Guyton and Hall Textbook of Medical Physiology, 12th Ed


Muscle Blood Flow and Cardiac Output During Exercise; the Coronary Circulation and Ischemic Heart Disease

image In this chapter we consider (1) blood flow to the skeletal muscles and (2) coronary artery blood flow to the heart. Regulation of each of these is achieved mainly by local control of vascular resistance in response to muscle tissue metabolic needs.

We also discuss the physiology of related subjects such as (1) cardiac output control during exercise, (2) characteristics of heart attacks, and (3) the pain of angina pectoris.

Blood Flow Regulation in Skeletal Muscle at Rest and During Exercise

Very strenuous exercise is one of the most stressful conditions that the normal circulatory system faces. This is true because there is such a large mass of skeletal muscle in the body, all of it requiring large amounts of blood flow. Also, the cardiac output often must increase in the nonathlete to four to five times normal, or in the well-trained athlete to six to seven times normal, to satisfy the metabolic needs of the exercising muscles.

Rate of Blood Flow Through the Muscles

During rest, blood flow through skeletal muscle averages 3 to 4 ml/min/100 g of muscle. During extreme exercise in the well-conditioned athlete, this can increase 25- to 50-fold, rising to 100 to 200 ml/min/100 g of muscle. Peak blood flows as high as 400 ml/min/100 g of muscle have been reported in thigh muscles of endurance-trained athletes.

Blood Flow During Muscle Contractions

Figure 21-1 shows a record of blood flow changes in a calf muscle of a human leg during strong rhythmical muscular exercise. Note that the flow increases and decreases with each muscle contraction. At the end of the contractions, the blood flow remains very high for a few seconds but then returns toward normal during the next few minutes.


Figure 21-1 Effects of muscle exercise on blood flow in the calf of a leg during strong rhythmical contraction. The blood flow was much less during contractions than between contractions.

(Adapted from Barcroft H, Dornhorst AC: The blood flow through the human calf during rhythmic exercise. J Physiol 109:402, 1949.)

The cause of the lower flow during the muscle contraction phase of exercise is compression of the blood vessels by the contracted muscle. During strong tetanic contraction, which causes sustained compression of the blood vessels, the blood flow can be almost stopped, but this also causes rapid weakening of the contraction.

Increased Blood Flow in Muscle Capillaries During Exercise

During rest, some muscle capillaries have little or no flowing blood. But during strenuous exercise, all the capillaries open. This opening of dormant capillaries diminishes the distance that oxygen and other nutrients must diffuse from the capillaries to the contracting muscle fibers and sometimes contributes a twofold to threefold increased capillary surface area through which oxygen and nutrients can diffuse from the blood to the tissues.

Control of Blood Flow in Skeletal Muscles

Local Regulation—Decreased Oxygen in Muscle Greatly Enhances Flow

The tremendous increase in muscle blood flow that occurs during skeletal muscle activity is caused mainly by chemicals acting directly on the muscle arterioles to cause dilation. One of the most important chemical effects is reduction of oxygen in the muscle tissues. When muscles are active they use oxygen rapidly, thereby decreasing the oxygen concentration in the tissue fluids. This in turn causes local arteriolar vasodilation because the arteriolar walls cannot maintain contraction in the absence of oxygen and because oxygen deficiency causes release of vasodilator substances. Adenosine may be an important vasodilator substance, but experiments have shown that even large amounts of adenosine infused directly into a muscle artery cannot increase blood flow to the same extent as during intense exercise and cannot sustain vasodilation in skeletal muscle for more than about 2 hours.

Fortunately, even after the muscle blood vessels have become insensitive to the vasodilator effects of adenosine, still other vasodilator factors continue to maintain increased capillary blood flow as long as the exercise continues. These factors include (1) potassium ions, (2) adenosine triphosphate (ATP), (3) lactic acid, and (4) carbon dioxide. We still do not know quantitatively how great a role each of these plays in increasing muscle blood flow during muscle activity; this subject was discussed in additional detail in Chapter 17.

Nervous Control of Muscle Blood Flow

In addition to local tissue vasodilator mechanisms, skeletal muscles are provided with sympathetic vasoconstrictor nerves and (in some species of animals) sympathetic vasodilator nerves as well.

Sympathetic Vasoconstrictor Nerves

The sympathetic vasoconstrictor nerve fibers secrete norepinephrine at their nerve endings. When maximally activated, this can decrease blood flow through resting muscles to as little as one-half to one-third normal. This vasoconstriction is of physiologic importance in circulatory shock and during other periods of stress when it is necessary to maintain a normal or even high arterial pressure.

In addition to the norepinephrine secreted at the sympathetic vasoconstrictor nerve endings, the medullae of the two adrenal glands also secrete large amounts of norepinephrine plus even more epinephrine into the circulating blood during strenuous exercise. The circulating norepinephrine acts on the muscle vessels to cause a vasoconstrictor effect similar to that caused by direct sympathetic nerve stimulation. The epinephrine, however, often has a slight vasodilator effect because epinephrine excites more of the beta-adrenergic receptors of the vessels, which are vasodilator receptors, in contrast to the alpha vasoconstrictor receptors excited especially by norepinephrine. These receptors are discussed in Chapter 60.

Total Body Circulatory Readjustments During Exercise

Three major effects occur during exercise that are essential for the circulatory system to supply the tremendous blood flow required by the muscles. They are (1) mass discharge of the sympathetic nervous system throughout the body with consequent stimulatory effects on the entire circulation, (2) increase in arterial pressure, and (3) increase in cardiac output.

