Guyton and Hall Physiology Chapter 21 - Muscle Blood Flow and Cardiac Output During Exercise.PDF

CHAPTER 21 UNIT IV Muscle Blood Flow and Cardiac Output ­During Exercise; the Coronary Circulation an...

CHAPTER 21 UNIT IV Muscle Blood Flow and Cardiac Output ­During Exercise; the Coronary Circulation and Ischemic Heart Disease In this chapter we consider the following: (1) blood flow vessels, the blood flow can be almost stopped, but this to the skeletal muscles; and (2) coronary artery blood flow also causes rapid weakening of the contraction. to the heart. Regulation of each of these types of blood flow is achieved mainly by local control of vascular resis- Increased Blood Flow in Muscle Capillaries During tance in response to muscle tissue metabolic needs. Exercise. During rest, some muscle capillaries have lit- We also discuss the physiology of related subjects, tle or no flowing blood, but during strenuous exercise, all including the following: (1) cardiac output control during the capillaries open. This opening of dormant capillaries exercise; (2) characteristics of heart attacks; and (3) the diminishes the distance that oxygen and other nutrients pain of angina pectoris. must diffuse from the capillaries to the contracting mus- cle fibers; it sometimes contributes a twofold to threefold increased capillary surface area through which oxygen BLOOD FLOW REGULATION IN and nutrients can diffuse from the blood to the tissues. SKELETAL MUSCLE AT REST AND DURING EXERCISE CONTROL OF SKELETAL MUSCLE BLOOD Strenuous exercise is one of the most stressful conditions FLOW that the normal circulatory system faces because there is such a large mass of skeletal muscle in the body, all of it Decreased Oxygen in Muscle Greatly Enhances Flow. requiring large amounts of blood flow. Also, the cardiac The large increase in muscle blood flow that occurs dur- output often must increase to four to five times normal ing skeletal muscle activity is caused mainly by chemicals in the nonathlete or to six to seven times normal in the released locally that act directly on the muscle arterioles well-­trained athlete to satisfy the metabolic needs of the to cause dilation. One of the most important chemical ef- exercising muscles. fects is reduction of the oxygen level in the muscle tissues. When muscles are active, they use oxygen rapidly, thereby decreasing the oxygen concentration in the tissue fluids. SKELETAL MUSCLE BLOOD FLOW RATE This in turn causes local arteriolar vasodilation because During rest, skeletal muscle blood flow averages 3 to 4 ml/ min/100 g of muscle. During extreme exercise in the well-­ Rhythmic exercise conditioned athlete, this blood flow can increase 25-­to 40 Blood flow (×100 ml/min) 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 for thigh muscles of endurance-­trained athletes. 20 Blood Flow During Muscle Contractions. Figure 21-­1 shows a record of blood flow changes in a calf muscle of a leg during strong rhythmic muscular exercise. Note that Calf the flow increases and decreases with each muscle con- flow traction. At the end of the contractions, the blood flow 0 0 10 16 18 remains high for a few seconds but then returns to normal Minutes during the next few minutes. The cause of the lower flow during the muscle contrac- Figure 21-­1. Effects of muscle exercise on blood flow in the calf of a leg during strong rhythmic contraction. The blood flow was much tion phase of exercise is compression of the blood vessels less during contractions than between contractions. (Modified from by the contracted muscle. During strong tetanic contrac- Barcroft H, Dornhorst AC: The blood flow through the human calf tion, which causes sustained compression of the blood during rhythmic exercise. J Physiol 109:402, 1949.) 259 UNIT IV The Circulation low oxygen levels cause the blood vessels to relax and because oxygen deficiency causes release of vasodilator Effects of Sympathetic Activation substances. Adenosine may be an important vasodilator At the onset of exercise, signals are transmitted not only substance, but experiments have shown that even large from the brain to the muscles to cause muscle contrac- amounts of adenosine infused directly into a muscle ar- tion but also into the vasomotor center to initiate sym-­ tery cannot increase blood flow to the same extent as dur- pathetic discharge in many other tissues. Simultaneously, ing intense exercise, and it cannot sustain vasodilation in the parasympathetic signals to the heart are attenuated. skeletal muscle for more than about 2 hours. Therefore, three major circulatory effects result: Fortunately, even after the muscle blood vessels have 1. The heart is stimulated to a greatly increased become insensitive to the vasodilator effects of adenosine, heart rate and increased pumping strength as a other vasodilator factors continue to maintain increased result of the sympathetic drive to the heart plus capillary blood flow as long as the exercise continues. release of the heart from normal parasympathetic These factors include the following: (1) potassium ions; inhibition. (2) adenosine triphosphate (ATP); (3) lactic acid; and (4) 2. Many of the arterioles of the peripheral circulation carbon dioxide. We still do not know quantitatively how are strongly contracted, except for the arterioles in much of a role each of these factors plays in increasing the active muscles, which are strongly vasodilated muscle blood flow during muscle activity; this subject was by the local vasodilator effects in the muscles, as discussed in additional detail in Chapter 17. noted earlier. Thus, the heart is stimulated to sup- ply the increased blood flow required by the mus- Nervous Control of Muscle Blood Flow. In addition to cles, while at the same time blood flow through local tissue vasodilator mechanisms, skeletal muscles are most nonmuscular areas of the body is temporarily provided with sympathetic vasoconstrictor nerves and, in reduced, thereby “lending” blood supply to the mus- some species of animals, sympathetic vasodilator nerves cles. This process accounts for as much as 2 L/min as well. of extra blood flow to the muscles, which is ex- The sympathetic vasoconstrictor nerve fibers secrete ceedingly important when considering a person norepinephrine at their nerve endings. When maxi- running for his or her life, when even a fractional mally activated, this mechanism can decrease blood increase in running speed may make the difference flow through resting muscles to as little as one-­half to between life and death. Two of the peripheral circu- one-­third normal. This vasoconstriction is of physiologic latory systems, the coronary and cerebral systems, importance in attenuating decreases of arterial pressure are spared this vasoconstrictor effect because both in circulatory shock and during other periods of stress, these circulatory areas have poor vasoconstrictor when it may even be necessary to increase blood pressure. innervation—fortunately so, because both the heart In