INTRODUCTION

Section 2 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Background

Myocardial ischemia is a condition in which oxygen deprivation to the heart muscle is accompanied by inadequate removal of metabolites because of reduced blood flow or perfusion.

In contrast, mere oxygen deprivation (hypoxia or anoxia) without reduction in the clearance of metabolites occurs in cyanotic congenital heart disease, cor pulmonale, severe anemia, asphyxiation, and carbon monoxide poisoning. Patients with these problems do not exhibit ischemic symptoms.

Pathophysiology

During ischemia, an imbalance occurs between myocardial oxygen supply and demand. Ischemia may manifest as (1) anginal discomfort, (2) ST-segment deviation on ECG, (3) reduced uptake of thallium 201 or technetium 99 in myocardial perfusion images, or (4) regional or global impairment of ventricular function.

Myocardial ischemia can occur as a result of increased myocardial oxygen demand, reduced myocardial oxygen supply, or both. In the presence of coronary obstruction, an increase of myocardial oxygen requirements caused by exercise, tachycardia, or emotion leads to a transitory imbalance. This condition is frequently termed demand ischemia and is responsible for most episodes of chronic stable angina. In other situations, the imbalance is caused by acute reduction of oxygen supply secondary to increased coronary vascular tone (ie, coronary vasospasm) or by marked reduction or cessation of coronary flow as a result of platelet aggregates or thrombi. This condition, termed supply ischemia, is responsible for myocardial infarction (MI) and most episodes of unstable angina (UA). In many circumstances, ischemia results from both an increase in oxygen demand and a reduction in supply.

The heart is an aerobic organ and therefore relies almost exclusively on the oxidation of substrates for generation of energy. It can develop only a small oxygen debt and still have enough energy to function normally. Thus, in a steady state, determination of the rate of myocardial oxygen consumption (ie, rate of myocardial ventilation oxygen consumption [MVO₂]) provides an accurate measure of its total metabolism. That the total metabolism of the arrested, quiescent heart is only a small fraction of that of the working organ has been known for many years. The small fraction of MVO₂ in the noncontracting heart is required for those physiologic processes not directly associated with contraction. Increases in the frequency of depolarization of the noncontracting heart are accompanied by only small increases in myocardial oxygen consumption.

• Determinants of myocardial oxygen consumption
• • Heart rate
  • Contractility
  • Systolic wall tension
  • Shortening against a load (Fenn effect)
  • Maintenance of cell viability in basal state
  • Depolarization
  • Activation
  • Maintenance of active state
  • Direct metabolic effect of catecholamines
  • Fatty acid uptake
• Heart rate: Myocardial oxygen consumption is linearly related to heart rate, ie, the faster the ventricular rate, the greater the myocardial oxygen consumption.
• Myocardial contractility
• • The net effect of positive inotropic stimuli (eg, calcium, catecholamines) on MVO₂ is the end result of their influence on two of its major determinants that change in opposite directions in the intact heart. These two are wall tension, which declines as a consequence of reduction in heart size, and myocardial contractility, which, by definition, is augmented by inotropic stimuli.
  • In the failing dilated ventricle treated with an inotropic agent, the increase in contractility reduces left ventricular (LV) end-diastolic pressure and volume, leading to a reduction in myocardial tension, which reduces MVO₂. The decrease in MVO₂ that might be expected to result from falling ventricular wall tension is opposed by the increase in contractility, which tends to increase MVO₂. Thus, the end result is such that the change in MVO₂ consequent to an inotropic stimulus depends on the extent to which intramyocardial tension is reduced in relation to the extent to which contractility is augmented.
  • In the absence of heart failure, drugs that stimulate myocardial contractility elevate MVO₂ because heart size and therefore wall tension are not substantially reduced and do not offset the effect on metabolism on stimulation of contractility.
  • Some researchers have suggested that almost the entire increase in MVO₂ produced by administration of positive inotropic agents (eg, calcium, epinephrine) results from the energy costs of enhanced excitation-contraction coupling, or, more specifically, a greater and more rapid calcium uptake by the sarcoplasmic reticulum, as well as from the increased contractile activity, rather than from a direct stimulating effect of positive inotropic agents on basal myocardial metabolism.
  • MVO₂ is also influenced by the substrate utilized. More specifically, it correlates directly with the fraction of energy derived from the metabolism of fatty acids, which in turn varies directly with arterial concentration of fatty acids, and inversely with concentrations of glucose and insulin.
• Myocardial systolic wall tension
• • As early as 1915, Evans and Matsuoka concluded from studies of the Starling heart-lung preparation that a relationship exists between myocardial tension during contraction and the metabolism of the contractile tissue. That ventricular pressure development is a key determinant of MVO₂ has subsequently been clearly established. Numerous investigations have suggested that MVO₂ per beat correlates well with the area under the LV pressure curve termed the tension-time index.