Effects of Mass Sympathetic Discharge

At the onset of exercise, signals are transmitted not only from the brain to the muscles to cause muscle contraction but also into the vasomotor center to initiate sympathetic discharge throughout the body. Simultaneously, the parasympathetic signals to the heart are attenuated. Therefore, three major circulatory effects result.

First, the heart is stimulated to greatly increased heart rate and increased pumping strength as a result of the sympathetic drive to the heart plus release of the heart from normal parasympathetic inhibition.

Second, most of the arterioles of the peripheral circulation are strongly contracted, except for the arterioles in the active muscles, which are strongly vasodilated by the local vasodilator effects in the muscles, as noted earlier. Thus, the heart is stimulated to supply the increased blood flow required by the muscles, while at the same time blood flow through most nonmuscular areas of the body is temporarily reduced, thereby “lending” blood supply to the muscles. This accounts for as much as 2 L/min of extra blood flow to the muscles, which is exceedingly important when one thinks of a person running for his life—even a fractional increase in running speed may make the difference between life and death. Two of the peripheral circulatory systems, the coronary and cerebral systems, are spared this vasoconstrictor effect because both these circulatory areas have poor vasoconstrictor innervation—fortunately so because both the heart and the brain are as essential to exercise as are the skeletal muscles.

Third, the muscle walls of the veins and other capacitative areas of the circulation are contracted powerfully, which greatly increases the mean systemic filling pressure. As we learned in Chapter 20, this is one of the most important factors in promoting increase in venous return of blood to the heart and, therefore, in increasing the cardiac output.

Increase in Arterial Pressure During Exercise Due to Sympathetic Stimulation

An important effect of increased sympathetic stimulation in exercise is to increase the arterial pressure. This results from multiple stimulatory effects, including (1) vasoconstriction of the arterioles and small arteries in most tissues of the body except the active muscles, (2) increased pumping activity by the heart, and (3) a great increase in mean systemic filling pressure caused mainly by venous contraction. These effects, working together, almost always increase the arterial pressure during exercise. This increase can be as little as 20 mm Hg or as great as 80 mm Hg, depending on the conditions under which the exercise is performed. When a person performs exercise under tense conditions but uses only a few muscles, the sympathetic nervous response still occurs everywhere in the body. In the few active muscles, vasodilation occurs, but everywhere else in the body the effect is mainly vasoconstriction, often increasing the mean arterial pressure to as high as 170 mm Hg. Such a condition might occur in a person standing on a ladder and nailing with a hammer on the ceiling above. The tenseness of the situation is obvious.

Conversely, when a person performs massive whole-body exercise, such as running or swimming, the increase in arterial pressure is often only 20 to 40 mm Hg. This lack of a large increase in pressure results from the extreme vasodilation that occurs simultaneously in large masses of active muscle.

Why Is the Arterial Pressure Increase During Exercise Important?

When muscles are stimulated maximally in a laboratory experiment but without allowing the arterial pressure to rise, muscle blood flow seldom rises more than about eightfold. Yet, we know from studies of marathon runners that muscle blood flow can increase from as little as 1 L/min for the whole body during rest to more than 20 L/min during maximal activity. Therefore, it is clear that muscle blood flow can increase much more than occurs in the aforementioned simple laboratory experiment. What is the difference? Mainly, the arterial pressure rises during normal exercise. Let us assume, for instance, that the arterial pressure rises 30 percent, a common increase during heavy exercise. This 30 percent increase causes 30 percent more force to push blood through the muscle tissue vessels. But this is not the only important effect; the extra pressure also stretches the walls of the vessels, and this effect, along with the locally released vasodilators and higher blood pressure, may increase muscle total flow to more than 20 times normal.

Importance of the Increase in Cardiac Output During Exercise

Many different physiologic effects occur at the same time during exercise to increase cardiac output approximately in proportion to the degree of exercise. In fact, the ability of the circulatory system to provide increased cardiac output for delivery of oxygen and other nutrients to the muscles during exercise is equally as important as the strength of the muscles themselves in setting the limit for continued muscle work. For instance, marathon runners who can increase their cardiac outputs the most are generally the same persons who have record-breaking running times.

Graphical Analysis of the Changes in Cardiac Output During Heavy Exercise

Figure 21-2 shows a graphical analysis of the large increase in cardiac output that occurs during heavy exercise. The cardiac output and venous return curves crossing at point A give the analysis for the normal circulation, and the curves crossing at point B analyze heavy exercise. Note that the great increase in cardiac output requires significant changes in both the cardiac output curve and the venous return curve, as follows.


Figure 21-2 Graphical analysis of change in cardiac output and right atrial pressure with onset of strenuous exercise. Black curves, normal circulation. Red curves, heavy exercise.

The increased level of the cardiac output curve is easy to understand. It results almost entirely from sympathetic stimulation of the heart that causes (1) increased heart rate, often up to rates as high as 170 to 190 beats/min, and (2) increased strength of contraction of the heart, often to as much as twice normal. Without this increased level of cardiac function, the increase in cardiac output would be limited to the plateau level of the normal heart, which would be a maximum increase of cardiac output of only about 2.5-fold rather than the 4-fold that can commonly be achieved by the untrained runner and the 7-fold that can be achieved in some marathon runners.