addition to the norepinephrine secreted at the sym- and brain are as essential to exercise as the skeletal pathetic vasoconstrictor nerve endings, the medullae of muscles. the two adrenal glands also secrete increased amounts 3. The muscle walls of the veins and other capacita- of norepinephrine plus even more epinephrine into the tive areas of the circulation are contracted pow- circulating blood during strenuous exercise. The circulat- erfully, which greatly increases the mean systemic ing norepinephrine acts on the muscle vessels to cause filling pressure. As we learned in Chapter 20, this a vasoconstrictor effect similar to that caused by direct effect is one of the most important factors in pro- sympathetic nerve stimulation. The epinephrine, how- moting the increase in venous return of blood to ever, often has a slight vasodilator effect because epi- the heart and, therefore, in increasing the cardiac nephrine excites more of the beta-­adrenergic receptors output. of the vessels, which are vasodilator receptors, in con- trast to the alpha vasoconstrictor receptors excited espe- Sympathetic Stimulation May Increase cially by norepinephrine. These receptors are discussed Arterial Pressure During Exercise in Chapter 61. An important effect of increased sympathetic stimula- tion in exercise is to increase the arterial pressure. This increased arterial pressure results from multiple stimula- CIRCULATORY READJUSTMENTS DURING tory effects, including the following: (1) vasoconstriction EXERCISE of the arterioles and small arteries in most tissues of the Three major effects occur during exercise that are body except the brain and active muscles, including the essential for the circulatory system to supply the tre- heart; (2) increased pumping activity by the heart; and (3) mendous blood flow required by the muscles: (1) sym- a great increase in mean systemic filling pressure caused pathetic nervous system activation in many tissues with mainly by venous contraction. These effects, working consequent stimulatory effects on the circulation; (2) together, almost always increase the arterial pressure dur- increase in arterial pressure; and (3) increase in cardiac ing exercise. This increase can be as little as 20 mm Hg output. or as much as 80 mm Hg, depending on the conditions 260  Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise under which the exercise is performed. When a person 25 performs exercise under tense conditions but uses only B venous return (L/min) a few muscles, the sympathetic nervous response still 20 Cardiac output and occurs. In the few active muscles, vasodilation occurs, but 15 elsewhere in the body the effect is mainly vasoconstric- UNIT IV tion, often increasing the mean arterial pressure to as high 10 as 170 mm Hg. Such a condition might occur in a person standing on a ladder and nailing with a hammer on the 5 A ceiling above. The tenseness of the situation is obvious. Conversely, when a person performs massive whole-­body 0 exercise, such as running or swimming, the increase in arte- 4 0 +4 +8 +12 +16 +20 +24 rial pressure is often only 20 to 40 mm Hg. This lack of a large Right atrial pressure (mm Hg) increase in pressure results from the extreme vasodilation Figure 21-­2. Graphic analysis of change in cardiac output, venous that occurs simultaneously in large masses of active muscle. return, and right atrial pressure with the onset of strenuous exercise. Black curves, Normal circulation. Red curves, heavy exercise. Why Is Increased Arterial Pressure During Exercise Important? When muscles are stimulated maximally in The increased level of the cardiac output curve is easy a laboratory experiment, but without allowing the arte- to understand. It results almost entirely from sympathetic rial pressure to rise, muscle blood flow seldom rises more stimulation of the heart, which causes the following: (1) than about eightfold. Yet, we know from studies of mara- increased heart rate, up to as high as 170 to 190 beats/ thon runners that muscle blood flow can increase from as min; and (2) increased strength of contraction of the heart little as 1 L/min for the whole body during rest to more to as much as twice normal. Without this increased level than 20 L/min during maximal activity. Therefore, it is of cardiac function, the increase in cardiac output would clear that muscle blood flow can increase much more than be limited to the plateau level of the normal heart, which that which occurs in this simple laboratory experiment. would be a maximum increase of cardiac output of only What is the difference? Mainly, the arterial pressure rises about 2.5-­fold rather than the 4-fold increase that can during normal exercise. Let us assume, for example, that commonly be achieved by the untrained runner and the the arterial pressure rises by 30% during heavy exercise. 7-fold increase that can be achieved in some marathon This 30% increase causes 30% more force to push blood runners. through the muscle tissue vessels. However, this is not the Now study the venous return curves. If no change only important effect—the extra pressure also stretches occurred from the normal venous return curve, the car- the walls of the vessels, and this effect, along with the lo- diac output could hardly rise at all in exercise because cally released vasodilators and higher blood pressure, may the upper plateau level of the normal venous return increase muscle total flow to more than 20 times normal. curve is only 6 L/min. Yet, two important changes do occur: Importance of Increased Cardiac Output 1. The mean systemic filling pressure rises at the on- During Exercise set of heavy exercise. This effect results partly from Many different physiologic effects occur at the same time the sympathetic stimulation that contracts the veins during exercise to increase cardiac output approximately and other capacitative parts of the circulation. In in proportion to the degree of exercise. In fact, the abil- addition, tensing of the abdominal and other skel- ity of the circulatory system to provide increased cardiac etal muscles of the body compresses many of the output for delivery of oxygen and other nutrients to the internal vessels, thus providing more compression muscles during exercise is equally as important as the of the entire capacitative vascular system and caus- strength of the muscles themselves in setting the limit for ing a still greater increase in the mean systemic fill- continued muscle work. For example, marathon runners ing pressure. During maximal exercise, these two who can increase their cardiac outputs the most are gen- effects together can increase the mean systemic fill- erally the ones who have record-­breaking running times. ing pressure from a normal level of 7 mm Hg to as high as 30 mm Hg. Graphic Analysis of Changes in Cardiac Output 2. The slope of the venous return curve rotates up- ­During Heavy Exercise. Figure 21-­2 shows a graphic ward. This upward rotation is caused by decreased analysis of the large increase in cardiac output that occurs resistance in virtually all the blood vessels in active during heavy exercise. The cardiac output and venous muscle tissue, which also causes resistance to ve- return curves crossing at point A represent the normal nous return to decrease, thus increasing the upward circulation, and the curves crossing at point B represent slope of the venous return curve. heavy exercise. Note that the great increase in cardiac Therefore, the combination of increased mean sys- output requires significant changes in both the cardiac temic filling pressure and decreased resistance to venous output curve and the venous return curve, as follows. return raises the entire level of the venous return curve. 