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Coronary Artery Disease
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Definition and Physiological Consequences
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Whenever coronary blood flow falls below that required to meet the metabolic needs of the heart, the myocardium is said to be
ischemic and the pumping capability of the heart is impaired. The most common cause of myocardial ischemia is atherosclerotic disease of the large coronary arteries. In atherosclerotic disease, localized lipid deposits called
plaques develop within the arterial walls. With severe disease, these plaques may become calcified and so large that they physically narrow the lumen of arteries (producing a stenosis) and thus greatly and permanently increase the normally low vascular resistance of these large arteries. This extra resistance adds to the resistance of other coronary vascular segments and tends to reduce coronary flow. If the coronary artery stenosis is not too severe, local metabolic vasodilator mechanisms may reduce arteriolar resistance sufficiently to compensate for the abnormally large arterial resistance. Thus, an individual with coronary artery disease may have perfectly normal coronary blood flow when resting. A coronary artery stenosis of any significance will, however, limit the extent to which coronary flow can increase above its resting value by reducing maximum achievable coronary flow. This occurs because, even with very low arteriolar resistance, the overall vascular resistance of the coronary vascular bed is high if resistance in the large arteries is high.
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Coronary artery disease can jeopardize cardiac function in several ways. Ischemic muscle cells are electrically irritable and unstable, and the danger of developing cardiac arrhythmias and fibrillation is enhanced. During ischemia, the normal cardiac electrical excitation pathways may be altered and often ectopic pacemaker foci develop. Electrocardiographic manifestations of myocardial ischemia can be observed in individuals with coronary artery disease during exercise stress tests. In addition, there is evidence that platelet aggregation and clotting function may be abnormal in atherosclerotic coronary arteries and the danger of thrombus or emboli formation is enhanced. It appears that certain platelet suppressants or anticoagulants such as aspirin may be beneficial in the treatment of this consequence of coronary artery disease. (Details of the blood clotting process are included in Appendix D.)
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Myocardial ischemia not only impairs the pumping ability of the heart but also produces intense, debilitating chest pain called angina pectoris. Anginal pain is often absent in individuals with coronary artery disease when they are resting but is induced during physical exertion or emotional excitement. Both of these situations elicit an increase in sympathetic tone that increases myocardial oxygen consumption. Myocardial ischemia and chest pain will result if coronary blood flow cannot keep pace with the increase in myocardial metabolism.
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Coronary artery imaging techniques (described in Chapter 4) have proven very useful at determining the extent of coronary artery disease. For example, calcification of plaques (which is a significant indicator of advanced atherosclerosis) can be assessed noninvasively with specialized CT scans or magnetic resonance imaging. Specific information about the site(s) and degree of narrowing of the major coronary vessels can also be obtained invasively by angiography with injection of a radioopaque dye directly into the coronary arteries.
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Primary treatment of chronic coronary artery disease (and atherosclerosis, in general) should include attempts to lower blood lipids by dietary and pharmacological techniques that prevent (and possibly reverse) further development of the plaques. The interested student should consult medical biochemistry and pharmacology texts for a complete discussion of this very important topic.
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Treatment of angina that is a result of coronary artery disease may involve several different pharmacological approaches. First, quick-acting vasodilator drugs such as nitroglycerin may be used to provide primary relief from an anginal attack. These drugs may act directly on coronary vessels to acutely increase coronary blood flow. In addition to increasing myocardial oxygen delivery, nitrates may reduce myocardial oxygen demand by dilating systemic veins, which reduces venous return, central venous filling, and cardiac preload, and by dilating systemic arterioles, which reduces arterial resistance, arterial pressure, and cardiac afterload. Second, β-adrenergic blocking agents such as propranolol may be used to block the effects of cardiac sympathetic nerves on the heart rate and contractility. These agents limit myocardial oxygen consumption and prevent it from increasing above the level that the compromised coronary blood flow can sustain. Third, calcium channel blockers such as verapamil may be used to dilate coronary and systemic blood vessels. These drugs, which block entry of calcium into the vascular smooth muscle cell, interfere with normal excitation–contraction coupling. They have been found to be useful for treating the type of angina caused by vasoconstrictive spasms of large coronary arteries (Prinzmetal’s angina).
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Invasive or surgical interventions are commonly used to eliminate a chronic coronary artery stenosis. X-ray techniques combined with radioopaque dye injections can be used to visualize a balloon-tipped catheter as it is threaded into the coronary artery to the occluded region. Rapid inflation of the balloon squeezes the plaque against the vessel wall and improves the patency of the vessel (coronary angioplasty). A small tube-like expandible device called a stent is often implanted inside the vessel at the angioplasty site. This rigid implant promotes continued patency of the vessel over a longer period than angioplasty alone. If angioplasty and stent placement are inappropriate or unsuccessful, coronary bypass surgery may be performed. The stenotic coronary artery segments are bypassed by implanting parallel low-resistance pathways formed from either natural (eg, saphenous vein or mammary artery) or artificial vessels.
