Regulation of the Heart and Vasculature

Parasympathetic Pathways

The cardiac parasympathetic fibers originate in the medulla oblongata, in cells that lie in the dorsal motor nucleus of the vagus nerve or in the nucleus ambiguus (see Chapter 11 ). 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 atrioventricular (AV) nodes.

The right and left vagus nerves 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 in such a way that left vagal stimulation also depresses the SA node and right vagal stimulation impedes AV conduction.

The SA and AV nodes are rich in acetylcholinesterase, 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 (≈50–100 msec) because the ACh released quickly activates special ACh-regulated potassium (K _ACh ) channels 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. These two features of the vagus nerves—brief latency and rapid decay of the response—enable them to exert beat-by-beat control of SA and AV nodal function.

Parasympathetic influences usually predominate over sympathetic effects at the SA node, as shown in Fig. 18.3 . When the frequency of sympathetic stimulation increases from 0 to 4 Hz, the HR increases by approximately 80 beats per minute in the absence of vagal nerve stimulation (0 Hz). However, when the vagus nerves are stimulated at 8 Hz, increasing the sympathetic stimulation frequency from 0 to 4 Hz has only a negligible influence on HR.

Sympathetic Pathways

The cardiac sympathetic fibers originate in the intermediolateral columns of the upper five or six thoracic segments and the 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, postganglionic sympathetic 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 (see 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 cyclic adenosine monophosphate (cAMP; see Chapter 13 ). Hence, sympathetic activity alters the HR and AV conduction much more slowly than vagal activity does. Whereas 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 HR. Stimuli applied to the H2 field of Forel in the posterior hypothalamus evoke various cardiovascular responses, including tachycardia and associated limb movements; these changes resemble those observed during muscular exercise. Undoubtedly, the cortical and hypothalamic 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 HR 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 sites (increase the HR) and augmentor sites (increase cardiac contractility) have been detected in animals with transected vagus nerves. 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 tends to cause an inverse change in HR. When arterial blood pressure rises above the normal mean resting value, baroreceptor activity increases and this tends to cause a decrease in heart rate, and vice versa ( Fig. 18.4 ). Baroreceptors located in the aortic arch and carotid sinuses are responsible for this reflex (see the section “ Arterial Baroreceptors ”). The effects of changes in carotid sinus pressure on the activity in cardiac autonomic nerves are described in Fig. 18.5 , which shows that over an intermediate range of carotid sinus pressures (100–180 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.

Bainbridge Reflex, Atrial Receptors, and Atrial Natriuretic Peptide

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

Many investigators have confirmed Bainbridge’s observations and have noted that the magnitude and direction of the response depend on the prevailing HR. When the HR is slow, intravenous infusions of blood or electrolyte solutions usually accelerate the heart. At more rapid HRs, however, such infusions ordinarily slow the heart. What accounts for these different responses? Increases in blood volume not only evoke Bainbridge reflex but also activate other reflexes (of note, the baroreceptor reflex). These other reflexes tend to elicit opposite changes in HR. Therefore, changes in HR 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.

Both atria have receptors that are affected by changes in blood volume and that influence the HR. 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 vagus nerves. 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 HR is large, changes in ventricular contractility are generally negligible. Furthermore, the neurally induced increase in HR is not usually accompanied by an increase in sympathetic activity in the peripheral arterioles.

Stimulation of the atrial receptors increases not only the HR 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 35 and 41 ). Stretch of the atrial walls also releases atrial natriuretic peptide (ANP) from the atria. ^a

a The myocytes of the ventricles secrete a related peptide in response to stretch. This peptide, termed brain natriuretic peptide (BNP) because of its initial discovery in the central nervous system, has actions similar to those of ANP (see Chapter 35 ).

ANP, a 28–amino acid peptide, exerts potent diuretic and natriuretic effects on the kidneys (see also Chapter 35 ) and vasodilator effects on the resistance and capacitance vessels. Thus ANP is an important regulator of blood volume and blood pressure.

Respiratory Sinus Arrhythmia

Rhythmic variations in HR, occurring at the frequency of respiration, are detectable in most individuals and tend to be more pronounced in children. The HR typically accelerates during inspiration and decelerates during expiration ( Fig. 18.7 ).

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 HR response to cessation of vagal stimulation is very quick because, as already noted, ACh released from the vagus nerves is rapidly hydrolyzed by acetylcholinesterase. This short latency enables the HR 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 HR. Thus respiratory sinus arrhythmia is brought about almost entirely 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 HR. 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 HR through the baroreceptor reflex.