261 UNIT IV The Circulation Coronary blood flow (ml/min) Aorta 300 Pulmonary artery 200 Left coronary artery Right coronary 100 artery Left circumflex branch 0 Left anterior Systole Diastole descending Figure 21-­4. Phasic flow of blood through the coronary capillaries branch of the human left ventricle during cardiac systole and diastole (as extrapolated from measured flows in dogs). Figure 21-­3. Coronary arteries. Most of the coronary venous blood flow from the In response to the changes in both the venous return left ventricular muscle returns to the right atrium of the curve and cardiac output curve, the new equilibrium heart by way of the coronary sinus, which is about 75% of point in Figure 21-­2 for cardiac output and right atrial the total coronary blood flow. On the other hand, most pressure is now point B, in contrast to the normal level at of the coronary venous blood from the right ventricu- point A. Note especially that the right atrial pressure has lar muscle returns through small anterior cardiac veins hardly changed, having risen only 1.5 mm Hg. In fact, in a that flow directly into the right atrium, not by way of the person with a strong heart, the right atrial pressure often coronary sinus. A very small amount of coronary venous falls below normal during very heavy exercise because blood also flows back into the heart through very minute of the greatly increased sympathetic stimulation of the thebesian veins, which empty directly into all chambers heart. In contrast, even a moderate level of exercise may of the heart. cause marked increases in right atrial pressure in patients with weakened hearts. NORMAL CORONARY BLOOD FLOW AVERAGES 5% OF CARDIAC OUTPUT CORONARY CIRCULATION The normal coronary blood flow in the resting person About one-third of all deaths in industrialized countries averages 70 ml/min/100 g of heart weight, or about of the Western world result from coronary artery disease, 225 ml/min, which is about 4% to 5% of the total cardiac and most older adults have at least some impairment of output. the coronary artery circulation. For this reason, under- During strenuous exercise, the heart in the young adult standing normal and pathological physiology of the coro- increases its cardiac output fourfold to sevenfold, and it nary circulation is one of the most important subjects in pumps this blood against a higher than normal arterial medicine. pressure. Consequently, the work output of the heart under severe conditions may increase 6-fold to 9-fold. At the same time, the coronary blood flow increases PHYSIOLOGIC ANATOMY OF THE 3-fold to 4-fold to supply the extra nutrients needed by CORONARY BLOOD SUPPLY the heart. This increase is not as much as the increase in Figure 21-­3 shows the heart and its coronary blood sup- workload, which means that the ratio of energy expendi- ply. Note that the main coronary arteries lie on the surface ture by the heart to coronary blood flow increases. Thus, of the heart, and smaller arteries then penetrate from the the efficiency of cardiac utilization of energy increases surface into the cardiac muscle mass. It is almost entirely to make up for the relative deficiency of coronary blood through these arteries that the heart receives its nutri- supply. tive blood supply. Only the inner one-­tenth millimeter of the endocardial surface can obtain significant nutrition Cardiac Muscle Compression Causes Phasic Changes directly from the blood inside the cardiac chambers, so in Coronary Blood Flow During Systole and Diastole. this source of muscle nutrition is minuscule. Figure 21-­4 shows the changes in blood flow through The left coronary artery supplies mainly the anterior the nutrient capillaries of the left ventricular coronary and left lateral portions of the left ventricle, whereas the system in ml/min in the heart during systole and dias- right coronary artery supplies most of the right ventricle, tole, as extrapolated from studies in experimental ani- as well as the posterior part of the left ventricle in 80% to mals. Note from this diagram that the coronary capil- 90% of people. lary blood flow in the left ventricle muscle falls to a low 262  Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise Epicardial coronary arteries Oxygen Demand Is a Major Factor in Local Coronary Blood Flow Regulation. Blood flow in the coronary ar- teries usually is regulated almost exactly in proportion to Cardiac the need of the cardiac musculature for oxygen. Normally, muscle about 70% of the oxygen in the coronary arterial blood UNIT IV Subendocardial arterial plexus is removed as the blood flows through the heart muscle. Because not much oxygen is left, little additional oxy- Figure 21-­5. Diagram of the epicardial, intramuscular, and subendo- cardial coronary vasculature. gen can be supplied to the heart musculature unless the coronary blood flow increases. Fortunately, the coronary value during systole, which is opposite to flow in vascular blood flow increases almost in direct proportion to any beds elsewhere in the body. The reason for this phenom- additional metabolic consumption of oxygen by the heart. enon is strong compression of the intramuscular blood The exact means whereby increased oxygen consump- vessels by the left ventricular muscle during systolic con- tion causes coronary dilation has not been determined. traction. Many researchers have speculated that a decrease in oxy- During diastole, the cardiac muscle relaxes and no lon- gen concentration in the heart causes vasodilator sub- ger obstructs blood flow through the left ventricular mus- stances to be released from the muscle cells and that these cle capillaries, so blood flows rapidly during all of diastole. substances dilate the arterioles. A substance with great Blood flow through the coronary capillaries of the vasodilator propensity is adenosine. In the presence of right ventricle also undergoes phasic changes during the very low concentrations of oxygen in the muscle cells, a cardiac cycle but, because the force of contraction of the large proportion of the cell’s ATP degrades to adenosine right ventricular muscle is far less than that of the left monophosphate (AMP). Small portions of this substance ventricular muscle, the inverse phasic changes are only are