial chemoreceptors tends to inhibit the medullary vagal center. This inhibition varies with the level of concomitant stimulation of respiration; small increases in respiration inhibit the vagal center slightly, whereas large increases in ventilation inhibit the vagal center more profoundly.

Figure 18-9 The primary effect of stimulation of peripheral chemoreceptors on the heart rate is to excite the cardiac vagal center in the medulla and thus to decrease the heart rate. Peripheral chemoreceptor stimulation also excites the respiratory center in the medulla. This effect produces hypocapnia and increases lung inflation, both of which secondarily inhibit the medullary vagal center. Thus, these secondary influences attenuate the primary reflex effect of peripheral chemoreceptor stimulation on heart rate.

An example of the primary inhibitory influence is shown in Figure 18-10. In this example, the lungs are completely collapsed and blood oxygenation is accomplished with an artificial oxygenator. When the carotid chemoreceptors are stimulated, an intense bradycardia and some degree of AV block ensue. Such effects are mediated primarily by efferent vagal fibers.

Figure 18-10 Changes in heart rate with carotid chemoreceptor stimulation during total heart bypass. The lungs remain deflated and respiratory gas exchange is accomplished by an artificial oxygenator. The lower tracing represents the oxygen saturation of the blood perfusing the carotid chemoreceptors. The blood perfusing the remainder of the body, including the myocardium, is fully saturated with oxygen.

(Modified from Levy MN et al: Circ Res 18:67, 1966.)

The pulmonary hyperventilation that is ordinarily evoked by carotid chemoreceptor stimulation influences the heart rate secondarily, both by initiating more pronounced pulmonary inflation reflexes and by producing hypocapnia (Fig. 18-9). Both influences tend to depress the primary cardiac response to chemoreceptor stimulation and thereby accelerate the heart. Hence, when pulmonary hyperventilation is not prevented, the primary and secondary effects neutralize each other, and carotid chemoreceptor stimulation affects the heart rate only moderately.

IN THE CLINIC

The electrocardiogram in Figure 18-11 was recorded from a quadriplegic patient who could not breathe spontaneously and required tracheal intubation and artificial respiration. When the tracheal catheter was briefly disconnected (near the beginning of the top strip in the figure) to permit nursing care, profound bradycardia quickly developed. The patient’s heart rate was 65 beats/min just before the tracheal catheter was disconnected. In less than 10 seconds after cessation of artificial respiration, his heart rate dropped to about 20 beats/min. This bradycardia could be prevented by blocking the effects of efferent vagal activity with atropine, and its onset could be delayed considerably by hyperventilating the patient before disconnecting the tracheal catheter.

Figure 18-11 Electrocardiogram of a 30-year-old quadriplegic man who could not breathe spontaneously and required tracheal intubation and artificial respiration. The two strips are continuous.

(Modified from Berk JL, Levy MN: Eur Surg Res 9:75, 1977.)

Ventricular Receptor Reflexes

Sensory receptors located near the endocardial surfaces of the ventricles initiate reflex effects similar to those elicited by the arterial baroreceptors. Excitation of these endocardial receptors diminishes the heart rate and peripheral resistance. Other sensory receptors have been identified in the epicardial regions of the ventricles. Although all these ventricular receptors are excited by various mechanical and chemical stimuli, their exact physiological functions remain unclear.

REGULATION OF MYOCARDIAL PERFORMANCE

Intrinsic Regulation of Myocardial Performance

As noted previously, the heart can initiate its own beat in the absence of any nervous or hormonal control. The myocardium can also adapt to changing hemodynamic conditions by means of mechanisms that are intrinsic to cardiac muscle itself. For example, racing greyhounds with denervated hearts perform almost as well as those with intact innervation. Their maximal running speed decreases by only 5% after complete cardiac denervation. In these dogs, the threefold to fourfold increase in cardiac output during a race is achieved principally by an increase in stroke volume. Normally, the increase in cardiac output with exercise is accompanied by a proportionate increase in heart rate; stroke volume does not change much (see Chapter 19). This adaptation in the denervated heart is not achieved entirely by intrinsic mechanisms; circulating catecholamines undoubtedly contribute. For example, if β-adrenergic receptor antagonists are given to greyhounds with denervated hearts, their racing performance is severely impaired.

IN THE CLINIC

Ventricular receptors have been implicated in the initiation of vasovagal syncope, a feeling of lightheadedness or brief loss of consciousness that may be triggered by psychological or orthostatic stress. The ventricular receptors are believed to be stimulated by reduced ventricular filling volume combined with vigorous ventricular contraction. In a person standing quietly, ventricular filling is diminished because blood tends to pool in the veins in the abdomen and legs, as explained in Chapter 17. Consequently, the reduction in cardiac output and arterial blood pressure leads to a generalized increase in sympathetic neural activity via the baroreceptor reflex (Fig. 18-5). The enhanced sympathetic activity to the heart evokes a vigorous ventricular contraction that thereby stimulates the ventricular receptors. Excitation of the ventricular receptors is believed to initiate the autonomic neural changes that evoke vasovagal syncope, namely, a combination of a profound, vagally mediated bradycardia and generalized arteriolar vasodilation mediated by a reduction in sympathetic neural activity.

