In 1772, the British physician William Heberden reported a disorder in which patients developed an uncomfortable sensation in the chest when walking. Labeling it angina pectoris, Heberden noted that this discomfort would disappear soon after the patient stood still but would recur with similar activities. Although he did not know the cause, it is likely that he was the first to describe the symptoms of ischemic heart disease, a condition of imbalance between myocardial oxygen supply and demand most often caused by atherosclerosis of the coronary arteries. Ischemic heart disease now afflicts millions of Americans and is the leading cause of death in industrialized nations.
The clinical presentation of ischemic heart disease can be highly variable and forms a spectrum of syndromes ( Table 6.1). For example, ischemia may be accompanied by the same exertional symptoms described by Heberden. In other cases, it may occur without any clinical manifestations at all, a condition termed silent ischemia. This chapter describes the causes and consequences of chronic ischemic heart disease syndromes and provides a framework for the diagnosis and treatment of affected patients.
Table 6.1.Clinical Definitions
|Ischemic heart disease||Condition in which imbalance between myocardial oxygen supply and demand results in myocardial hypoxia and accumulation of waste metabolites, most often caused by atherosclerotic disease of the coronary arteries (often termed coronary artery disease)|
|Angina pectoris||Uncomfortable sensation in the chest and neighboring anatomic structures produced by myocardial ischemia|
|Stable angina||Chronic pattern of transient angina pectoris, precipitated by physical activity or emotional upset, relieved by rest within a few minutes; episodes often associated with temporary depression of the ST segment, but permanent myocardial damage does not result|
|Variant angina||Typical anginal discomfort, usually at rest, which develops because of coronary artery spasm rather than an increase of myocardial oxygen demand; episodes often associated with transient shifts of the ST segment, usually ST elevation (also termed Prinzmetal angina)|
|Silent ischemia||Asymptomatic episodes of myocardial ischemia; can be detected by electrocardiogram and other laboratory techniques|
|Unstable angina||Pattern of increased frequency and duration of angina episodes produced by less exertion or at rest; high frequency of progression to myocardial infarction if untreated|
|Myocardial infarction||Region of myocardial necrosis usually caused by prolonged cessation of blood supply; most often results from acute thrombus at site of coronary atherosclerotic stenosis; may be first clinical manifestation of ischemic heart disease, or there may be a history of angina pectoris|
Angina pectoris remains the most common manifestation of ischemic heart disease and literally means “strangling in the chest.” Although other conditions may lead to similar discomfort, angina refers specifically to the uncomfortable sensation in the chest and neighboring structures that arises from an imbalance between myocardial oxygen supply and demand.
Determinants of Myocardial Oxygen Supply and Demand
In the normal heart, the oxygen requirements of the myocardium are continuously matched by the coronary arterial supply. Even during vigorous exercise, when the metabolic needs of the heart increase, so does the delivery of oxygen to the myocardial cells so that the balance is maintained. The following sections describe the key determinants of myocardial oxygen supply and demand in a normal person ( Fig. 6.1) and how they are altered by the presence of atherosclerotic coronary artery disease (CAD).
Figure 6.1.Major determinants of myocardial oxygen supply and demand.
P, ventricular pressure; r, ventricular radius; h, ventricular wall thickness.
Myocardial Oxygen Supply
The supply of oxygen to the myocardium depends on the oxygen content of the blood and the rate of coronary blood flow. The oxygen content is determined by the hemoglobin concentration and the degree of systemic oxygenation. In the absence of anemia or lung disease, oxygen content remains fairly constant. In contrast, coronary blood flow is much more dynamic, and regulation of that flow is responsible for matching the oxygen supply with metabolic requirements.
As in all blood vessels, coronary artery flow (Q) is directly proportional to the vessel’s perfusion pressure (P) and is inversely proportional to coronary vascular resistance (R). That is,
However, unlike other arterial systems in which the greatest blood flow occurs during systole, the predominance of coronary perfusion takes place during diastole. The reason for this is that systolic flow is impaired by the compression of the small coronary branches as they course through the contracting myocardium. Coronary flow is unimpaired in diastole because the relaxed myocardium does not compress the coronary vasculature. Thus, in the case of the coronaries, perfusion pressure can be approximated by the aortic diastolic pressure. Conditions that decrease aortic diastolic pressure (such as hypotension or aortic valve regurgitation) decrease coronary artery perfusion pressure and may lessen myocardial oxygen supply.
Coronary vascular resistance is the other major determinant of coronary blood flow. In the normal artery, this resistance is dynamically modulated by (1) forces that externally compress the coronary arteries and (2) factors that alter intrinsic coronary tone.
External compression is exerted on the coronary vessels during the cardiac cycle by contraction of the surrounding myocardium. The degree of compression is directly related to intramyocardial pressure and is therefore greatest during systole, as described in the previous section. Moreover, when the myocardium contracts, the subendocardium, adjacent to the high intraventricular pressure, is subjected to greater force than are the outer muscle layers. This is one reason that the subendocardium is the region most vulnerable to ischemic damage.