Now study the venous return curves. If no change occurred from the normal venous return curve, the cardiac output could hardly rise at all in exercise because the upper plateau level of the normal venous return curve is only 6 L/min. Yet two important changes do occur:

1. The mean systemic filling pressure rises tremendously at the onset of heavy exercise. This results partly from the sympathetic stimulation that contracts the veins and other capacitative parts of the circulation. In addition, tensing of the abdominal and other skeletal muscles of the body compresses many of the internal vessels, thus providing more compression of the entire capacitative vascular system, causing a still greater increase in mean systemic filling pressure. During maximal exercise, these two effects together can increase the mean systemic filling pressure from a normal level of 7 mm Hg to as high as 30 mm Hg.

2. The slope of the venous return curve rotates upward. This is caused by decreased resistance in virtually all the blood vessels in active muscle tissue, which also causes resistance to venous return to decrease, thus increasing the upward slope of the venous return curve.

Therefore, the combination of increased mean systemic filling pressure and decreased resistance to venous return raises the entire level of the venous return curve.

In response to the changes in both the venous return curve and the cardiac output curve, the new equilibrium point in Figure 21-2 for cardiac output and right atrial pressure is now point B, in contrast to the normal level at point A. Note especially that the right atrial pressure has hardly changed, having risen only 1.5 mm Hg. In fact, in a person with a strong heart, the right atrial pressure often falls below normal in very heavy exercise because of the greatly increased sympathetic stimulation of the heart during exercise.

Coronary Circulation

About one third of all deaths in industrialized countries of the Western world result from coronary artery disease, and almost all elderly people have at least some impairment of the coronary artery circulation. For this reason, understanding normal and pathological physiology of the coronary circulation is one of the most important subjects in medicine.

Physiologic Anatomy of the Coronary Blood Supply

Figure 21-3 shows the heart and its coronary blood supply. Note that the main coronary arteries lie on the surface of the heart and smaller arteries then penetrate from the surface into the cardiac muscle mass. It is almost entirely through these arteries that the heart receives its nutritive blood supply. Only the inner 1/10 millimeter of the endocardial surface can obtain significant nutrition directly from the blood inside the cardiac chambers, so this source of muscle nutrition is minuscule.


Figure 21-3 The coronary arteries.

The left coronary artery supplies mainly the anterior and left lateral portions of the left ventricle, whereas the right coronary artery supplies most of the right ventricle, as well as the posterior part of the left ventricle in 80 to 90 percent of people.

Most of the coronary venous blood flow from the left ventricular muscle returns to the right atrium of the heart by way of the coronary sinus, which is about 75 percent of the total coronary blood flow. And most of the coronary venous blood from the right ventricular muscle returns through small anterior cardiac veins that flow directly into the right atrium, not by way of the coronary sinus. A very small amount of coronary venous blood also flows back into the heart through very minute thebesian veins, which empty directly into all chambers of the heart.

Normal Coronary Blood Flow—About 5 Percent of Cardiac Output

The resting coronary blood flow in the resting human being averages 70 ml/min/100 g heart weight, or about 225 ml/min, which is about 4 to 5 percent of the total cardiac output.

During strenuous exercise, the heart in the young adult increases its cardiac output fourfold to sevenfold, and it pumps this blood against a higher than normal arterial pressure. Consequently, the work output of the heart under severe conditions may increase sixfold to ninefold. At the same time, the coronary blood flow increases threefold to fourfold to supply the extra nutrients needed by the heart. This increase is not as much as the increase in workload, which means that the ratio of energy expenditure by the heart to coronary blood flow increases. Thus, the “efficiency” of cardiac utilization of energy increases to make up for the relative deficiency of coronary blood supply.

Phasic Changes in Coronary Blood Flow During Systole and Diastole—Effect of Cardiac Muscle Compression

Figure 21-4 shows the changes in blood flow through the nutrient capillaries of the left ventricular coronary system in ml/min in the human heart dur- ing systole and diastole, as extrapolated from studies in experimental animals. Note from this diagram that the coronary capillary blood flow in the left ventricle muscle falls to a low value during systole, which is opposite to flow in vascular beds elsewhere in the body. The reason for this is strong compression of the left ventricular muscle around the intramuscular vessels during systolic contraction.


Figure 21-4 Phasic flow of blood through the coronary capillaries of the human left ventricle during cardiac systole and diastole (as extrapolated from measured flows in dogs).

During diastole, the cardiac muscle relaxes and no longer obstructs blood flow through the left ventricular muscle capillaries, so blood flows rapidly during all of diastole.

Blood flow through the coronary capillaries of the right ventricle also undergoes phasic changes during the cardiac cycle, but because the force of contraction of the right ventricular muscle is far less than that of the left ventricular muscle, the inverse phasic changes are only partial, in contrast to those in the left ventricular muscle.

Epicardial Versus Subendocardial Coronary Blood Flow—Effect of Intramyocardial Pressure

Figure 21-5 demonstrates the special arrangement of the coronary vessels at different depths in the heart muscle, showing on the outer surface epicardial coronary arteries that supply most of the muscle. Smaller, intramuscular arteries derived from the epicardial arteries penetrate the muscle, supplying the needed nutrients. Lying immediately beneath the endocardium is a plexus of subendocardial arteries. During systole, blood flow through the subendocardial plexus of the left ventricle, where the intramuscular coronary vessels are compressed greatly by ventricular muscle contraction, tends to be reduced. But the extra vessels of the subendocardial plexus normally compensate for this. Later in the chapter, we explain how this peculiar difference between blood flow in the epicardial and subendocardial arteries plays an important role in certain types of coronary ischemia.