  • Furthermore, that the myocardial wall tension time integral is a more definitive determinant of MVO₂ than the developed pressure has been emphasized. Later studies demonstrated that the frequency of ventricular contraction is an important determinant as well. Augmentation of the heart rate elevates the MVO₂ by increasing the frequency of tension development per unit of time, as well as by increasing contractility.
  • Rooke and Feigl provided evidence that MVO₂ is influenced by stroke volume, ie, myocardial shortening, although less so than by tension development. Their investigation, as well as others', have further determined that the systolic pressure-heart rate product correlates closely with MVO₂ and that the LV systolic pressure volume area, consisting of the sum of the area within the systolic pressure-volume loop, is a useful index of MVO₂.
• Regulation of coronary blood flow - Metabolic regulation
• • Relationship between coronary blood flow and myocardial oxygen consumption
  • • Coronary blood flow is closely coupled to MVO₂ in normal hearts. This linkage is necessary because the myocardium depends almost completely on aerobic metabolism. The oxygen content of coronary venous blood is low, permitting little additional oxygen extraction, and oxygen stores in the heart are low.
    • Changes in myocardial oxygen balance lead to alterations in coronary vascular resistance with great rapidity, generally in less than 1 second. For example, occlusion of a coronary artery for less than 1 second produces an increase in coronary blood flow above baseline immediately following release of the occlusion. This response is called coronary reactive hyperemia. The mechanisms that link cardiac metabolic activity with coronary vascular resistance have been extensively investigated, and these investigations have focused on adenosine, other nucleotides, nitric oxide (NO), prostaglandins, carbon dioxide, and hydrogen ion as the most likely potential mediators.
  • Adenosine
  • • Adenosine is formed by degradation of adenine nucleotides under conditions in which ATP utilization exceeds the capacity of myocardial cells to resynthesize high-energy phosphate compounds, resulting in production of adenosine monophosphate (AMP). The enzyme 5'-nucleotidase is responsible for formation of adenosine from AMP. Accordingly, adenosine and its metabolites, inosine and hypoxanthine, appear in interstitial fluid and in the coronary sinus venous effluent.
    • Adenosine is a powerful coronary dilator that is considered to be an important, perhaps the critical, mediator linking metabolically induced vasodilation to diminished coronary perfusion. Adenosine production increases during an imbalance in the supply-to-demand ratio for oxygen, and the rise in interstitial concentration of adenosine parallels the increase in coronary blood flow. Adenosine plays a significant role in regulation of coronary blood flow during reactive hyperemia, hypoxia, inotropic stimulation with isoproterenol, dobutamine, and mental stress.
    • On the other hand, adenosine plays no significant role in the coronary vasodilation associated with inotropic stimulation with norepinephrine or the metabolic stress induced by rapid atrial pacing. Thus, adenosine is certainly not the only vasoactive factor involved in metabolic regulation of coronary blood flow. Others include NO, vasodilator prostaglandins, ATP-sensitive K channels (K-ATP) as well as myocardial oxygen and carbon dioxide tensions.
  • Nitric oxide
  • • This substance increases blood flow during metabolic stimuli. Inhibition of NO reduces the magnitude of metabolic hyperemia in animals and in peripheral and coronary circulation in humans. NO production is augmented in response to metabolic stimuli by at least 2 mechanisms. Hypoxia is a stimulus to release of NO from endothelium. Furthermore, NO is a principal mediator of flow-mediated dilation.
    • Although hypoxia may initiate hyperemia, flow-mediated dilation sustains and amplifies it. In support of this, inhibition of NO attenuates the late phase of reactive hyperemia, when flow-mediated dilation would be expected to occur.
  • Other metabolic mediators
  • • Inhibition of synthesis of vasodilator prostaglandins and inhibition of K-ATP channels also reduce metabolic vasodilation. Vasoactive factors probably act in concert to regulate coronary blood flow in response to metabolic needs. Thus, the reactive hyperemia following 10-20 seconds of occlusion can be reduced by approximately 30% each by inhibitors of adenosine, NO, prostaglandins, and K-ATP.
    • Loss or inhibition of one mediator is compensated for by up-regulation of others. While inhibition of K-ATP, adenosine, and NO individually has, at most, a modest effect on the increase in coronary blood flow during exercise in dogs, inhibition of all 3 simultaneously nearly abolishes the flow increase.
• Regulation of coronary blood flow – Endothelial control of coronary vascular tone
• • Vasoactive agents that influence the tone of large and small coronary vessels can be carried in the blood plasma (eg, epinephrine, vasopressin), or they can be released from circulating blood elements such as platelets (eg, serotonin, adenosine diphosphate [ADP]) or from nerve endings in the vascular adventitia (eg, norepinephrine, vasoactive intestinal peptide). Furthermore, vasoactive factors can be formed locally by the vascular endothelium.