IN THE CLINIC

The heart is partially or completely denervated in various clinical situations: (1) a surgically transplanted heart is totally denervated, although the intrinsic, postganglionic parasympathetic fibers persist; (2) atropine blocks vagal effects on the heart, and propranolol blocks sympathetic β-adrenergic influences; (3) certain drugs, such as reserpine, deplete cardiac norepinephrine stores and thereby restrict or abolish sympathetic control; and (4) in chronic congestive heart failure, cardiac norepinephrine stores are often severely diminished, and any sympathetic influences are attenuated.

Two principal intrinsic mechanisms, namely, the Frank-Starling mechanism and rate-induced regulation, enable the myocardium to adapt to changes in hemodynamic conditions. The Frank-Starling mechanism (Starling’s law of the heart) is invoked in response to changes in the resting length of myocardial fibers. Rate-induced regulation is evoked by changes in the frequency of the heartbeat.

Frank-Starling Mechanism

About a century ago, the German physiologist Otto Frank and the English physiologist Ernest Starling independently studied the response of isolated hearts to changes in preload and afterload (see Chapter 16). When ventricular filling pressure (preload) is increased, ventricular volume increases progressively and after several beats attains a constant, larger volume. At equilibrium, the volume of blood ejected by the ventricles (stroke volume) with each heartbeat increases to equal the greater quantity of venous return to the right atrium.

The increased ventricular volume facilitates ventricular contraction and enables the ventricles to pump a greater stroke volume. This increase in ventricular volume is associated with an increase in length of the individual ventricular cardiac fibers. The increase in fiber length alters cardiac performance mainly by altering the number of myofilament cross-bridges that interact (see Chapter 16). More recent evidence indicates that the principal mechanism involves a stretch-induced change in the sensitivity of cardiac myofilaments to Ca⁺⁺ (see Chapter 16). An optimal fiber length exists, however. Excessively high filling pressures that overstretch the myocardial fibers may depress rather than enhance the pumping capacity of the ventricles.

Starling also showed that isolated heart preparations could adapt to changes in the counterforce to the ventricular ejection of blood during systole (i.e., afterload). As the left ventricle contracts, it does not eject blood into the aorta until the ventricle has developed a pressure that just exceeds the prevailing aortic pressure (see Chapter 16). The aortic pressure during ventricular ejection essentially constitutes the left ventricular afterload. In Starling’s experiments, arterial pressure was controlled by a hydraulic device in the tubing that led from the ascending aorta to the right atrial blood reservoir. Venous return to the right atrium was held constant by maintaining the hydrostatic level of the blood reservoir. As Starling raised arterial pressure to a new, constant level, the left ventricle responded at first to the increased afterload by pumping a diminished stroke volume. Because venous return was held constant, the diminution in stroke volume was accompanied by a rise in ventricular diastolic volume, as well as by an increase in the length of the myocardial fibers. This change in end-diastolic fiber length finally enabled the ventricle to pump a normal stroke volume against the greater peripheral resistance. Again, a change in the number of cross-bridges between the thick and thin filaments probably contributes to this adaptation, but the major factor appears to be a stretch-induced change in the sensitivity of the contractile proteins to Ca⁺⁺.

Cardiac adaptation to alterations in heart rate also involves changes in ventricular volume. During bradycardia, for example, the increased duration of diastole permits greater ventricular filling. The consequent increase in myocardial fiber length increases stroke volume. Therefore, the reduction in heart rate may be fully compensated by the increase in stroke volume, and cardiac output may therefore remain constant.

When cardiac compensation involves ventricular dilation, one must consider how the increased size of the ventricle affects the generation of intraventricular pressure. According to the Laplace relationship (see Chapter 17), if the ventricle enlarges, the force required by each myocardial fiber to generate a given intraventricular systolic pressure must be appreciably greater than that developed by the fibers in a ventricle of normal size. Thus, more energy is required for a dilated heart to perform a given amount of external work than for a normal-sized heart. Hence, computation of afterload on contracting myocardial fibers in the walls of the ventricles must consider ventricular dimensions along with intraventricular (and aortic) pressure.

The relatively rigid pericardium that encloses the heart determines the pressure-volume relationship at high levels of pressure and volume. The pericardium limits heart volume even under normal conditions, when an individual is at rest and the heart rate is slow. In patients with chronic congestive heart failure, the sustained cardiac dilation and hypertrophy may stretch the pericardium considerably. In such patients, the pericardial limitation of cardiac filling is exerted at pressures and volumes entirely different from those in normal individuals.

To assess changes in ventricular performance, the Frank-Starling mechanism is often represented by a family of ventricular function curves. To construct a control ventricular function curve, for example, blood volume is altered over a range of values, and stroke work (i.e., stroke volume × mean arterial pressure) and end-diastolic ventricular pressure are measured at each step. Similar observations are then made during the desired experimental intervention. For example, the ventricular function curve obtained during infusion of norepinephrine lies above and to the left of the control ventricular function curve (Fig. 18-12). Clearly, for a given level of left ventricular end-diastolic pressure (an index of preload), the left ventricle performs more work during the norepinephrine infusion than during control conditions. Hence, the upward and leftward shift of the ventricular function curve signifies improved ventricular contractility. Conversely, a shift downward and to the right indicates impaired contractility and a tendency toward cardiac failure.