Figure 21-5 Diagram of the epicardial, intramuscular, and subendocardial coronary vasculature.

Control of Coronary Blood Flow

Local Muscle Metabolism Is the Primary Controller of Coronary Flow

Blood flow through the coronary system is regulated mostly by local arteriolar vasodilation in response to the nutritional needs of cardiac muscle. That is, whenever the vigor of cardiac contraction is increased, the rate of coronary blood flow also increases. Conversely, decreased heart activity is accompanied by decreased coronary flow. This local regulation of coronary blood flow is almost identical to that occurring in many other tissues of the body, especially in the skeletal muscles.

Oxygen Demand as a Major Factor in Local Coronary Blood Flow Regulation

Blood flow in the coronary arteries usually is regulated almost exactly in proportion to the need of the cardiac musculature for oxygen. Normally, about 70 percent of the oxygen in the coronary arterial blood is removed as the blood flows through the heart muscle. Because not much oxygen is left, very little additional oxygen can be supplied to the heart musculature unless the coronary blood flow increases. Fortunately, the coronary blood flow does increase almost in direct proportion to any additional metabolic consumption of oxygen by the heart.

However, the exact means by which increased oxygen consumption causes coronary dilation has not been determined. It is speculated by many research workers that a decrease in the oxygen concentration in the heart causes vasodilator substances to be released from the muscle cells and that these dilate the arterioles. A substance with great vasodilator propensity is adenosine. In the presence of very low concentrations of oxygen in the muscle cells, a large proportion of the cell’s ATP degrades to adenosine monophosphate; then small portions of this are further degraded and release adenosine into the tissue fluids of the heart muscle, with resultant increase in local coronary blood flow. After the adenosine causes vasodilation, much of it is reabsorbed into the cardiac cells to be reused.

Adenosine is not the only vasodilator product that has been identified. Others include adenosine phosphate compounds, potassium ions, hydrogen ions, carbon dioxide, prostaglandins, and nitric oxide. Yet the mechanisms of coronary vasodilation during increased cardiac activity have not been fully explained by adenosine. Pharmacologic agents that block or partially block the vasodilator effect of adenosine do not prevent coronary vasodilation caused by increased heart muscle activity. Studies in skeletal muscle have also shown that continued infusion of adenosine maintains vascular dilation for only 1 to 3 hours, and yet muscle activity still dilates the local blood vessels even when the adenosine can no longer dilate them. Therefore, the other vasodilator mechanisms listed earlier should be remembered.

Nervous Control of Coronary Blood Flow

Stimulation of the autonomic nerves to the heart can affect coronary blood flow both directly and indirectly. The direct effects result from action of the nervous transmitter substances acetylcholine from the vagus nerves and norepinephrine and epinephrine from the sympathetic nerves on the coronary vessels themselves. The indirect effects result from secondary changes in coronary blood flow caused by increased or decreased activity of the heart.

The indirect effects, which are mostly opposite to the direct effects, play a far more important role in normal control of coronary blood flow. Thus, sympathetic stimulation, which releases norepinephrine and epinephrine, increases both heart rate and heart contractility and increases the rate of metabolism of the heart. In turn, the increased metabolism of the heart sets off local blood flow regulatory mechanisms for dilating the coronary vessels, and the blood flow increases approximately in proportion to the metabolic needs of the heart muscle. In contrast, vagal stimulation, with its release of acetylcholine, slows the heart and has a slight depressive effect on heart contractility. These effects in turn decrease cardiac oxygen consumption and, therefore, indirectly constrict the coronary arteries.

Direct Effects of Nervous Stimuli on the Coronary Vasculature

The distribution of parasympathetic (vagal) nerve fibers to the ventricular coronary system is not very great. However, the acetylcholine released by parasympathetic stimulation has a direct effect to dilate the coronary arteries.

There is much more extensive sympathetic innervation of the coronary vessels. In Chapter 60, we see that the sympathetic transmitter substances norepinephrine and epinephrine can have either vascular constrictor or vascular dilator effects, depending on the presence or absence of constrictor or dilator receptors in the blood vessel walls. The constrictor receptors are called alpha receptors and the dilator receptors are called beta receptors. Both alpha and beta receptors exist in the coronary vessels. In general, the epicardial coronary vessels have a preponderance of alpha receptors, whereas the intramuscular arteries may have a preponderance of beta receptors. Therefore, sympathetic stimulation can, at least theoretically, cause slight overall coronary constriction or dilation, but usually constriction. In some people, the alpha vasoconstrictor effects seem to be disproportionately severe, and these people can have vasospastic myocardial ischemia during periods of excess sympathetic drive, often with resultant anginal pain.

Metabolic factors, especially myocardial oxygen consumption, are the major controllers of myocardial blood flow. Whenever the direct effects of nervous stimulation alter the coronary blood flow in the wrong direction, the metabolic control of coronary flow usually overrides the direct coronary nervous effects within seconds.