  • • The vascular endothelium performs a wide array of homeostatic functions within normal blood vessels. Located between the vascular lumen and the smooth muscle cells within the media of the vessel wall, the monolayer of endothelial cells can transduce blood-borne signals, sense mechanical forces within the lumen, and regulate vascular tone through production of a variety of factors. The endothelium produces both potent vasodilators, such as endothelium-derived relaxing factor (EDRF), NO, prostacyclin, and endothelium-derived hyperpolarizing factor (EDHF), and vasoconstrictors such as endothelin-1 (ET-1).
    • Endothelium-derived vasoactive factors are of great interest because endothelium can be damaged by atherosclerosis and by cardiovascular risk factors. Endothelial dysfunction may then lead to disturbances in coronary blood flow, can contribute to the pathogenesis of myocardial ischemia, and is a central feature in evolution of atherosclerosis and thrombosis.
  • Endothelium-derived relaxing factor
  • • Perhaps the most important vasodilator substance produced by endothelial cells is EDRF. The discovery of EDRF in 1980 by Furchgott resulted from the observation that intact endothelium is required for acetylcholine (ACH)-induced vasodilation. In the presence of endothelium, ACH produces dose-dependent vasodilation. When the endothelium is removed, ACH induces only constriction.
    • It became apparent that ACH has 2 distinct and opposite actions on blood vessels: an endothelium-mediated dilation and a smooth muscle–mediated constriction. In any vessel, the net result is related to the sum of these actions. In most healthy arteries, endothelium-dependent vasodilation predominates over direct vasoconstriction. EDRF has been identified as the NO radical. NO is formed in endothelial cells from the substrate L-arginine by the action of NO synthase.
    • The relaxing effect of NO is mediated by its diffusion to smooth muscle cells, in which it causes activation of intracellular guanylate cyclase, a rise in cyclic guanosine monophosphate (cGMP), and a consequent fall in intracellular calcium. Once released from endothelial cells, NO has a short half-life, limited by interaction with other free radicals in tissues, principally superoxide, and by entering red blood cells to react with oxyhemoglobin. In many vascular beds, NO is continuously released, contributing to maintenance of a vasodilator state.
    • Release of NO above this basal level is stimulated by, besides ACH, products of thrombosis (eg, thrombin), aggregating platelets (eg, serotonin, ADP), other chemical stimuli (eg, histamine, bradykinin), and increased shear stress resulting from an increase in blood flow; this last is responsible for so-called flow-mediated vasodilation. Vasoconstriction, such as that induced by alpha-adrenergic agonists, may also stimulate release of NO. Although their net effect on the blood vessel may be vasoconstriction, the presence of an endothelium-dependent vasodilating influence attenuates the constriction.
    • Only a few vasodilators can act independently of the endothelium and directly on vascular smooth muscle. These include the nitrovasodilators (eg, nitroglycerin, nitroprusside) and prostacyclin. Adenosine elicits both endothelium-independent and endothelium-dependent dilation; at high adenosine concentrations, endothelium-independent dilation dominates, while NO contributes to the dilator effects of adenosine at lower adenosine concentration.
  • Endothelium-dependent vasodilation in healthy human epicardial arteries
  • • Endothelium-dependent vasodilation has been documented as an important mechanism in many vascular beds in all mammals. The importance of NO secretion in vasodilation of healthy human epicardial arteries was first demonstrated by intracoronary infusion of ACH at the time of cardiac catheterization. This vasodilation can be inhibited by blocking NO synthesis with N-monomethyl L-arginine (L-NMMA). Similarly, L-NMMA inhibits flow-mediated dilation of human epicardial arteries.
    • Other endothelium-dependent substances that dilate healthy human coronary arteries include serotonin, histamine, bradykinin, and substance P.
  • Impairment of endothelium-dependent vasodilation in coronary arteries
  • • Substantial evidence has accumulated that the inappropriate vasoconstriction that characterizes atherosclerosis is related to vasodilator dysfunction of the endothelium, permitting unopposed constriction of vascular smooth muscle. The response to endothelium-dependent stimuli that dilate healthy human coronary arteries is markedly impaired in patients with either early or advanced atherosclerosis. ACH constricts atherosclerotic coronary arteries, reflecting the loss of NO and ACH's unopposed constrictor effects on vascular smooth muscle.
    • Although abnormal vasomotor responses to ACH have served as a marker of endothelial dysfunction, the role of ACH in regulation of vascular tone has not been established. The finding of endothelial vasodilator dysfunction in human coronary atherosclerosis has been confirmed for other more physiologic stimuli that release NO, including serotonin, ADP, and increased coronary blood flow (ie, flow-mediated dilation). For example, whereas serotonin, a product released from aggregating platelets, dilates normal human coronary arteries, it constricts atherosclerotic arteries.