then further degraded and release adenosine to the partial, in contrast to those in the left ventricular muscle. tissue fluids of the heart muscle, with a resultant increase in local coronary blood flow. After adenosine causes vaso- Epicardial Versus Subendocardial Coronary Blood dilation, much of it is reabsorbed into the cardiac cells to Flow—Effect of Intramyocardial Pressure. Figure 21-­ be reused for production of ATP. 5 demonstrates the special arrangement of the coronary Adenosine is not the only vasodilator product that vessels at different depths in the heart muscle, showing has been identified; others include adenosine phosphate on the outer surface epicardial coronary arteries which compounds, potassium ions, hydrogen ions, carbon diox- supply most of the muscle. Smaller intramuscular arteries ide, prostaglandins, and nitric oxide. The mechanisms of derived from the epicardial arteries penetrate the mus- coronary vasodilation during increased cardiac activity cle, supplying the needed nutrients. Lying immediately have not been fully explained by adenosine. Pharmaco- beneath the endocardium is a plexus of subendocardial logic agents that block or partially block the vasodilator arteries. During systole, blood flow through the subendo- effect of adenosine do not completely prevent coronary cardial plexus of the left ventricle, where the intramuscu- vasodilation caused by increased heart muscle activity. lar coronary vessels are compressed greatly by ventricular Studies in skeletal muscle have also shown that the con- muscle contraction, tends to be reduced. However, the tinued infusion of adenosine maintains vascular dilation extra vessels of the subendocardial plexus normally com- for only 1 to 3 hours, yet muscle activity still dilates the pensate for this reduction. Later in the chapter, we explain local blood vessels, even when the adenosine can no lon- how this peculiar difference between blood flow in the ger dilate them. Therefore, the other vasodilator mecha- epicardial and subendocardial arteries plays an important nisms listed earlier should be remembered. role in certain types of coronary ischemia. Nervous Control of Coronary Blood Flow Stimulation of the autonomic nerves to the heart can CONTROL OF CORONARY BLOOD FLOW affect coronary blood flow directly and indirectly. The Local Muscle Metabolism Is the Primary direct effects result from action of the nervous transmit- Controller of Coronary Flow ter substances acetylcholine from the vagus nerves and norepinephrine from the sympathetic nerves on the coro- Blood flow through the coronary system is regulated nary vessels. The indirect effects result from secondary mostly by local arteriolar vasodilation in response to the changes in coronary blood flow caused by increased or nutritional needs of cardiac muscle. That is, whenever decreased activity of the heart. the vigor of cardiac contraction is increased, the rate of The indirect effects, which are mostly opposite to the coronary blood flow also increases. Conversely, decreased direct effects, play a far more important role in the normal heart activity is accompanied by decreased coronary flow. control of coronary blood flow. Thus, sympathetic stimu- This local regulation of coronary blood flow is similar to lation, which releases norepinephrine from the sympa- that which occurs in many other tissues of the body, espe- thetic nerves and epinephrine, as well as norepinephrine cially in the skeletal muscles. from the adrenal medullae, increases both heart rate and 263 UNIT IV The Circulation heart contractility and increases the rate of metabolism of amounts of lactic acid in the cardiac tissue. This is prob- the heart. In turn, the increased metabolism of the heart ably one of the causes of cardiac pain in cardiac ischemic sets off local blood flow regulatory mechanisms for dilat- conditions, as discussed later in this chapter. ing the coronary vessels and blood flow increases approx- As is true in other tissues, more than 95% of the meta- imately in proportion to the metabolic needs of the heart bolic energy liberated from foods is used to form ATP in muscle. In contrast, vagal stimulation, with its release of the mitochondria. This ATP in turn acts as the conveyer acetylcholine, slows the heart and has a slightly depressive of energy for cardiac muscular contraction and other cel- effect on heart contractility. These effects decrease car- lular functions. In severe coronary ischemia, the ATP diac oxygen consumption and, therefore, indirectly con- degrades first to adenosine diphosphate and then to AMP strict the coronary arteries. and adenosine. Because the cardiac muscle cell membrane is slightly permeable to adenosine, much of this agent can Direct Effects of Nervous Stimuli on Coronary diffuse from the muscle cells into the circulating blood. ­Vasculature. The distribution of parasympathetic (vagal) The released adenosine is believed to be one of the nerve fibers to the ventricular coronary system is not very substances that causes dilation of the coronary arterioles great. However, the acetylcholine released by parasympa- during coronary hypoxia, as discussed earlier. However, thetic stimulation has a direct effect to dilate the coronary loss of adenosine also has a serious cellular consequence. arteries. Within as little as 30 minutes of severe coronary ischemia, Much more extensive sympathetic innervation of the as occurs after a myocardial infarct, about half of the coronary vessels occurs. In Chapter 61, we see that the adenine base can be lost from the affected cardiac mus- sympathetic transmitter substances norepinephrine and cle cells. Furthermore, this loss can be replaced by new epinephrine can have vascular constrictor or vascular synthesis of adenine at a rate of only 2%/hour. Therefore, dilator effects, depending on the presence or absence of once a serious bout of coronary ischemia has persisted constrictor or dilator receptors in the blood vessel walls. for 30 minutes or longer, relief of the ischemia may be too The constrictor receptors are called alpha receptors, and late to prevent injury and death of the cardiac cells. This the dilator receptors are called beta receptors. Both alpha is almost certainly one of the major causes of cardiac cel- and beta receptors exist in the coronary vessels. In gen- lular death during myocardial ischemia. eral, the epicardial coronary vessels have a preponderance of alpha receptors, whereas the intramuscular arteries ISCHEMIC HEART DISEASE may have a preponderance of beta receptors. Therefore, sympathetic stimulation can, at least theoretically, cause The most common cause of death in the Western coun- slight overall coronary constriction or dilation, but usu- tries is ischemic heart disease, which results from insuf- ally constriction. In some people, the alpha vasoconstric- ficient coronary blood flow. About 35% of people in the tor effects seem to be disproportionately severe, and these United States aged 65 years and older die