Special Features of Cardiac Muscle Metabolism

The basic principles of cellular metabolism, discussed in Chapters 67 through 72, apply to cardiac muscle the same as for other tissues, but there are some quantitative differences. Most important, under resting conditions, cardiac muscle normally consumes fatty acids to supply most of its energy instead of carbohydrates (about 70 percent of the energy is derived from fatty acids). However, as is also true of other tissues, under anaerobic or ischemic conditions, cardiac metabolism must call on anaerobic glycolysis mechanisms for energy. Unfortunately, glycolysis consumes tremendous quantities of the blood glucose and at the same time forms large amounts of lactic acid in the cardiac tissue, which is probably one of the causes of cardiac pain in cardiac ischemic conditions, as discussed later in this chapter.

As is true in other tissues, more than 95 percent of the metabolic energy liberated from foods is used to form ATP in the mitochondria. This ATP in turn acts as the conveyer of energy for cardiac muscular contraction and other cellular functions. In severe coronary ischemia, the ATP degrades first to adenosine diphosphate, then to adenosine monophosphate and adenosine. Because the cardiac muscle cell membrane is slightly permeable to adenosine, much of this can diffuse from the muscle cells into the circulating blood.

The released adenosine is believed to be one of the substances that causes dilation of the coronary arterioles during coronary hypoxia, as discussed earlier. However, loss of adenosine also has a serious cellular consequence. Within as little as 30 minutes of severe coronary ischemia, as occurs after a myocardial infarct, about one half of the adenine base can be lost from the affected cardiac muscle cells. Furthermore, this loss can be replaced by new synthesis of adenine at a rate of only 2 percent per hour. Therefore, once a serious bout of coronary ischemia has persisted for 30 or more minutes, relief of the ischemia may be too late to prevent injury and death of the cardiac cells. This almost certainly is one of the major causes of cardiac cellular death during myocardial ischemia.

Ischemic Heart Disease

The most common cause of death in Western culture is ischemic heart disease, which results from insufficient coronary blood flow. About 35 percent of people in the United States die of this cause. Some deaths occur suddenly as a result of acute coronary occlusion or fibrillation of the heart, whereas other deaths occur slowly over a period of weeks to years as a result of progressive weakening of the heart pumping process. In this chapter, we discuss acute coronary ischemia caused by acute coronary occlusion and myocardial infarction. In Chapter 22, we discuss congestive heart failure, the most frequent cause of which is slowly increasing coronary ischemia and weakening of the cardiac muscle.

Atherosclerosis as a Cause of Ischemic Heart Disease

The most frequent cause of diminished coronary blood flow is atherosclerosis. The atherosclerotic process is discussed in connection with lipid metabolism in Chapter 68. Briefly, this process is the following.

In people who have genetic predisposition to atherosclerosis, who are overweight or obese and have a sedentary lifestyle, or who have high blood pressure and damage to the endothelial cells of the coronary blood vessels, large quantities of cholesterol gradually become deposited beneath the endothelium at many points in arteries throughout the body. Gradually, these areas of deposit are invaded by fibrous tissue and frequently become calcified. The net result is the development of atherosclerotic plaques that actually protrude into the vessel lumens and either block or partially block blood flow. A common site for development of atherosclerotic plaques is the first few centimeters of the major coronary arteries.

Acute Coronary Occlusion

Acute occlusion of a coronary artery most frequently occurs in a person who already has underlying atherosclerotic coronary heart disease but almost never in a person with a normal coronary circulation. Acute occlusion can result from any one of several effects, two of which are the following:

1. The atherosclerotic plaque can cause a local blood clot called a thrombus, which in turn occludes the artery. The thrombus usually occurs where the arteriosclerotic plaque has broken through the endothelium, thus coming in direct contact with the flowing blood. Because the plaque presents an unsmooth surface, blood platelets adhere to it, fibrin is deposited, and red blood cells become entrapped to form a blood clot that grows until it occludes the vessel. Or, occasionally, the clot breaks away from its attachment on the atherosclerotic plaque and flows to a more peripheral branch of the coronary arterial tree, where it blocks the artery at that point. A thrombus that flows along the artery in this way and occludes the vessel more distally is called a coronary embolus.

2. Many clinicians believe that local muscular spasm of a coronary artery also can occur. The spasm might result from direct irritation of the smooth muscle of the arterial wall by the edges of an arteriosclerotic plaque, or it might result from local nervous reflexes that cause excess coronary vascular wall contraction. The spasm may then lead to secondary thrombosis of the vessel.

Lifesaving Value of Collateral Circulation in the Heart

The degree of damage to the heart muscle caused either by slowly developing atherosclerotic constriction of the coronary arteries or by sudden coronary occlusion is determined to a great extent by the degree of collateral circulation that has already developed or that can open within minutes after the occlusion.

In a normal heart, almost no large communications exist among the larger coronary arteries. But many anastomoses do exist among the smaller arteries sized 20 to 250 micrometers in diameter, as shown in Figure 21-6.


Figure 21-6 Minute anastomoses in the normal coronary arterial system.

When a sudden occlusion occurs in one of the larger coronary arteries, the small anastomoses begin to dilate within seconds. But the blood flow through these minute collaterals is usually less than one-half that needed to keep alive most of the cardiac muscle that they now supply; the diameters of the collateral vessels do not enlarge much more for the next 8 to 24 hours. But then collateral flow does begin to increase, doubling by the second or third day and often reaching normal or almost normal coronary flow within about 1 month. Because of these developing collateral channels, many patients recover almost completely from various degrees of coronary occlusion when the area of muscle involved is not too great.