    • Loss of endothelium-dependent dilation occurs early in atherosclerosis, even prior to its detection by angiography. This loss of NO bioavailability is related to risk factors for atherosclerosis and is caused by reduced synthesis as well as accelerated breakdown of NO.
  • The following risk factors are associated with impaired endothelium-dependent vasodilation:
  • • Dyslipidemia
    • Hypertension
    • Diabetes mellitus
    • Cigarette smoking
    • Menopause
    • Hyperhomocystinemia
    • Aging
    • Family history of coronary artery disease (CAD)
    • Mutations in the enzyme nitric oxide synthetase (NOS)
  • Endothelial dysfunction and myocardial ischemia
  • • The impairment of endothelial function that occurs in atherosclerosis and in the presence of risk factors for atherosclerosis plays an important role in subsequent development of acute coronary syndromes. When superimposed on coronary artery stenosis, loss of endothelium-dependent dilation and resultant unopposed coronary artery constriction predisposes patients to myocardial ischemia, a physiologic phenomenon that has been documented in patients with stable angina in several studies. With exercise performed at the time of coronary angiography, epicardial arteries of healthy subjects were noted to dilate. In patients with stable angina, however, paradoxical vasoconstriction typically occurred at the site of coronary stenoses or even in mildly irregular coronary arterial segments.
    • Numerous studies also support the notion that endothelial dysfunction is important in microvascular ischemia syndromes (including syndrome X) characteristically found in individuals with chest pain but no hemodynamically significant coronary artery stenoses.
    • That exercise causes dilation in arteries with normal endothelium (evinced by a normal dilatory response to ACH) but causes constriction of coronary arteries with endothelial dysfunction has also been confirmed. A similar pattern of dilation of normal coronary arteries and paradoxical constriction of atherosclerotic coronary arteries with dysfunctional endothelium has been observed with mental stress, the cold pressor test, and increased heart rate. In patients with dysfunctional endothelium, loss of flow-mediated and catecholamine-stimulated NO release permits unopposed arterial constriction by catecholamines. Thus, loss of NO may contribute to impaired dilation or exaggerated constriction of epicardial and resistance vessels and lead to myocardial ischemia.
    • While plaque fissuring or rupture with platelet aggregation and thrombus formation is a hallmark of UA and MI, coronary artery constriction is mediated by the paradoxical response of these atheromatous vessels to products of platelet aggregation and thrombosis, namely serotonin, which is released from aggregating platelets. Patients with unstable coronary syndromes and complex plaques have augmented release of serotonin into the coronary circulation. Furthermore, patients with recent UA or MI show evidence of endothelial vasodilator dysfunction in the infarct-related artery (when tested with ACH) that is more pronounced than in arteries with stable stenoses of similar severity.
    • Reductions in NO are associated not only with enhanced vasoconstriction at sites of disrupted atherosclerotic plaques but also with a predilection toward destabilization of plaques. In other words, reduction of NO can lead to destabilization and rupture of atheromatous plaques. Therefore, NO is viewed as an important antiatherogenic and plaque-stabilizing substance.
    • Coronary resistance vessels may be affected by endothelial dysfunction in the absence of obstructive epicardial artery disease. Impaired endothelium-dependent dilation of coronary resistance vessels undoubtedly accounts for some cases of syndrome X, ie, angina with stress test evidence of myocardial ischemia and angiographically normal coronary arteries as described above.
  • Endothelium-derived hyperpolarizing factor
  • • Convincing evidence indicates that factors other than NO and prostacyclin can mediate endothelium-dependent vasodilation by hyperpolarizing the underlying smooth muscle. This occurs through activation of calcium-activated potassium channels in vascular smooth muscle cells and has been attributed to the diffusible factor EDHF. EDHF appears to be far more important in small arterioles than in larger conduit arteries and is released by many of the same stimuli that stimulate NO, including ACH, bradykinin, substance P, and shear stress.
    • EDHF has been demonstrated in human coronary and peripheral arterioles in vitro. NO inhibits production of EDHF. Thus, some investigators have suggested that when diseases reduce NO bioavailability, release of this intrinsic inhibition may maintain endothelial vasodilator function through up-regulation of EDHF. Aging and long-standing hypercholesterolemia appear to reduce EDHF and NO in human peripheral arterioles. As with NO, EDHF is a multipotent substance with anti-inflammatory properties, whose full significance in normal human coronary physiology remains to be established.
  • Prostacyclin
  • • Prostacyclin is a potent vasodilator derived from the endothelium through the actions of cyclooxygenase. Its role in the control of vascular tone was controversial until recently. Aspirin administration has little effect on arterial blood pressure in humans, suggesting that inhibition of cyclooxygenase does not cause generalized systemic vasoconstriction. Administration of indomethacin reduces resting coronary blood flow in humans, but these coronary constrictor effects may not be due to inhibition of prostacyclin synthesis.