Central factors are also responsible for respiratory cardiac arrhythmia. The respiratory center in the medulla directly influences the cardiac autonomic centers (see Fig. 18.8 ). In heart-lung bypass studies, the chest is opened, the lungs are collapsed, venous return is diverted to a pump-oxygenator, and arterial blood pressure is maintained at a constant level. In such studies, rhythmic movement of the rib cage attests to the activity of the medullary respiratory centers and is often accompanied by rhythmic changes in HR 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. Stimulation of carotid chemoreceptors consistently increases ventilatory rate and depth (see Chapter 25 ), but ordinarily it changes the HR only slightly. The magnitude of the ventilatory response determines whether the HR increases or decreases as a result of carotid chemoreceptor stimulation. Mild chemoreceptor-induced stimulation of respiration decreases the HR moderately; more pronounced stimulation increases the HR only slightly. If the pulmonary response to chemoreceptor stimulation is blocked, the HR 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 HR. 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.

An example of the primary inhibitory influence is shown in Fig. 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, intense bradycardia and some degree of AV block ensue. Such effects are mediated primarily by efferent vagal fibers.

The pulmonary hyperventilation that is ordinarily evoked by carotid chemoreceptor stimulation influences the HR secondarily, both by initiating more pronounced pulmonary inflation reflexes and by producing hypocapnia (see Fig. 18.9 ). Both influences tend to depress the primary cardiac response to chemoreceptor stimulation and thereby accelerate the HR. Hence, when pulmonary hyperventilation is not prevented, the primary and secondary effects neutralize each other, and carotid chemoreceptor stimulation affects the HR only moderately.

IN THE CLINIC

The electrocardiogram in Fig. 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, indicated by the arrow) to allow nursing care, profound bradycardia developed after nine heart beats. The patient’s heart rate was 65 beats per minute just before the tracheal catheter was disconnected. In less than 10 seconds after cessation of artificial respiration, his heart rate dropped to approximately 20 beats per minute. This bradycardia could be prevented by blocking the effects of efferent vagal activity with atropine, and its onset could be delayed considerably by hyperventilation of the patient before the tracheal catheter is disconnected.

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 causes the HR and peripheral resistance to diminish. 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.

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 CO during a race is achieved principally by an increase in SV. Normally, the increase in CO with exercise is accompanied by a proportionate increase in HR; SV 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.

Two principal intrinsic mechanisms, the Frank-Starling mechanism and rate-induced regulation, enable the myocardium to adapt to changes in hemodynamic conditions. The Frank-Starling mechanism (Frank-Starling 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

In the 1910s, 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, becomes constant and larger. At equilibrium, the volume of blood ejected by the ventricles (SV) 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 SV. 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 Chapters 13 and 16 ). There exists an optimal fiber length, however. Excessively high filling pressures that overstretch the myocardial fibers may depress rather than enhance the pumping capacity of the ventricles (see Fig. 16.36 ).

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 Fig. 16.40 ). 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. To hold venous return to the right atrium constant, the hydrostatic level of the blood reservoir was maintained. As Starling raised arterial pressure to a new constant level, the left ventricle responded at first to the increased afterload by pumping a diminished SV. Because venous return was held constant, the diminution in SV 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 SV against the greater peripheral resistance. As mentioned, 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 HR also involves changes in ventricular volume. During bradycardia, for example, the increased duration of diastole allows greater ventricular filling. The consequent increase in myocardial fiber length increases SV. Therefore, the reduction in HR may be fully compensated by the increase in SV, and CO may therefore remain constant.

When cardiac compensation involves ventricular dilation, the effect of the increased size of the ventricle on the generation of intraventricular pressure must be considered. According to Laplace’s 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 to do so. Hence, computation of afterload on contracting myocardial fibers in the walls of the ventricles must account for 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 HR 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., SV × 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.

Balance Between Right and Left Ventricular Output

The Frank-Starling mechanism is well suited to match CO to venous return. Any sudden, excessive output by one ventricle soon causes an increase in venous return to the second ventricle. The consequent increase in diastolic fiber length in the second ventricle augments the output of that ventricle to correspond to the output of its mate. In this way, the Frank-Starling mechanism maintains a precise balance between the output of the right and left ventricles. If the two ventricles were not arranged in series in a closed circuit, any small but maintained imbalance in output of the two ventricles would be catastrophic.

The curves that relate CO to mean atrial pressure for the two ventricles do not coincide; the curve for the left ventricle usually lies below that for the right ventricle ( Fig. 18.13 ). At equal right and left atrial pressures (points A and B in Fig. 18.13 ), right ventricular output exceeds left ventricular output. Hence, venous return to the left ventricle (a function of right ventricular output) exceeds left ventricular output, and left ventricular diastolic volume and pressure rise. According to the Frank-Starling mechanism, left ventricular output therefore increases (from point B toward point C in Fig. 18.13 ). Only when the output of both ventricles is identical (points A and C) is equilibrium reached. Under such conditions, however, left atrial pressure (point C) exceeds right atrial pressure (point A). This is precisely the relationship that ordinarily prevails.