When atherosclerosis constricts the coronary arteries slowly over a period of many years rather than suddenly, collateral vessels can develop at the same time while the atherosclerosis becomes more and more severe. Therefore, the person may never experience an acute episode of cardiac dysfunction. But, eventually, the sclerotic process develops beyond the limits of even the collateral blood supply to provide the needed blood flow, and sometimes the collateral blood vessels themselves develop atherosclerosis. When this occurs, the heart muscle becomes severely limited in its work output, often so much so that the heart cannot pump even normally required amounts of blood flow. This is one of the most common causes of the cardiac failure that occurs in vast numbers of older people.

Myocardial Infarction

Immediately after an acute coronary occlusion, blood flow ceases in the coronary vessels beyond the occlusion except for small amounts of collateral flow from surrounding vessels. The area of muscle that has either zero flow or so little flow that it cannot sustain cardiac muscle function is said to be infarcted. The overall process is called a myocardial infarction.

Soon after the onset of the infarction, small amounts of collateral blood begin to seep into the infarcted area, and this, combined with progressive dilation of local blood vessels, causes the area to become overfilled with stagnant blood. Simultaneously the muscle fibers use the last vestiges of the oxygen in the blood, causing the hemoglobin to become totally deoxygenated. Therefore, the infarcted area takes on a bluish-brown hue, and the blood vessels of the area appear to be engorged despite lack of blood flow. In later stages, the vessel walls become highly permeable and leak fluid; the local muscle tissue becomes edematous, and the cardiac muscle cells begin to swell because of diminished cellular metabolism. Within a few hours of almost no blood supply, the cardiac muscle cells die.

Cardiac muscle requires about 1.3 ml of oxygen per 100 grams of muscle tissue per minute just to remain alive. This is in comparison with about 8 ml of oxygen per 100 grams delivered to the normal resting left ventricle each minute. Therefore, if there is even 15 to 30 percent of normal resting coronary blood flow, the muscle will not die. In the central portion of a large infarct, however, where there is almost no collateral blood flow, the muscle does die.

Subendocardial Infarction

The subendocardial muscle frequently becomes infarcted even when there is no evidence of infarction in the outer surface portions of the heart. The reason for this is that the subendocardial muscle has extra difficulty obtaining adequate blood flow because the blood vessels in the subendocardium are intensely compressed by systolic contraction of the heart, as explained earlier. Therefore, any condition that compromises blood flow to any area of the heart usually causes damage first in the subendocardial regions, and the damage then spreads outward toward the epicardium.

Causes of Death After Acute Coronary Occlusion

The most common causes of death after acute myocardial infarction are (1) decreased cardiac output; (2) damming of blood in the pulmonary blood vessels and then death resulting from pulmonary edema; (3) fibrillation of the heart; and, occasionally, (4) rupture of the heart.

Decreased Cardiac Output—Systolic Stretch and Cardiac Shock

When some of the cardiac muscle fibers are not functioning and others are too weak to contract with great force, the overall pumping ability of the affected ventricle is proportionately depressed. Indeed, the overall pumping strength of the infarcted heart is often decreased more than one might expect because of a phenomenon called systolic stretch, shown in Figure 21-7. That is, when the normal portions of the ventricular muscle contract, the ischemic portion of the muscle, whether it is dead or simply nonfunctional, instead of contracting is forced outward by the pressure that develops inside the ventricle. Therefore, much of the pumping force of the ventricle is dissipated by bulging of the area of nonfunctional cardiac muscle.


Figure 21-7 Systolic stretch in an area of ischemic cardiac muscle.

When the heart becomes incapable of contracting with sufficient force to pump enough blood into the peripheral arterial tree, cardiac failure and death of peripheral tissues ensue as a result of peripheral ischemia. This condition is called coronary shock, cardiogenic shock, cardiac shock, or low cardiac output failure. It is discussed more fully in the next chapter. Cardiac shock almost always occurs when more than 40 percent of the left ventricle is infarcted. And death occurs in over 70 percent of patients once they develop cardiac shock.

Damming of Blood in the Body’s Venous System

When the heart is not pumping blood forward, it must be damming blood in the atria and in the blood vessels of the lungs or in the systemic circulation. This leads to increased capillary pressures, particularly in the lungs.

This damming of blood in the veins often causes little difficulty during the first few hours after myocardial infarction. Instead, symptoms develop a few days later for the following reason: The acutely diminished cardiac output leads to diminished blood flow to the kidneys. Then, for reasons that are discussed in Chapter 22, the kidneys fail to excrete enough urine. This adds progressively to the total blood volume and, therefore, leads to congestive symptoms. Consequently, many patients who seemingly are getting along well during the first few days after onset of heart failure will suddenly develop acute pulmonary edema and often will die within a few hours after appearance of the initial pulmonary symptoms.

Fibrillation of the Ventricles After Myocardial Infarction

Many people who die of coronary occlusion die because of sudden ventricular fibrillation. The tendency to develop fibrillation is especially great after a large infarction, but fibrillation can sometimes occur after small occlusions as well. Indeed, some patients with chronic coronary insufficiency die suddenly from fibrillation without any acute infarction.

There are two especially dangerous periods after coronary infarction during which fibrillation is most likely to occur. The first is during the first 10 minutes after the infarction occurs. Then there is a short period of relative safety, followed by a second period of cardiac irritability beginning 1 hour or so later and lasting for another few hours. Fibrillation can also occur many days after the infarct but less likely so.