    • Patients with atherosclerosis have increased prostacyclin production. In patients with coronary atherosclerosis or risk factors, administration of aspirin to inhibit cyclooxygenase has revealed that prostacyclin significantly contributes to resting vasodilator tone in epicardial arteries and resistance arterioles and plays a role in flow-mediated coronary dilation and metabolic vasodilation. Thus, prostacyclin-mediated coronary vasodilation appears to be most important in a setting characterized by deficiency of NO and may provide a useful compensatory mechanism.
  • Endothelium-derived constricting factors
  • • The endothelium not only mediates vasodilation, it is a source of vasoconstrictor factors as well. The best characterized of these are the endothelins. ET-1 is a 21-amino-acid peptide that has a potent vasoconstrictor effect. Two other isoforms of endothelin have been discovered (ie, ET-2, ET-3), but endothelium produces only ET-1. Unlike NO, which can be rapidly released in response to vasodilator stimuli and then inactivated within seconds, ET-1–mediated constriction is slow in onset and lasts from minutes to hours. Agents that stimulate ET-1 (eg, thrombin, angiotensin II [AII], epinephrine, vasopressin) do so by de novo transcription of messenger RNA. Most likely, ET-1 contributes to regulation of vascular tone via a tonic vasoconstrictor influence.
    • In addition to its influence on vascular tone, ET-1 stimulates smooth muscle proliferation, vascular remodeling and leukocyte adhesion, and recruitment. It may thus play a significant role in inflammation and atherogenesis and an as yet undetermined role in restenosis after thrombolysis or percutaneous coronary interventions (PCIs), with or without stenting.
    • Plasma concentrations of ET-1 are elevated in a number of vascular disorders, including hypercholesterolemia, hypertension, atherosclerosis, acute MI, and congestive heart failure (CHF). Aside from vascular endothelium, macrophages and activated smooth muscle cells are rich sources of ET-1 in the vessel wall. These cells are numerous in vulnerable or ruptured plaques. Consistent with this is the finding that the culprit plaques of patients with acute coronary syndromes express significantly greater ET-1 immunoreactivity than plaques of patients with stable angina. Plaques of patients with acute coronary syndromes are also rich in lipid, and oxidized low-density lipoprotein (LDL) is a potent stimulus of ET-1 synthesis.
• Regulation of coronary blood flow - Autoregulation
• • The ability to maintain myocardial perfusion at constant levels in the face of changing blood pressure is termed autoregulation. Autoregulation is difficult to study in humans because aortic pressure is not only the driving perfusion pressure for the coronary circulation, but it is also the afterload for the LV, a major determinant of MVO₂.
  • Autoregulation is perhaps the principal reason why patients with CAD and epicardial stenosis do not have evidence of resting perfusion deficits or myocardial ischemia at all times. Reductions in perfusion pressure distal to arterial stenoses are compensated for by autoregulatory dilation of the resistance vessels. Perfusion pressure distal to coronary stenoses was recently measured in patients with a pressure wire, and myocardial perfusion in the same territory was assessed by positron emission tomography (PET). Myocardial perfusion remained relatively constant over a pressure range of 45-125 mm Hg.
  • The ability of autoregulation to compensate for the effect of proximal epicardial obstruction may be compromised in several clinical situations.
  • • A fall in aortic pressure can lower perfusion pressure distal to a stenosis below the critical levels at which autoregulation is effective, thereby compromising myocardial perfusion, intensifying myocardial ischemia, and increasing LV filling pressure, which reduces the perfusion gradient further. These events may cause a vicious cycle, especially in patients with left main or 3-vessel CAD; they may necessitate insertion of an intraaortic balloon pump to raise diastolic perfusion pressure and to restore autoregulation of the coronary circulation, thereby lessening myocardial ischemia.
    • Chronic hypertension and LV hypertrophy narrow the range of autoregulation, especially in the subendocardium, where autoregulation is ordinarily more limited than in the subepicardium. LV hypertrophy amplifies the detrimental effects of coronary stenoses on myocardial perfusion, and patients with severe ventricular hypertrophy may have subendocardial ischemia even in the absence of coronary stenosis.
    • Conditions that alter the function of vascular smooth muscle in coronary arterioles attenuate autoregulation. Adenosine and dipyridamole abolish autoregulation; in the setting of coronary stenoses, their administration may cause myocardial ischemia, especially in the subendocardium. In endotoxic shock, the myocardium produces massive amounts of NO, which causes autoregulatory dysfunction and potentially predisposes patients to myocardial ischemia.
  • Mechanisms of autoregulation
  • • NO: Inhibition of NO raises the lower autoregulatory threshold by about 15 mm Hg. Involvement of NO may be related to the ability of endothelium to sense changes in perfusion pressure through pressure-sensitive ion channels. Little current evidence supports a role for adenosine or K-ATP in coronary autoregulation.