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Acute Coronary Occlusion—Myocardial Infarction
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An acute interruption in coronary blood flow is most often a result of the sudden arrival of a blood clot (eg, an embolism released from a clot in a fibrillating atrium) or the formation of an intravascular clot at the site of a ruptured atherosclerotic plaque. Either of these events may abruptly occlude or significantly narrow a major coronary artery. This is indeed a crisis situation and demands immediate attention. The physiological consequences of such an immediate occlusion are discussed in the preceding text under the topic of “
Cardiogenic Shock.” Treatments may include emergency coronary angioplasty (described earlier) with the placement of a stent, which may allow immediate restoration of flow to the ischemic area. Another method for treatment of
acute myocardial infarction is the intravascular injection of thrombolytic substances (eg, streptokinase or tissue plasminogen-activating factors) that dissolve blood clots. This approach is most successful when these “clot busters” are given within a few hours of the infarction.
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Chronic Heart Failure—Systolic Dysfunction
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Heart (or cardiac or myocardial)
failure is said to exist whenever ventricular function is depressed through myocardial damage, insufficient coronary flow, or any other condition that directly impairs the mechanical performance of the heart muscle. By definition,
systolic heart failure is associated with a left ventricular ejection fraction of less than 40%. This also implies that the heart is operating on a
lower-than-normal cardiac function curve, that is, a reduced cardiac output at any given filling pressure. Acute heart failure has already been discussed in the preceding text in the context of sudden coronary artery occlusion, cardiogenic shock, and as part of the decompensatory mechanisms operating in progressive and irreversible shock. Often, however, sustained cardiac “challenges” may induce a chronic state of heart failure. Such challenges might include (1) progressive coronary artery disease, (2) sustained elevation in cardiac afterload as that which accompanies arterial hypertension or aortic valve stenosis, or (3) reduced functional muscle mass following myocardial infarction. In some instances, external causes of cardiac failure cannot be identified and some primary genetic abnormality in myocyte cytoskeletal or sarcomeric protein is to blame. This situation is referred to as
primary cardiomyopathy. Regardless of the precipitating cause, most forms of failure are associated eventually with a reduced myocyte function. Many specific structural, functional, and biochemical myocyte alterations accompany severe systolic heart failure. Some of the more well-documented abnormalities include (1) reduced calcium sequestration by the sarcoplasmic reticulum and upregulation of the sarcolemmal Na/Ca exchanger (leading to low intracellular calcium levels for excitation–contraction coupling), (2) low affinity of troponin for calcium (leading to reduced cross-bridge formation and contractile ability), (3) altered substrate metabolism from fatty acid to glucose oxidation, and (4) impaired respiratory chain activity (leading to impaired energy production).
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The primary disturbance in systolic heart failure (acute or chronic) is depressed cardiac output and thus lowered arterial pressure. Consequently, all the compensatory responses important in shock (Figure 11–1) are also important in heart failure. In chronic heart failure, however, the cardiovascular disturbances may not be sufficient to produce a state of shock. Moreover, long-term compensatory mechanisms are especially important in chronic heart failure.
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The circumstances of chronic systolic heart failure are well illustrated by cardiac output and venous function curves such as those shown in Figure 11–3. The normal cardiac output and normal venous function curves intersect at point A in Figure 11–3. A cardiac output of 5 L/min at a central venous pressure of less than 2 mm Hg is indicated by the normal operating point (A). With heart failure, the heart operates on a much lower-than-normal cardiac output curve. Thus, acute heart failure alone (uncompensated) shifts the cardiovascular operation from the normal point (A) to a new position, as illustrated by point B in Figure 11–3—that is, cardiac output falls below normal while central venous pressure rises above normal. The decreased cardiac output leads to decreased arterial pressure and reflex activation of the cardiovascular sympathetic nerves. Increased sympathetic nerve activity tends to (1) raise the cardiac function curve toward normal and (2) increase peripheral venous pressure through venous constriction, and thus raise the venous function curve above normal. Cardiovascular operation will shift from point B to point C in Figure 11–3. Thus, the depressed cardiac output is substantially improved by the immediate consequences of increased sympathetic nerve activity. Note, however, that the cardiac output at point C is still below normal. The arterial pressure associated with cardiovascular operation at point C is likely to be near normal, however, because higher-than-normal total peripheral resistance will accompany higher-than-normal sympathetic nerve activity.