of this cause. people can have vasospastic myocardial ischemia during Some deaths occur suddenly as a result of acute coronary periods of excess sympathetic drive, often with resultant occlusion or fibrillation of the heart, whereas other deaths anginal pain. occur slowly over a period of weeks to years as a result of Metabolic factors, especially myocardial oxygen con- progressive weakening of the heart pumping process. In sumption, are the major controllers of myocardial blood this chapter, we discuss acute coronary ischemia caused flow. Whenever the direct effects of nervous stimulation by acute coronary occlusion and myocardial infarction. In reduce coronary blood flow, the metabolic control of cor- Chapter 22, we discuss congestive heart failure, which is onary flow usually overrides the direct coronary nervous frequently caused by slowly increasing coronary ischemia effects within seconds. and weakening of the cardiac muscle. Atherosclerosis Is a Major Cause of Ischemic Heart SPECIAL FEATURES OF CARDIAC MUSCLE Disease. A frequent cause of diminished coronary blood METABOLISM flow is atherosclerosis. The atherosclerotic process is dis- The basic principles of cellular metabolism, discussed cussed in connection with lipid metabolism in Chapter in Chapters 68 through 73, apply to cardiac muscle the 69. Briefly, in people who have a genetic predisposition to same as for other tissues, but some quantitative differ- atherosclerosis, who are overweight or obese and have a ences exist. Most importantly, under resting conditions, sedentary lifestyle, or who have high blood pressure and cardiac muscle normally consumes more fatty acids than damage to the endothelial cells of the coronary blood ves- carbohydrates to supply its energy (≈ 70% of the energy is sels, large quantities of cholesterol gradually become de- derived from fatty acids). However, as is also true of other posited beneath the endothelium at many points in arter- tissues, under anaerobic or ischemic conditions, cardiac ies throughout the body. Gradually, these areas of deposit metabolism must call on anaerobic glycolysis mechanisms are invaded by fibrous tissue and frequently become calci- for energy. However, glycolysis consumes large quantities fied. The net result is the development of atherosclerotic of the blood glucose and, at the same time, forms large plaques, which actually protrude into the vessel lumens 264  Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise and block or partially block blood flow. A common site for development of atherosclerotic plaques is the first few Artery centimeters of the major coronary arteries. Acute Coronary Artery Occlusion UNIT IV Acute occlusion of a coronary artery usually occurs in a Vein person who already has underlying atherosclerotic coro- nary heart disease but almost never occurs in a person with a normal coronary circulation. Acute occlusion can have various causes, two of which are the following: 1. The atherosclerotic plaque can cause a local blood clot called a thrombus that occludes the artery. The thrombus usually occurs where the arteriosclerotic plaque has broken through the endothelium, thus coming into direct contact with the flowing blood. Because the plaque presents an unsmooth surface, Artery blood platelets adhere to it, fibrin is deposited, and red blood cells become trapped to form a blood clot that grows until it occludes the vessel. Occasionally, Vein the clot breaks away from its attachment on the ath- erosclerotic plaque and flows to a more peripheral Figure 21-­6. Minute anastomoses in the normal coronary arterial system. 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 of coronary occlusion when the area of muscle involved is distally is called a coronary embolus. not too large. 2. Many clinicians believe that local muscular spasm of When atherosclerosis constricts the coronary arteries a coronary artery also can occur. The spasm might slowly over a period of many years, rather than suddenly, result from direct irritation of the smooth muscle collateral vessels can develop at the same time, while the of the arterial wall by the edges of an arterioscle- atherosclerosis becomes more and more severe. Therefore, rotic plaque, or it might result from local nervous the person may never experience an acute episode of car- reflexes that cause excess coronary vascular wall diac dysfunction. Eventually, however, the sclerotic process contraction. The spasm may then lead to secondary develops beyond the limits of even the collateral blood sup- thrombosis of the vessel. ply to provide the needed blood flow, and sometimes, the collateral blood vessels themselves develop atherosclerosis. Lifesaving Value of Collateral Circulation in the When this occurs, the heart muscle becomes severely lim- Heart. The degree of damage to the heart muscle caused ited in its work output, and the heart cannot pump even by slowly developing atherosclerotic constriction of the normally required amounts of blood flow. This is one of coronary arteries or by sudden coronary occlusion is the most common causes of cardiac failure in older people. determined to a great extent by the degree of collateral circulation that has already developed or that can open Myocardial Infarction within minutes after the occlusion. In a normal heart, Immediately after an acute coronary occlusion, blood almost no large communications exist among the larger flow ceases in the coronary vessels beyond the occlusion, coronary arteries. However, many anastomoses do exist except for small amounts of collateral flow from sur- among the smaller arteries of 20 to 250 micrometers in rounding vessels. The area of muscle that has zero flow or diameter, as shown in Figure 21-­6. so little flow that it cannot sustain cardiac muscle func- When a sudden occlusion occurs in one of the larger tion is said to be infarcted. The overall process is called a coronary arteries, the small anastomoses begin to dilate myocardial infarction. within seconds. However, the blood flow through these Soon after the onset of the infarction, small amounts minute collaterals is usually less than half of that needed of collateral blood begin to infiltrate the infarcted area, to keep most of the cardiac muscle alive that they now which, combined with progressive dilation of local blood supply. The diameters of the collateral vessels do not vessels, causes the area to become overfilled with stag- enlarge much more for the next 8 to 24 hours. Then, nant blood. Simultaneously the muscle fibers use the last however, collateral flow begins to increase, doubling bits of the oxygen in the blood, causing the hemoglobin by the second or third day and often reaching normal to become totally deoxygenated. Therefore, the infarcted or almost normal coronary flow within about 1 month. area takes on a bluish-­brown hue, and the blood vessels of Because of these developing collateral channels, many the area appear to be engorged, despite lack of blood flow. patients recover