    • Myogenic control: Arteriolar smooth muscle reacts to increased intraluminal pressure by contracting. The resultant augmentation of resistance tends to return blood flow toward normal despite the higher perfusion pressure. This mechanism, termed myogenic control, is an important mechanism in some vascular beds. Currently, the contribution of myogenic responses in coronary resistance vessels is thought to be relatively small.
• Regulation of coronary blood flow - Extravascular compressive forces
• • Systolic compressive forces
  • • Because the systolic ventricular wall compresses intramyocardial vessels, most of the coronary blood flow to the LV occurs during diastole. Thus, the contracting heart obstructs its own blood supply. At the peak of systole, backflow may even be noted in the coronary arteries, particularly in intramural and small epicardial arteries. The extravascular systolic compressive force has 2 components: LV systolic intracavitary pressure and vascular narrowing caused by compression and bending of vascular arterioles coursing through the ventricular wall during ventricular systole.
    • LV systolic intracavitary pressure is transmitted fully to the subendocardium but drops to almost zero at the epicardial surface. The "throttling" effect of systole on myocardial perfusion is particularly important when systolic intraventricular pressure exceeds coronary perfusion, as occurs with obstruction to LV outflow by valvular or subvalvular aortic stenosis or with severe aortic regurgitation. Because an increase in heart rate increases the total duration of systolic compression of the coronary arteries, with a concomitant decrease in diastolic coronary perfusion time, while augmenting myocardial oxygen demand, tachycardia may actually cause myocardial ischemia.
    • The importance of extravascular compressive forces is greatly magnified when coronary vascular tone is diminished, as may occur during administration of arteriolar vasodilators or during metabolic vasodilation associated with physical activity.
    • Because compressive forces exerted by the right ventricle (RV) are ordinarily much smaller than those by the LV, ventricular perfusion is reduced but not interrupted during systole. When RV systolic pressure is elevated significantly by disease, however, such as in severe cor pulmonale or in pulmonic stenosis, perfusion of the RV may be compromised, even in the absence of atheromatous disease in the epicardial arteries that supply the RV.
  • Diastolic compressive forces
  • • Coronary perfusion pressure has been assumed to be the pressure gradient between the coronary arteries and the pressure in either the right atrium or LV in diastole.
    • When coronary perfusion pressure is lowered, diastolic blood flow ceases when coronary perfusion pressure reaches 40-50 mm Hg, the so-called pressure at zero flow. This pressure is largely determined by diastolic compressive forces.
• Regulation of coronary blood flow - Transmural distribution of myocardial blood flow
• • Extravascular compressive forces are greater in the subendocardium than in the subepicardial layer. Subendocardial arterioles are particularly susceptible to compression from ventricular systole. Therefore, systolic flow is reduced to a greater extent in the subendocardium than in the subepicardium. Nevertheless, average flow throughout the cardiac cycle is greater in subendocardial arterioles than the subepicardium. This is due to preferential dilation of the subendocardial arterioles, which causes a large increase in diastolic flow in the subendocardium owing to greater wall stress in the subendocardium than in the subepicardial muscle.
  • Subendocardial ischemia
  • • The subendocardium is more vulnerable to ischemic damage than the mid myocardium or subepicardium. Epicardial coronary stenoses are associated with reductions in the subendocardial-to-subepicardial flow ratio. This pattern of redistribution of flow away from the endocardium is further exaggerated during exercise, mental stress, and pacing-induced tachycardia. Potent arteriolar vasodilators, such as dipyridamole or adenosine, also cause redistribution of blood flow from the endocardium to the epicardium.
    • When the absolute amount of blood flow is restricted, as in the presence of epicardial stenoses, this transmural redistribution leads to a coronary steal phenomenon, with subendocardial flow even falling below resting values. Severe pressure-induced LV hypertrophy, as well as heart failure with elevated LV end-diastolic pressure, may also reduce the endocardial-to-epicardial flow ratio. When the markedly elevated LV end-diastolic pressure in heart failure is corrected, subendocardial coronary flow reserve (CFR) is restored and the endocardial-to-epicardial flow ratio is normalized. Thus, impairment of endocardial perfusion in heart failure may be a direct consequence of elevated LV diastolic pressure and the diastolic compressive forces exerted on subendocardial perfusion.
    • A low subendocardial-to-subepicardial flow ratio can be increased by elevation of aortic pressure, which preferentially increases perfusion of the subendocardial region, whose arterioles are maximally dilated and in which flow is pressure dependent.
    • Overperfusion of the epicardial region is prevented by autoregulatory arteriolar constriction. Potent vasoconstrictors, such as ET-1 and alpha-adrenergic agonists, or inhibitors of adenosine-induced arteriolar dilation, such as theophylline, cause arteriolar constriction and redistribution of blood flow to the endocardium. As long as the absolute blood flow is not appreciably reduced, this may result in lessening of myocardial ischemia. Reduction of myocardial oxygen demand also decreases epicardial blood flow and increases perfusion pressure and thereby flow to the ischemic subendocardial region.