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In the long term, cardiovascular operation cannot remain at point C in
Figure 11–3. Operation at point C involves higher-than-normal sympathetic activity, and this will inevitably cause a gradual increase in blood volume by the mechanisms that are described in
Chapter 9. Over several days, there is a progressive rise in the venous function curve as a result of increased blood volume and, consequently, increased mean circulatory filling pressure. Recall that this process involves a sympathetically induced release of renin from the kidney, which activates the renin–angiotensin–aldosterone system that promotes fluid retention. This will progressively shift the cardiovascular operating point from C to D to E, as shown in
Figure 11–3.
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Note that increased fluid retention (C → D → E in Figure 11–3) causes a progressive increase in cardiac output toward normal and simultaneously allows a reduction in sympathetic nerve activity toward the normal value. Reduced sympathetic activity is beneficial for several reasons. First, decreased arteriolar constriction permits renal and splanchnic blood flow to return toward more normal values. Second, myocardial oxygen consumption may fall as sympathetic nerve activity falls, even though cardiac output tends to increase. Recall that the increased heart rate and increased cardiac contractility caused by sympathetic nerve activation greatly increase myocardial oxygen consumption. Reduced myocardial oxygen consumption is especially beneficial in situations where inadequate coronary blood flow is the cause of the heart failure. In any case, once enough fluid has been retained that a normal cardiac output can been achieved with normal sympathetic nerve activity, the individual is said to be in a “compensated” state of chronic heart failure.3
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Unfortunately, the consequences of fluid retention in chronic cardiac failure are not all beneficial. Note that in Figure 11–3 fluid retention (C → D → E) will cause both peripheral and central venous pressures to be much higher than their normal values. Chronically high central venous pressure causes chronically increased end-diastolic volume (cardiac dilation). Up to a point, cardiac performance is very much improved by increased cardiac filling volume. Excessive cardiac dilation, however, can impair cardiac function because increased total wall tension is required to generate pressure within an enlarged ventricular chamber (T = P × r; Chapter 2). This increases the myocardial oxygen demand.
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The high venous pressure associated with fluid retention also adversely affects organ function because high venous pressure produces transcapillary fluid filtration, edema formation, and congestion (hence the commonly used term congestive heart failure). Left-sided heart failure is accompanied by pulmonary edema with dyspnea (shortness of breath) and respiratory crisis.4 Right-sided heart failure is associated with distended neck veins, ankle edema, and fluid accumulation in the abdomen (ascites) with liver congestion and dysfunction.5
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In the example shown in Figure 11–3, the depression in the cardiac output curve because of heart failure is only moderately severe. Thus, it is possible, through moderate fluid retention, to achieve a normal cardiac output with essentially normal sympathetic activity (point E). The situation at point E is relatively stable because the stimuli for further fluid retention have been removed. If, however, the heart failure is more severe, the cardiac output curve may be so depressed that normal cardiac output cannot be achieved by any amount of fluid retention. In these cases fluid retention is extremely marked, as is the elevation in venous pressure, and the complications of congestion are very serious problems.
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Another way of looking at the effects of left ventricular cardiac failure is given in Figure 11–4. The left ventricular pressure–volume loops describing the events of a cardiac cycle from a failing heart are displaced far to the right of those from normal hearts. The untreated patient described in this figure is in serious trouble with a reduced stroke volume and ejection fraction and high filling pressure. Furthermore, the slope of the line describing the end-systolic pressure–volume relationship is shifted downward and is less steep, indicating the reduced contractility of the cardiac muscle. However, because of this flatter relationship, small reductions in cardiac afterload (ie, arterial blood pressure) will produce substantial increases in stroke volume, as indicated in Figure 11–4, and will significantly help this patient.
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As might be expected from the previous discussion, the most common symptoms of patients with congestive heart failure are associated with the inability to increase cardiac output (low exercise tolerance and fatigue) and with the compensatory fluid accumulation (tissue congestion, shortness of breath, and peripheral swelling). In severe cases, the ability of the cardiac cells to respond to increases in sympathetic stimulation is diminished by a reduction in the effective number (downregulation) of the myocyte β1-adrenergic receptors. This further reduces the ability of the myocytes to increase their contractility as well as the ability of the heart to increase its beating rate in response to sympathetic stimulation. Thus, low maximal heart rates contribute to the reduced exercise tolerance.
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Treatment of the patient with congestive systolic heart failure is a difficult challenge. Treatment of the precipitating condition is of course the ideal approach, but often this cannot be done effectively. Cardiac glycosides (eg, digitalis)6 have been used to improve cardiac contractility (ie, to increase the ejection fraction, shift the cardiac function curve upward, increasing contractile force of the myocyte at any given starting length).7 These drugs are unfortunately quite toxic and often have undesirable side effects.