almost completely from various degrees In later stages, the vessel walls become highly permeable 265 UNIT IV The Circulation and leak fluid, the local muscle tissue becomes edema- tous, 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/100 g of muscle tissue/min just to remain alive. In compari- son, about 8 ml oxygen/100 g are delivered to the normal resting left ventricle each minute. Therefore, if there is even 15% to 30% of normal resting coronary blood flow, Normal the muscle will not die. In the central portion of a large contraction infarct, however, where there is almost no collateral blood flow, the muscle does die. Nonfunctional Subendocardial Infarction. The subendocardial mus- muscle cle frequently becomes infarcted, even when there is no evidence of infarction in the outer surface portions of the heart. This occurs because the subendocardial muscle has a higher oxygen consumption and extra difficulty obtain- ing adequate blood flow because the blood vessels in the Systolic stretch 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 subendocardi- al regions, and the damage then spreads outward toward Figure 21-­7. Systolic stretch in an area of ischemic cardiac muscle. the epicardium. more than 40% of the left ventricle is infarcted, and death CAUSES OF DEATH AFTER ACUTE occurs in more than 70% of patients once cardiac shock CORONARY OCCLUSION develops. The most common causes of death after acute myocardial infarction are the following: (1) decreased cardiac output; Damming of Blood in the Body’s Venous System. (2) damming of blood in the pulmonary blood vessels and When the heart is not pumping blood forward, it must then death resulting from pulmonary edema; (3) fibril- be damming blood in the atria and in the blood vessels lation of the heart; and, occasionally (4) rupture of the of the lungs or in the systemic circulation. This leads to heart. increased capillary pressures, particularly in the lungs. Damming of blood in the veins often causes little dif- Decreased Cardiac Output—Systolic Stretch and ficulty during the first few hours after a myocardial infarc- ­Cardiac Shock. When some of the cardiac muscle fibers tion. Instead, symptoms develop a few days later because are not functioning and others are too weak to contract the acutely diminished cardiac output leads to diminished with great force, the overall pumping ability of the affected blood flow to the kidneys. Then, for reasons discussed in ventricle is proportionately depressed. The overall pump- Chapter 22, the kidneys fail to excrete enough urine. This ing strength of the infarcted heart is often decreased more adds progressively to the total blood volume and, there- than one might expect because of a phenomenon called fore, leads to congestive symptoms. Consequently, many systolic stretch, shown in Figure 21-­7. That is, when the patients who seemingly are getting along well during the normal portions of the ventricular muscle contract, the is- first few days after the onset of heart failure will suddenly chemic portion of the muscle, whether it is dead or simply experience acute pulmonary edema and often will die nonfunctional, instead of contracting is forced outward by within a few hours after the appearance of the initial pul- the pressure that develops inside the ventricle. Therefore, monary symptoms. much of the pumping force of the ventricle is dissipated by bulging of the area of nonfunctional cardiac muscle. Fibrillation of the Ventricles After Myocardial Infarc- When the heart becomes incapable of contracting with tion. In many people who die of coronary occlusion, sufficient force to pump enough blood into the peripheral death occurs because of sudden ventricular fibrillation. arterial tree, cardiac failure and death of peripheral tissues The tendency for fibrillation to develop is especially great ensue as a result of peripheral ischemia. This condition, after a large infarction, but fibrillation can sometimes called coronary shock, cardiogenic shock, cardiac shock, or occur after small occlusions as well. Some patients with low cardiac output failure, is discussed more fully in the chronic coronary insufficiency die suddenly of fibrillation next chapter. Cardiac shock almost always occurs when without having any acute infarction. 266  Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise Fibrillation is most likely to occur during two espe- Mild Mild cially dangerous periods after coronary infarction. The ischemia ischemia first period is during the first 10 minutes after the infarc- tion occurs. Then, there is a short period of relative safety, followed by a second period of cardiac irritability begin- Non- Non- UNIT IV ning 1 hour or so later and lasting for another few hours. functional functional Fibrillation can also occur many days after the infarct but Dead fibers is less likely to occur then. At least four factors are involved in the tendency for Nonfunctional the heart to fibrillate, as follows: 1. Acute loss of blood supply to the cardiac muscle causes rapid depletion of potassium from the ischem- ic musculature. This also increases the potassium concentration in the extracellular fluids surrounding Dead fibers Fibrous tissue the cardiac muscle fibers. Experiments in which po- Figure 21-­8. Top, Small and large areas of coronary ischemia. Bot- tassium has been injected into the coronary system tom, Stages of recovery from myocardial infarction. have demonstrated that an elevated extracellular po- tassium concentration increases the irritability of the cardiac musculature and, therefore, its likelihood of wall becomes stretched very thin. When this happens, the fibrillating. dead muscle bulges outward to a severe degree with each 2. Ischemia of the muscle causes an injury current, heart contraction, and this systolic stretch becomes great- described in Chapter 12 in relation to electrocar- er and greater until finally the heart ruptures. One of the diograms in patients with acute myocardial infarc- methods used to assess the progress of severe myocardial tion. That is, the ischemic musculature often cannot infarction is to record by cardiac imaging, with echocar- completely repolarize its membranes after a heart- diography, magnetic resonance imaging (MRI), or com- beat, and thus the external surface of this muscle puted tomography (CT), whether the degree of systolic remains negative with respect to normal cardiac stretch is worsening. muscle membrane potential elsewhere in the heart. When a ventricle does rupture, loss of blood into Therefore, electric current flows from this ischemic the pericardial space causes rapid development of car- area of the heart to the normal area and can elicit diac tamponade—that is, compression of the heart from abnormal impulses, which can cause fibrillation. the outside by blood collecting in the pericardial cavity. 