• Regulation of coronary blood flow - Neural and neurotransmitter control
• • Coronary blood flow is controlled predominantly by local metabolic, autoregulatory, and endothelial factors that match coronary blood flow to myocardial oxygen demand and to the driving perfusion pressure. Neural control of the coronary circulation complements these local effects. Epicardial arteries and coronary arterioles are extensively innervated by sympathetic and parasympathetic fibers, and adrenergic and muscarinic receptors are expressed in these locations.
  • Sympathetic control
  • • Alpha-adrenergic vasoconstriction: When the cardiac inotropic and chronotropic actions of activation of sympathetic fibers are blocked by beta-adrenoreceptor antagonists, coronary vasoconstriction mediated by means of alpha-receptors results.
    • Reflex alpha-adrenergic vasoconstriction: Hypotension leads to activation of sympathetic fibers and inhibition of vagal stimulation. The resultant increases in myocardial oxygen demand and blood flow are countered by alpha-adrenergic vasoconstriction.
    • This restraint imposed by the alpha-adrenergic system results in increased myocardial oxygen extraction. In humans, alpha-adrenergic coronary constriction can be demonstrated by activation of another reflex sympathetic pathway, the cold pressor test (ie, immersion of a hand into ice-cold water).
    • Beta-adrenergic vasodilation: Beta-receptor activation leads to coronary vasodilation, mediated mostly by a beta1-receptor in conduit arteries and by beta2-receptors in resistance arterioles.
• Regulation of coronary blood flow - Effects of coronary stenoses
• • Limitation of coronary blood flow imposed by atherosclerosis is related to the geometric features of stenoses, including their severity and length, their stiffness or partial distensibility permitting active or passive vasomotion, and the presence of superimposed platelet aggregation and thrombosis. At normal levels of coronary arterial flow, both frictional and separation losses contribute to the stenosis resistance and to the presence of a pressure gradient. Increases in blood flow and pressure drops across the stenosis are related in an exponential manner. Augmentation of coronary blood flow is associated with elevations in pressure gradient across the stenotic orifice and reductions in poststenotic perfusion pressure.
  • Brown and colleagues have called attention to several common clinical situations in which reduction in poststenotic pressure contributes to myocardial ischemia.
  • • Pharmacologic vasodilators, such as dipyridamole or adenosine, increase transstenotic blood flow and reduce poststenotic pressure. When subendocardial resistance vessels become near fully dilated, their perfusion pressure becomes pressure dependent because of the limits of autoregulation. Flow is redistributed away from the subendocardium to the subepicardium.
    • During physical activity, coronary blood flow rises to meet the increased myocardial oxygen demand, leading to an increase in transstenotic pressure gradient and a fall in distal perfusion pressure, resulting in reduction of blood flow from the subendocardium while flow to the subepicardium continues to increase, an effect similar to that observed with administration of pharmacologic vasodilators.
    • The reduced oxygen-carrying capacity of anemia is compensated for by increase in coronary blood flow because the myocardium cannot increase its oxygen extraction significantly. This decreases poststenotic pressure and compromises subendocardial perfusion. Thus, anemia is poorly tolerated in patients with CAD.
  • Severity of stenosis
  • • At any level of blood flow, the single most important determinant of stenosis resistance is the minimum diameter of the stenosis. The transstenotic pressure drop is inversely proportional to the fourth power of the minimum luminal diameter. As described below, varying degrees of stenosis can cause myocardial ischemia in different individuals and under different physiologic circumstances. Thus, with stenoses of intermediate severity by angiographic criteria, functional studies may be necessary to ascertain the potential for myocardial ischemia.
    • In the presence of severe stenoses, a relatively small change in luminal diameter, such as that caused by active or passive vasomotion, is amplified to produce marked hemodynamic effects.
  • Entrance and exit effects
  • • Blood flow velocity increases and pressure decreases in a narrowed arterial segment.
    • Since most stenoses have abrupt transitions, where blood flow velocity increases rapidly and perfusion pressure decreases dramatically, these effects are particularly pronounced at the exits of stenoses.
  • Length of stenoses
  • • For most stenoses, the length of the narrowing has only modest effects on its physiologic significance.
    • In long narrowed segments, however, significant turbulence of blood flow occurs along the wall of the stenotic segment, and energy is lost when eddies collide with the coronary arterial wall, leading to inadequate poststenotic perfusion pressure.
  • Effects of coronary stenosis in the intact coronary bed
  • • Resting coronary flow is not impeded by mild or moderately severe stenoses and is an insensitive measure for evaluation of CAD. Maximal coronary blood flow begins to decline, however, when diameter stenosis exceeds 30-45%. The capacity to increase coronary blood flow in response to increased oxygen demand is abolished when diameter stenosis exceeds 90%.