At least four factors enter into the tendency for the heart to fibrillate:

1. Acute loss of blood supply to the cardiac muscle causes rapid depletion of potassium from the ischemic musculature. This also increases the potassium concentration in the extracellular fluids surrounding the cardiac muscle fibers. Experiments in which potassium has been injected into the coronary system have demonstrated that an elevated extracellular potassium concentration increases the irritability of the cardiac musculature and, therefore, its likelihood of fibrillating.

2. Ischemia of the muscle causes an “injury current,” which is described in Chapter 12 in relation to electrocardiograms in patients with acute myocardial infarction. That is, the ischemic musculature often cannot completely repolarize its membranes after a heartbeat, so the external surface of this muscle remains negative with respect to normal cardiac muscle membrane potential elsewhere in the heart. Therefore, electric current flows from this ischemic area of the heart to the normal area and can elicit abnormal impulses that can cause fibrillation.

3. Powerful sympathetic reflexes often develop after massive infarction, principally because the heart does not pump an adequate volume of blood into the arterial tree, which leads to reduced blood pressure. The sympathetic stimulation also increases irritability of the cardiac muscle and thereby predisposes to fibrillation.

4. Cardiac muscle weakness caused by the myocardial infarction often causes the ventricle to dilate excessively. This increases the pathway length for impulse conduction in the heart and frequently causes abnormal conduction pathways all the way around the infarcted area of the cardiac muscle. Both of these effects predispose to development of circus movements because, as discussed in Chapter 13, excess prolongation of conduction pathways in the ventricles allows impulses to re-enter muscle that is already recovering from refractoriness, thereby initiating a “circus movement” cycle of new excitation and causing the process to continue on and on.

Rupture of the Infarcted Area

During the first day or so after an acute infarct, there is little danger of rupture of the ischemic portion of the heart, but a few days later, the dead muscle fibers begin to degenerate, and the heart wall becomes stretched very thin. When this happens, the dead muscle bulges outward severely with each heart contraction, and this systolic stretch becomes greater and greater until finally the heart ruptures. In fact, one of the means used in assessing progress of severe myocardial infarction is to record by cardiac imaging (i.e., x-rays) whether the degree of systolic stretch is worsening.

When a ventricle does rupture, loss of blood into the pericardial space causes rapid development of cardiac tamponade—that is, compression of the heart from the outside by blood collecting in the pericardial cavity. Because of this compression of the heart, blood cannot flow into the right atrium, and the patient dies of suddenly decreased cardiac output.

Stages of Recovery from Acute Myocardial Infarction

The upper left part of Figure 21-8 shows the effects of acute coronary occlusion in a patient with a small area of muscle ischemia; to the right is shown a heart with a large area of ischemia. When the area of ischemia is small, little or no death of the muscle cells may occur, but part of the muscle often does become temporarily nonfunctional because of inadequate nutrition to support muscle contraction.


Figure 21-8 Top, Small and large areas of coronary ischemia. Bottom, Stages of recovery from myocardial infarction.

When the area of ischemia is large, some of the muscle fibers in the center of the area die rapidly, within 1 to 3 hours where there is total cessation of coronary blood supply. Immediately around the dead area is a nonfunctional area, with failure of contraction and usually failure of impulse conduction. Then, extending circumferentially around the nonfunctional area is an area that is still contracting but weakly so because of mild ischemia.

Replacement of Dead Muscle by Scar Tissue

In the lower part of Figure 21-8, the various stages of recovery after a large myocardial infarction are shown. Shortly after the occlusion, the muscle fibers in the center of the ischemic area die. Then, during the ensuing days, this area of dead fibers becomes bigger because many of the marginal fibers finally succumb to the prolonged ischemia. At the same time, because of enlargement of collateral arterial channels supplying the outer rim of the infarcted area, much of the nonfunctional muscle recovers. After a few days to 3 weeks, most of the nonfunctional muscle becomes functional again or dies—one or the other. In the meantime, fibrous tissue begins developing among the dead fibers because ischemia can stimulate growth of fibroblasts and promote development of greater than normal quantities of fibrous tissue. Therefore, the dead muscle tissue is gradually replaced by fibrous tissue. Then, because it is a general property of fibrous tissue to undergo progressive contraction and dissolution, the fibrous scar may grow smaller over a period of several months to a year.

Finally, the normal areas of the heart gradually hypertrophy to compensate at least partially for the lost dead cardiac musculature. By these means, the heart recovers either partially or almost completely within a few months.

Value of Rest in Treating Myocardial Infarction

The degree of cardiac cellular death is determined by the degree of ischemia and the workload on the heart muscle. When the workload is greatly increased, such as during exercise, in severe emotional strain, or as a result of fatigue, the heart needs increased oxygen and other nutrients for sustaining its life. Furthermore, anastomotic blood vessels that supply blood to ischemic areas of the heart must also still supply the areas of the heart that they normally supply. When the heart becomes excessively active, the vessels of the normal musculature become greatly dilated. This allows most of the blood flowing into the coronary vessels to flow through the normal muscle tissue, thus leaving little blood to flow through the small anastomotic channels into the ischemic area so that the ischemic condition worsens. This condition is called the “coronary steal” syndrome. Consequently, one of the most important factors in the treatment of a patient with myocardial infarction is observance of absolute body rest during the recovery process.