3. Powerful sympathetic reflexes often develop after Because of this compression of the heart, blood cannot massive infarction, principally because the heart flow into the right atrium, and the patient dies of suddenly does not pump an adequate volume of blood into decreased cardiac output. the arterial tree, which leads to reduced blood pres- sure. The sympathetic stimulation also increases ir- STAGES OF RECOVERY FROM ACUTE ritability of the cardiac muscle and thereby predis- MYOCARDIAL INFARCTION poses to fibrillation. 4. Cardiac muscle weakness caused by the myocardial The upper left part of Figure 21-­8 shows the effects of acute infarction often causes the ventricle to dilate exces- coronary occlusion in a patient with a small area of muscle sively. This excessive dilation increases the pathway ischemia; to the right is shown a heart with a large area of length for impulse conduction in the heart and ischemia. When the area of ischemia is small, little or no frequently causes abnormal conduction pathways death of the muscle cells may occur, but part of the muscle all the way around the infarcted area of the cardi- often does become temporarily nonfunctional because of ac muscle. Both of these effects predispose to the inadequate nutrition to support muscle contraction. development of circus movements because, as dis- When the area of ischemia is large, some of the muscle cussed in Chapter 13, excess prolongation of con- fibers in the center of the area die rapidly, within 1 to 3 duction pathways in the ventricles allows impulses hours, where there is total cessation of coronary blood to re-­enter muscle that is already recovering from supply. Immediately around the dead area is a nonfunc- refractoriness, thereby initiating a circus movement tional area, with failure of contraction and usually failure cycle of new excitation and resulting in continua- of impulse conduction. Then, extending circumferentially tion of the process. around the nonfunctional area, is an area that is still con- tracting but only weakly because of mild ischemia. Rupture of Infarcted Area. During the first day or so after an acute infarct, there is little danger of rupture of Replacement of Dead Muscle by Scar Tissue. In the the ischemic portion of the heart, but a few days later, lower part of Figure 21-­8, the various stages of recovery the dead muscle fibers begin to degenerate, and the heart after a large myocardial infarction are shown. Shortly af- 267 UNIT IV The Circulation ter the occlusion, the muscle fibers in the center of the cardiac reserve of 300% to 400%. Even when the cardiac ischemic area die. Then, during the ensuing days, this reserve is reduced to as little as 100%, the person can still area of dead fibers enlarges because many of the marginal perform most normal daily activities but not strenuous fibers finally succumb to the prolonged ischemia. At the exercise, which would overload the heart. same time, because of the enlargement of collateral arte- rial channels supplying the outer rim of the infarcted area, PAIN IN CORONARY HEART DISEASE much of the nonfunctional muscle recovers. After a few days to 3 weeks, most of the nonfunctional muscle be- Normally, a person cannot “feel” the heart, but isch- comes functional again or dies. In the meantime, fibrous emic cardiac muscle often does cause a pain sensation tissue begins developing among the dead fibers because that is sometimes severe. Exactly what causes this pain ischemia can stimulate growth of fibroblasts and pro- is not known, but it is believed that ischemia causes mote development of greater than normal quantities of the muscle to release acidic substances such as lactic fibrous tissue. Therefore, the dead muscle tissue is gradu- acid or other pain-­promoting products, such as his- ally replaced by fibrous tissue. Then, because it is a general tamine, kinins, or cellular proteolytic enzymes, which property of fibrous tissue to undergo progressive contrac- are not removed rapidly enough by the slowly moving tion and dissolution, the fibrous scar may grow smaller coronary blood flow. The high concentrations of these over a period of several months to a year. abnormal products then stimulate pain nerve endings Finally, the normal areas of the heart gradually hyper- in the cardiac muscle, sending pain impulses through trophy to compensate, at least partially, for the lost dead sensory afferent nerve fibers into the central nervous cardiac musculature. By these means, the heart recov- system. ers partially or almost completely within a few months, depending on the severity of the infarction and cardiac Angina Pectoris (Cardiac Pain). In most people who tissue death. sustain progressive constriction of their coronary arter- ies, cardiac pain, called angina pectoris, begins to appear Value of Rest in Treating Myocardial Infarction. The whenever the load on the heart becomes too great in re- degree of cardiac cellular death is determined by the de- lation to the available coronary blood flow. This pain is gree of ischemia and workload on the heart muscle. When usually felt beneath the upper sternum over the heart. the workload is greatly increased, such as during exercise, In addition, the pain is often referred to distant surface in severe emotional strain, or as a result of fatigue, the areas of the body, usually to the left arm and left shoulder heart needs increased oxygen and other nutrients for but also frequently to the neck and even to the side of the sustaining its life. Furthermore, anastomotic blood ves- face. The reason for this distribution of pain is that during sels that supply blood to ischemic areas of the heart must embryonic life, the heart originates in the neck, as do the also still supply the areas of the heart that they normally arms. Therefore, both the heart and these surface areas of supply. When the heart becomes excessively active, the the body receive pain nerve fibers from the same spinal vessels of the normal musculature become greatly di- cord segments. lated. This dilation allows most of the blood flowing into Most people who have chronic angina pectoris feel the coronary vessels to flow through the normal muscle pain when they exercise or when they experience emo- tissue, thus leaving little blood to flow through the small tions that increase metabolism of the heart or temporar- anastomotic channels into the ischemic area. As a result, ily constrict the coronary vessels because of sympathetic the ischemic condition worsens, a condition called the vasoconstrictor nerve signals. Anginal pain is also exac- coronary steal syndrome. Consequently, an important fac- erbated by cold temperatures or by having a full stom- tor in the treatment of a patient with myocardial infarc- ach, both of which increase the workload of the heart. tion is observance of absolute body rest during the recov- The pain usually lasts for only a few minutes. However, ery process. 