Intrinsic Control of Coronary Arterial Tone
Unlike most tissues, the heart cannot increase oxygen extraction on demand because in its basal state it removes nearly as much oxygen as possible from its blood supply. Thus, any additional oxygen requirement must be met by an increase in blood flow, and autoregulation of coronary vascular resistance is the most important mediator of this process. Factors that participate in the regulation of coronary vascular resistance include the accumulation of local metabolites, endothelium-derived substances, and neural innervation.
The accumulation of local metabolites significantly affects coronary vascular tone and acts to modulate myocardial oxygen supply to meet changing metabolic demands. During states of hypoxemia, aerobic metabolism and oxidative phosphorylation in the mitochondria are inhibited. High-energy phosphates, including adenosine triphosphate (ATP), cannot be regenerated.
Consequently, adenosine diphosphate (ADP) and adenosine monophosphate (AMP) accumulate and are subsequently degraded to adenosine. Adenosine is a potent vasodilator and is thought to be the prime metabolic mediator of vascular tone. By binding to receptors on vascular smooth muscle, adenosine decreases calcium entry into cells, which leads to relaxation, vasodilatation, and increased coronary blood flow. Other meta bolites that act locally as vasodilators include lactate, acetate, hydrogen ions, and carbon dioxide.
Box 6.1.Endothelium-Derived Relaxing Factor, Nitric Oxide, and the Nobel Prize%
Normal arterial endothelial cells synthesize potent vasodilator substances that contribute to the modulation of vascular tone. Among the first of these to be identified were prostacyclin (an arachidonic acid metabolite) and a substance termed endothelium-derived relaxing factor (EDRF).
EDRF was first studied in the 1970s. In experimental preparations, it was shown that acetylcholine (ACh) has two opposite actions on blood vessels. Its direct effect on vascular smooth muscle cells is to cause vasoconstriction, but when an intact endothelial lining overlies the smooth muscle cells, vasodilation occurs instead. Subsequent experiments showed that ACh causes the endothelial cells to release a chemical mediator (that was termed EDRF), which quickly diffuses to the adjacent smooth muscle cells and results in their relaxation with subsequent vasodilation of the vessel.
Subsequent research demonstrated that the mysterious EDRF is actually the nitric oxide (NO) radical. Binding of ACh (or another endothelial-dependent vasodilator such as serotonin or histamine) to endothelial cells catalyzes the formation of NO from the amino acid L-arginine (see figure). NO then diffuses to the adjacent vascular smooth muscle, where it activates guanylyl cyclase (G-cyclase). G-cyclase in turn forms cyclic guanosine monophosphate (cGMP), which results in smooth muscle cell relaxation through mechanisms that involve a reduction in cytosolic Ca++
In contrast to the endothelial-dependent vasodilators, some agents cause smooth muscle relaxation independent of the presence of endothelial cells. For example, the drugs sodium nitroprusside and nitroglycerin result in vasodilation by providing an exogenous source of NO to vascular smooth muscle cells, thereby activating G-cyclase and forming cGMP without endothelial cell participation.
In the cardiac catheterization laboratory, the intracoronary administration of ACh in a normal person causes vasodilation of the vessel, presumably through the release of NO. However, in conditions of endothelial dysfunction, such as atherosclerosis, intracoronary ACh administration results in paradoxical vasoconstriction instead. This likely reflects reduced production of NO by the dysfunctional endothelial cells, resulting in unopposed direct vasoconstriction of the smooth muscle by ACh.
Of particular interest is that the loss of vasodilatory response to infused ACh is evident in persons with certain cardiac risk factors (e.g., elevated LDL cholesterol, hypertension, cigarette smoking) even before the physical appearance of atheromatous plaque. Thus, the impaired release of NO may be an early and sensitive predictor for the later development of atherosclerotic lesions.
The significance of these discoveries was highlighted in 1998, when the Nobel Prize in medicine was awarded to the scientists who discovered the critical role of NO as a cardiovascular signaling molecule.
Endothelial cells of the arterial wall produce numerous vasoactive substances that contribute to the regulation of vascular tone. Vasodilators produced by the endothelium include nitric oxide (NO), prostacyclin, and endotheliumderived hyperpolarizing factor (EDHF). Endothelin 1 is an example of an endotheliumderived vasoconstrictor.
The discovery and significance of endothelium-derived NO are highlighted in Box 6.1. In brief, NO regulates the vascular tone by diffusing into and then relaxing neighboring arterial smooth muscle by a cyclic guanosine monophosphate (cGMP)–dependent mechanism. The production of NO by normal endothelium occurs in the basal state and is additionally stimulated by many substances and conditions.
For example, its release is augmented when the endothelium is exposed to acetylcholine (ACh), thrombin, products of aggregating platelets (e.g., serotonin and ADP), or even the shear stress of blood flow. Although the direct effect of many of these substances on vascular smooth muscle is to cause vasoconstriction, the induced release of NO from the normal endothelium results in vasodilatation instead ( Fig. 6.2).
Figure 6.2.Endothelium-derived vasoactive substances and their regulators.
Endothelium-derived vasodilators are shown on the left and include nitric oxide (NO), prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF). Endothelin 1 is an endothelium-derived vasoconstrictor. In the normal state, the vasodilator influence predominates over that of vasoconstriction. ACh, acetylcholine.