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Treatment of the congestive symptoms involves balancing the need for enhanced cardiac filling with the problems of too much fluid. Drugs that promote renal fluid loss (diuretics such as furosemide or thiazides) are extremely helpful as are the angiotensin-converting enzyme (ACE) inhibitors and the angiotensin II receptor blockers (ARBs).8 A potent diuretic can quickly save a patient from drowning in the pulmonary exudate and reduce diastolic volume of the dilated heart to acceptable levels, but it can also lower blood pressure to dangerous levels.
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Chronic heart failure patients often have elevated sympathetic drive if they have not completely compensated for the depressed cardiac function by fluid retention and increased blood volume. Although high sympathetic drive is an important initial compensatory mechanism, the energy cost of a chronically elevated heart rate and contractility can put the heart with diminished coronary circulation at a disadvantage. Therefore, treatment with β-adrenergic receptor blockers can reduce metabolic demand to a level more easily met by a compromised vascular supply. Again, if elimination of the effect of elevated sympathetic drive on the heart is too aggressive, cardiac output may fall and worsen a failure state.
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Chronic Heart Failure—Diastolic Dysfunction
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Although systolic dysfunction is often the primary cause of heart failure, some degree of diastolic dysfunction is also commonly present and may precede systolic problems. As shown in
Figure 11–5, diastolic dysfunction implies a stiffened heart during diastole such that increases in cardiac filling pressure do not produce normal increases in end-diastolic volume. Some individuals (primarily elderly patients with hypertension and cardiac hypertrophy) who have some symptoms of cardiac failure (exertional dyspnea, fluid retention, pulmonary edema, and high end-diastolic pressures) seem to have normal systolic function (ejection fractions >40%), and normal or even reduced ventricular end-diastolic volumes despite increased cardiac filling pressure. Thus, the terms
diastolic heart failure and
heart failure with preserved systolic function have been used to describe this situation.
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Potential causes of altered diastolic properties in heart failure include (1) decreased cardiac tissue passive compliance due to extracellular remodeling, collagen cross-linking, and other extracellular matrix protein alterations, (2) increased myofibrillar passive stiffness due to alterations in the myofibrillar protein titin, (3) delayed myocyte relaxation early in diastole due to slow cytosolic calcium removal processes, (4) inadequate adenosine triphosphate levels required to disconnect the myofilament cross-bridges rapidly, and (5) residual, low-grade cross-bridge cycling during diastole due to calcium leaking from the sarcoplasmic reticulum.
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At this point, therapeutic strategies that directly influence diastolic properties are not well developed. Attempts to reduce interstitial fibrosis (with ACE inhibitors and/or angiotensin receptor antagonists) and to reduce diastolic calcium leak from the sarcoplasmic reticulum (with β-adrenergic blockers) have had limited success. Reduction of afterload seems to be most helpful, especially if it reduces left ventricular hypertrophy.
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3 The extracellular fluid volume remains expanded after reaching the compensated state even though sympathetic activity may have returned to near-normal levels. Net fluid loss requires a period of less-than-normal sympathetic activity, which does not occur. For reasons not well understood, the cardiopulmonary baroreceptor reflexes apparently become less responsive to the increased central venous pressure and volume associated with heart failure.
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4 Patients often complain of difficulty breathing especially during the night (paroxysmal nocturnal dyspnea). Being recumbent promotes a fluid shift from the extremities into the central venous pool and lungs, making the patient’s pulmonary problems worse. Such patients often sleep more comfortably when propped up.
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5 Plasma volume expansion along with abnormal liver function reduces the concentration of plasma proteins by as much as 30%. This reduction in plasma oncotic pressure contributes to the development of interstitial edema that accompanies congestive heart failure.
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6 A “tea” made from the leaves of the foxglove plant (Digitalis purpurea) was used for centuries as a common folk remedy for the treatment of “dropsy” (congestive heart failure with significant peripheral edema). With the formal recognition of its medicinal benefits in the late 18th century by the English physician Sir William Withering, digitalis became a valuable official pharmacological tool.
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7 The mechanism of cardiac glycoside action is thought to involve the inhibition of the sodium/potassium adenosine triphosphatase (Na+/K+-ATPase) leading to increases in intracellular [Na+], which is then exchanged for extracellular calcium via the Na+/Ca2+ exchanger. This results in “loading” of the sarcoplasmic reticulum during diastole and increased calcium release for subsequent excitation–contraction coupling.
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8 The ACE inhibitors are very helpful to the congestive heart failure patient for several reasons. By inhibiting the conversion of angiotensin I into its more active form, angiotensin II, peripheral vasoconstriction is reduced (which improves cardiac pumping by afterload reduction) and aldosterone levels are reduced (which promotes diuresis). In addition, ACE inhibitors as well as the ARBs seem to prevent some of the apparently inappropriate myocyte and collagen growth (ie, remodeling) that occurs with cardiac overload and failure.