IN THE CLINIC

The fact that left atrial pressure exceeds right atrial pressure accounts for the observation that in individuals with congenital atrial septal defects in which the two atria communicate with each other via a patent foramen ovale, the direction of shunt flow is usually from left to the right side of the heart.

Rate-Induced Regulation

Myocardial performance is also regulated by changes in the frequency at which the myocardial fibers contract. The effects of changes in contraction frequency on the force developed in an isometrically contracting papillary muscle are shown in Fig. 18.14 . Initially, the cardiac muscle is stimulated to contract once every 20 seconds. When the muscle is suddenly made to contract once every 0.63 seconds, the force developed increases progressively over the next several beats. At the new steady state, the force developed is more than five times greater than the force at the larger contraction interval. A return to the larger interval (20 seconds) has the opposite influence on the development of force.

The rise in the force developed when the contraction interval is decreased is caused by a gradual increase in intracellular [Ca ⁺⁺ ]. Two mechanisms contribute to the rise in intracellular [Ca ⁺⁺ ]: an increase in the number of depolarizations per minute and an increase in the inward Ca ⁺⁺ current per depolarization.

In the first mechanism, Ca ⁺⁺ enters the myocardial cell during each action potential plateau (see Chapters 13 and 16 ). As the interval between beats is diminished, the number of plateaus per minute increases. Although the duration of each action potential (and of each plateau) decreases as the interval between beats is reduced, the overriding effect of the increased number of plateaus per minute on the influx of Ca ⁺⁺ prevails, and intracellular [Ca ⁺⁺ ] increases.

In the second mechanism, as the interval between beats is suddenly diminished, the inward calcium current (i _Ca ) progressively increases with each successive beat until a new steady state is attained at the new basic cycle length. In an isolated ventricular myocyte, influx of Ca ⁺⁺ into the myocyte increases on successive depolarizations ( Fig. 18.15 ). Both the increased magnitude and the slowed inactivation of i _Ca result in greater Ca ⁺⁺ influx into the myocyte during the later depolarizations than during the first depolarization. This greater Ca ⁺⁺ influx strengthens contraction.

Transient changes in the intervals between beats also profoundly affect the strength of contraction. When the left ventricle contracts prematurely ( Fig. 18.16 , beat A), the premature contraction (extrasystole) itself is weak, whereas contraction B (postextrasystolic contraction) after the compensatory pause is very strong. In the intact circulatory system, this response depends partly on the Frank-Starling mechanism. Inadequate time for ventricular filling just before the premature beat results in the weak premature contraction. Subsequently, the exaggerated degree of filling associated with the long compensatory pause (see Fig. 18.16 , beat B) contributes to the vigorous postextrasystolic contraction.

The weakness of the premature beat is directly related to its degree of prematurity: The earlier the premature beat, the weaker its force of contraction. The curve that represents strength of contraction of a premature beat in relation to the coupling interval is called a mechanical restitution curve . Fig. 18.17 shows the restitution curve obtained in an isolated ventricular muscle preparation.

Restitution of the force of contraction depends on the time course of the intracellular circulation of Ca ⁺⁺ in cardiac myocytes during contraction and relaxation. During relaxation, the Ca ⁺⁺ that dissociates from the contractile proteins is taken up by the sarcoplasmic reticulum for subsequent release. However, there is a lag of approximately 500 to 800 msec before this Ca ⁺⁺ is available for release from the sarcoplasmic reticulum in response to the next depolarization. Thus the strength of the premature beat is reduced because the time during the preceding relaxation is insufficient to allow much of the Ca ⁺⁺ taken up by the sarcoplasmic reticulum to become available for release during the premature beat. Conversely, the postextrasystolic beat is considerably stronger than normal because more Ca ⁺⁺ is released from the sarcoplasmic reticulum as a result of the relatively large amount of Ca ⁺⁺ taken up by it during the time that had elapsed from the end of the last regular beat until the beginning of the postextrasystolic beat.

Extrinsic Regulation of Myocardial Performance

Although a completely isolated heart can adapt well to changes in preload and afterload, various extrinsic factors also influence the heart in an individual. Often, these extrinsic regulatory mechanisms may overwhelm the intrinsic mechanisms. The extrinsic regulatory factors may be subdivided into nervous and chemical components.