Prostacyclin, an arachidonic acid metabolite, has vasodilator properties similar to those of NO (see Fig. 6.2). It is released from endothelial cells in response to many stimuli, including hypoxia, shear stress, ACh, and platelet products (e.g., serotonin). It causes relaxation of vascular smooth muscle by a cyclic AMP-dependent mechanism.
EDHF also appears to have important vasodilatory properties. Like endothelial-derived NO, it is a diffusible substance released by the endothelium that hyperpolarizes (and therefore relaxes) neighboring vascular smooth muscle cells. EDHF is released by many of the same factors that stimulate NO, including ACh and normal pulsatile blood flow. In the coronary circulation, EDHF appears to be more important in modulating relaxation in small arterioles than in the large conduit arteries.
Endothelin 1 is a potent vasoconstrictor produced by endothelial cells that partially counteracts the actions of the endothelial vasodilators. Its expression is stimulated by several factors, including thrombin, angiotensin II, epinephrine, and the shear stress of blood flow.
Under normal circumstances, the healthy endothelium promotes vascular smooth muscle relaxation (vasodilatation) through elaboration of substances such as NO and prostacyclin, the influences of which predominate over the endothelial vasoconstrictors (see Fig. 6.2). However, as described later in the chapter, dysfunctional endothelium (e.g., in atherosclerotic vessels) secretes reduced amounts of vasodilators, causing the balance to shift toward vasoconstriction instead.
The neural control of vascular resistance has both sympathetic and parasympathetic components. Under normal circumstances, the contribution of the parasympathetic nervous system appears minor, but sympathetic receptors play an important role. Coronary vessels contain both ?-adrenergic and ?2-adrenergic receptors. Stimulation of ?-adrenergic receptors results in vasoconstriction, whereas ?2-receptors promote vasodilatation.
It is the interplay among the metabolic, endothelial, and neural regulating factors that determines the net impact on coronary vascular tone. For example, catecholamine stimulation of the heart may initially cause coronary vasoconstriction via the ?-adrenergic receptor neural effect. However, catecholamine stimulation also increases myocardial oxygen consumption through increased heart rate and contractility (?1-adrenergic effect), and the resulting increased production of local metabolites induces net coronary dilatation instead.
Myocardial Oxygen Demand
The three major determinants of myocardial oxygen demand are (1) ventricular wall stress, (2) heart rate, and (3) contractility (which is also termed the inotropic state). Additionally, very small amounts of oxygen are consumed in providing energy for basal cardiac metabolism and electrical depolarization.
Ventricular wall stress (?) is the tangential force acting on the myocardial fibers, tending to pull them apart, and energy is expended in opposing that force. Wall stress is related to intraventricular pressure (P), the radius of the ventricle (r), and ventricular wall thickness (h) and is approximated by Laplace’s relationship:
Thus, wall stress is directly proportional to systolic ventricular pressure. Circumstances that increase pressure development in the left ventricle, such as aortic stenosis or hypertension, increase wall stress and myocardial oxygen consumption. Conditions that decrease ventricular pressure, such as antihypertensive therapy, reduce myocardial oxygen consumption.
Because wall stress is also directly proportional to the radius of the left ventricle, conditions that augment left ventricular (LV) filling (e.g., mitral or aortic regurgitation) raise wall stress and oxygen consumption. Conversely, any physiologic or pharmacologic maneuver that decreases LV filling and size (e.g., nitrate therapy) reduces wall stress and myocardial oxygen consumption.
Finally, wall stress is inversely proportional to ventricular wall thickness because the force is spread over a greater muscle mass. A hypertrophied heart has lower wall stress and oxygen consumption per gram of tissue than a thinnedwall heart. Thus, when hypertrophy develops in conditions of chronic pressure overload, such as aortic stenosis, it serves a compensatory role in reducing oxygen consumption.
The second major determinant of myocardial oxygen demand is heart rate. If the heart rate accelerates—during physical exertion, for example—the number of contractions and the amount of ATP consumed per minute increases and oxygen requirements rise. Conversely, slowing the heart rate (e.g., with a ?-blocker drug) decreases ATP utilization and oxygen consumption.
The third major determinant of oxygen demand is myocardial contractility, a measure of the force of contraction (see Chapter 9). Circulating catecholamines, or the administration of positive inotropic drugs, directly increase the force of contraction, which augments oxygen utilization. Conversely, negative inotropic effectors, such as ?-adrenergic-blocking drugs, decrease myocardial oxygen consumption.
In the normal state, autoregulatory mechanisms adjust coronary tone to match myocardial oxygen supply with oxygen requirements. In the absence of obstructive coronary disease, these mechanisms maintain a fairly constant rate of coronary flow, as long as the aortic perfusion pressure is approximately 60 mm Hg or greater. In the setting of advanced coronary atherosclerosis, however, the fall in perfusion pressure distal to the arterial stenosis, along with dysfunction of the endothelium of the involved segment, sets the stage for a mismatch between the available blood supply and myocardial metabolic demands.