Function of the Heart After Recovery from Myocardial Infarction

Occasionally, a heart that has recovered from a large myocardial infarction returns almost to full functional capability, but more frequently its pumping capability is permanently decreased below that of a healthy heart. This does not mean that the person is necessarily a cardiac invalid or that the resting cardiac output is depressed below normal, because the normal heart is capable of pumping 300 to 400 percent more blood per minute than the body requires during rest—that is, a normal person has a “cardiac reserve” of 300 to 400 percent. Even when the cardiac reserve is reduced to as little as 100 percent, the person can still perform most normal daily activities but not strenuous exercise that would overload the heart.

Pain in Coronary Heart Disease

Normally, a person cannot “feel” his or her heart, but ischemic cardiac muscle often does cause pain sensation, sometimes severe. Exactly what causes this pain is not known, but it is believed that ischemia causes the muscle to release acidic substances, such as lactic acid, or other pain-promoting products, such as histamine, kinins, or cellular proteolytic enzymes, that are not removed rapidly enough by the slowly moving coronary blood flow. The high concentrations of these abnormal products then stimulate pain nerve endings in the cardiac muscle, sending pain impulses through sensory afferent nerve fibers into the central nervous system.

Angina Pectoris

In most people who develop progressive constriction of their coronary arteries, cardiac pain, called angina pectoris, begins to appear whenever the load on the heart becomes too great in relation to the available coronary blood flow. This pain is usually felt beneath the upper sternum over the heart, and in addition it is often referred to distant surface areas of the body, most commonly to the left arm and left shoulder but also frequently to the neck and even to the side of the face. The reason for this distribution of pain is that the heart originates during embryonic life in the neck, as do the arms. Therefore, both the heart and these surface areas of the body receive pain nerve fibers from the same spinal cord segments.

Most people who have chronic angina pectoris feel pain when they exercise or when they experience emotions that increase metabolism of the heart or temporarily constrict the coronary vessels because of sympathetic vasoconstrictor nerve signals. Anginal pain is also exacerbated by cold temperatures or by having a full stomach, both of which increase the workload of the heart. The pain usually lasts for only a few minutes. However, some patients have such severe and lasting ischemia that the pain is present all the time. The pain is frequently described as hot, pressing, and constricting; it is of such quality that it usually makes the patient stop all unnecessary body activity and come to a complete state of rest.

Treatment with Drugs

Several vasodilator drugs, when administered during an acute anginal attack, can often give immediate relief from the pain. Commonly used short-acting vasodilators are nitroglycerin and other nitrate drugs. Other vasodilators, such as angiotensin converting enzyme inhibitors, angiotensin receptor blockers, calcium channel blockers, and ranolazine, may be beneficial in treating chronic stable angina pectoris.

Another class of drugs used for prolonged treatment of angina pectoris is the beta blockers, such as propranolol. These drugs block sympathetic beta-adrenergic receptors, which prevents sympathetic enhancement of heart rate and cardiac metabolism during exercise or emotional episodes. Therefore, therapy with a beta blocker decreases the need of the heart for extra metabolic oxygen during stressful conditions. For obvious reasons, this can also reduce the number of anginal attacks, as well as their severity.

Surgical Treatment of Coronary Artery Disease

Aortic-Coronary Bypass Surgery

In many patients with coronary ischemia, the constricted areas of the coronary arteries are located at only a few discrete points blocked by atherosclerotic disease and the coronary vessels elsewhere are normal or almost normal. A surgical procedure was developed in the 1960s, called aortic-coronary bypass, for removing a section of a subcutaneous vein from an arm or leg and then grafting this vein from the root of the aorta to the side of a peripheral coronary artery beyond the atherosclerotic blockage point. One to five such grafts are usually performed, each of which supplies a peripheral coronary artery beyond a block.

Anginal pain is relieved in most patients. Also, in patients whose hearts have not become too severely damaged before the operation, the coronary bypass procedure may provide the patient with normal survival expectation. If the heart has already been severely damaged, however, the bypass procedure is likely to be of little value.

Coronary Angioplasty

Since the 1980s, a procedure has been used to open partially blocked coronary vessels before they become totally occluded. This procedure, called coronary artery angioplasty, is the following: A small balloon-tipped catheter, about 1 millimeter in diameter, is passed under radiographic guidance into the coronary system and pushed through the partially occluded artery until the balloon portion of the catheter straddles the partially occluded point. Then the balloon is inflated with high pressure, which markedly stretches the diseased artery. After this procedure is performed, the blood flow through the vessel often increases threefold to fourfold, and more than 75 percent of the patients who undergo the procedure are relieved of the coronary ischemic symptoms for at least several years, although many of the patients still eventually require coronary bypass surgery.

Small stainless steel mesh tubes called “stents” are sometimes placed inside a coronary artery dilated by angioplasty to hold the artery open, thus preventing its restenosis. Within a few weeks after the stent is placed in the coronary artery, the endothelium usually grows over the metal surface of the stent, allowing blood to flow smoothly through the stent. However, reclosure (restenosis) of the blocked coronary artery occurs in about 25 to 40 percent of patients treated with angioplasty, often within 6 months of the initial procedure. This is usually due to excessive formation of scar tissue that develops underneath the healthy new endothelium that has grown over the stent. Stents that slowly release drugs (drug-eluting stents) may help to prevent the excessive growth of scar tissue.

Newer procedures for opening atherosclerotic coronary arteries are constantly in experimental development. One of these employs a laser beam from the tip of a coronary artery catheter aimed at the atherosclerotic lesion. The laser literally dissolves the lesion without substantially damaging the rest of the arterial wall.


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