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 and is of such HEART FUNCTION AFTER RECOVERY quality that it usually makes the patient stop all unneces- FROM MYOCARDIAL INFARCTION sary body activity. Occasionally, a heart that has recovered from a large myocardial infarction returns almost to full functional Drug Treatment. Several vasodilator drugs, when ad- capability, but more frequently, its pumping capability ministered during an acute anginal attack, can often is permanently decreased below that of a healthy heart. provide immediate relief from the pain. Commonly used This does not mean that the person is necessarily a car- short-­acting vasodilators are nitroglycerin and other ni- diac invalid or that the resting cardiac output is depressed trate drugs. Other drugs, such as angiotensin-­converting below normal because the normal heart is capable of enzyme inhibitors, angiotensin receptor blockers, calci- pumping 300% to 400% more blood per minute than the um channel blockers, and ranolazine, may be beneficial in body requires during rest—that is, a normal person has a treating chronic stable angina pectoris. 268  Chapter 21 Muscle Blood Flow and Cardiac Output During Exercise Another class of drugs used for the prolonged treat- (restenosis) of the blocked coronary artery occurs in ment of angina pectoris is the beta blockers, such as pro- about 25% to 40% of patients treated with angioplasty, pranolol. These drugs block sympathetic beta-­adrenergic often within 6 months of the initial procedure. Resteno- receptors, which prevents sympathetic enhancement sis is usually due to the excessive formation of scar tissue of heart rate and cardiac metabolism during exercise that develops underneath the healthy new endothelium UNIT IV or emotional episodes. Therefore, therapy with a beta that has grown over the stent. Stents that slowly release blocker decreases the need of the heart for extra meta- drugs (drug-­eluting stents) may help prevent the exces- bolic oxygen during stressful conditions. For obvious rea- sive growth of scar tissue. sons, this therapy can also reduce the number of anginal Newer procedures for opening atherosclerotic coro- attacks, as well as their severity. nary arteries are constantly in experimental development. One of these procedures uses a laser beam from the tip of a coronary artery catheter aimed at the atherosclerotic SURGICAL TREATMENT OF CORONARY lesion. The laser literally dissolves the lesion without sub- ARTERY DISEASE stantially damaging the remainder of the arterial wall. 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 Bibliography atherosclerotic disease, and the coronary vessels elsewhere Allaqaband H, Gutterman DD, Kadlec AO: Physiological consequenc- are normal or almost normal. In the 1960s, a surgical pro- es of coronary arteriolar dysfunction and its influence on cardiovas- cedure called aortic-­coronary bypass or coronary artery by- cular disease. Physiology (Bethesda) 33:338, 2018. pass grafting (CABG) was developed, in which a section of a Alexander JH, Smith PK: Coronary-­artery bypass grafting. N Engl J Med 374:1954, 2016. subcutaneous vein is removed from an arm or leg and then Anderson JL, Morrow DA: Acute myocardial infarction. N Engl J Med grafted from the root of the aorta to the side of a peripheral 376:2053, 2017. coronary artery beyond the atherosclerotic blockage point. Casey DP, Joyner MJ: Compensatory vasodilatation during hypoxic One to five such grafts are usually performed, each of which exercise: mechanisms responsible for matching oxygen supply to supplies a peripheral coronary artery beyond a block. demand. J Physiol 590:6321, 2012. Crea F, Liuzzo G: Pathogenesis of acute coronary syndromes. J Am Anginal pain is relieved in most patients after coro- Coll Cardiol 61:1, 2013. nary bypass surgery. Also, in patients whose hearts have Deussen A, Ohanyan V, Jannasch A, et al: Mechanisms of metabolic not become too severely damaged before the operation, coronary flow regulation. J Mol Cell Cardiol 52:794, 2012. the coronary bypass procedure may provide the patient Doenst T, Haverich A, Serruys P, Bonow RO, Kappetein P, et al: PCI with normal life expectancy. If the heart has already been and CABG for treating stable coronary artery disease. J Am Coll Cardiol 73:964, 2019. severely damaged, however, the bypass procedure may be Dora KA: Endothelial-­smooth muscle cell interactions in the regulation of little value. of vascular tone in skeletal muscle. Microcirculation 23:626, 2016. Drew RC: Baroreflex and neurovascular responses to skeletal mus- Coronary Angioplasty. Since the 1980s, a procedure has cle mechanoreflex activation in humans: an exercise in integrative been used to open partially blocked coronary vessels be- physiology. Am J Physiol Regul Integr Comp Physiol 313:R654, 2017. fore they become totally occluded. This procedure, called Duncker DJ, Bache RJ: Regulation of coronary blood flow during ex- coronary artery angioplasty, is performed as follows. A ercise. Physiol Rev 88:1009, 2008. small balloon-­tipped catheter, about 1 millimeter in diam- Foreman RD, Garrett KM, Blair RW: Mechanisms of cardiac pain. eter, is passed under radiographic guidance into the coro- Compr Physiol 5:929, 2015. Goodwill AG, Dick GM, Kiel AM, Tune JD: Regulation of coronary nary system and pushed through the partially occluded blood flow. Compr Physiol 7:321, 2017. artery until the balloon portion of the catheter straddles Gori T, Polimeni A, Indolfi C, Räber L, Adriaenssens T, Münzel T: Pre- the partially occluded point. The balloon is then inflated dictors of stent thrombosis and their implications for clinical prac- with high pressure, which stretches the diseased artery tice. Nat Rev Cardiol 16:243, 2019 markedly. After this procedure is performed, the blood Guyton AC, Jones CE, Coleman TG: Circulatory Pathology: Cardiac Output and Its Regulation. Philadelphia: WB Saunders, 1973. flow through the vessel often increases 3-fold to 4-fold, Joyner MJ, Casey DP: Regulation of increased blood flow (hyperemia) and more than 75% of patients who undergo the proce- to muscles during exercise: a hierarchy of competing physiological dure are relieved of the coronary ischemic symptoms for needs. Physiol Rev 95:549, 2015. at least several years, although many of the patients still Meier P, Schirmer SH, Lansky AJ, et al: The collateral circulation of the eventually require coronary bypass surgery. heart. BMC Med 11:143, 2013. Mitchell JH: Abnormal cardiovascular response to exercise in hyper- Small stainless steel mesh tubes called stents are tension: contribution of neural factors. Am J Physiol Regul Integr sometimes placed inside a coronary artery dilated by Comp Physiol 312:R851, 2017. angioplasty to hold the artery open, thus preventing its Sandoval Y, Jaffe AS: Type 2 Myocardial infarction. J Am Coll Cardiol restenosis. Within a few weeks after the stent is placed 73:1846, 2019. in the coronary artery, the endothelium usually grows Taqueti VR, Di Carli MF: Coronary microvascular disease pathogenic over the metal surface of the stent, allowing blood to mechanisms and therapeutic options. J Am Coll Cardiol 72:2625, 2018. flow smoothly through the stent. However, reclosure 269