    • The simple use of relative percent diameter stenosis determined by coronary angiography has important limitations because it does not account for other geometric characteristics of the stenosis (eg, absolute diameter, length, entrance and exit angles, eccentricity). Determination of relative percent diameter narrowing may be misleading in the setting of diffuse disease, where segments adjacent to the stenosis are also reduced in caliber.
    • The hemodynamic effects of serial stenoses are also difficult to assess from angiography alone. Unsurprisingly, the correlation between percent diameter stenosis and the physiological significance of a given obstruction in patients is poor, especially for lesions of moderate severity.
• Regulation of coronary blood flow - Coronary flow reserve and hyperemia
• • Severe myocardial ischemia produces maximal coronary dilation. Therefore, when a coronary artery is occluded, release of the occlusion is followed by a marked increase in coronary flow. This response is termed reactive hyperemia. Reactive hyperemia can follow an occlusion as brief as 200 milliseconds. Maximal reactive hyperemia follows coronary occlusions of 20 seconds. Longer occlusions increase the duration, but not the degree, of reactive hyperemia.
  • • Reactive hyperemia is a response driven partly by a requirement to repay oxygen debt. However, the hyperemic response is less pronounced when coronary arteries are perfused with deoxygenated blood for the same duration, suggesting that factors other than mere lack of oxygen stimulate the hyperemic response, including local accumulation of adenosine, prostacyclin, and NO.
    • After release of coronary occlusion, autoregulation is abolished, and coronary blood flow is directly related to the driving pressure. Therefore, maximal hyperemic coronary blood flow is closely dependent on coronary arterial (or central aortic) pressure at the time of the measurement.
  • Maximal blood flow is a more sensitive stimulus for assessing hemodynamic severity of stenoses than resting blood flow. Three types of stimuli have been used to elicit maximal coronary blood flow in humans: (1) transient coronary occlusion, (2) pharmacologic vasodilators, and (3) metabolic stress.
  • • Transient coronary occlusion can be induced in humans, and coronary blood flow responses can be evaluated during balloon angioplasty. Pharmacologic vasodilators, such as adenosine and papaverine, are used to elicit hyperemia. Adenosine can be administered by both intravenous and intracoronary routes, is generally safe, and has rapid onset of action and brief duration of action. Papaverine can be administered only by the intracoronary route, has a slower onset of action and a longer duration of action, and has a greater number of adverse effects. Papaverine, when administered in appropriate concentrations, causes a maximal increase in coronary blood flow similar to that obtained with reactive hyperemia after balloon angioplasty.
    • Intense treadmill or bicycle exercise, a potent metabolic stimulus, also yields near-maximal flow increases. Exercise is the most physiological stress and is particularly suited for noninvasive laboratory testing, but it is difficult to apply at the time of cardiac catheterization. Rapid atrial pacing produces only modest submaximal increases in coronary blood flow and can significantly underestimate the degree of ischemia that occurs with maximal stresses such as exercise.
• Coronary collateral circulation and angiogenesis
• • Coronary collateral vessels: During total or near-total occlusion of a coronary artery, perfusion of ischemic myocardium occurs by way of collateral circulation: vascular channels that interconnect epicardial arteries. Preexisting collaterals are thin-walled structures ranging in diameter from 20-200 micrometers. Acute coronary occlusion produces no infarction at all in individuals with a well-developed network of collaterals, whereas individuals who lack such a network of collaterals develop rapid and complete infarctions upon acute coronary occlusion.
  • Collateral formation: Arteriogenesis refers to formation of new vessels capable of delivering blood flow to areas at risk of myocardial ischemia. In the coronary circulation, an accepted hypothesis holds that angiogenesis results from enlargement of preexisting rudimentary collaterals to form mature collateral vessels. Typically, epicardial collaterals fall into this category. Preexisting collaterals are normally closed and nonfunctional because no pressure gradient exists between the arteries they connect. After coronary occlusion, the distal pressure drops precipitously, and preexisting collaterals open virtually instantly. Arteriogenesis occurs in the following 3 stages:
  • • Stage I (24 h): This stage involves passive widening of the preexisting channels, facilitating increased flow.
    • Stage II (24 h to 3 wk): This stage is characterized by inflammation and cellular proliferation involving the endothelium, smooth muscle cells, and fibroblasts.
    • Stage III (3 wk to 6 mo): This stage is characterized by collateral maturation and involves thickening of the vessel wall due to deposition of extracellular matrix and further cellular proliferation. In its final stage, the mature collateral vessel may reach 1 mm in luminal diameter, and its 3-layer structure is nearly indistinguishable from a normal coronary artery of the same size.
  • Mechanisms promoting collateral growth
  • • Shear stress: Pressure gradients across rudimentary collaterals augment blood flow velocity and shear stress.
    • Inflammation
    • Growth factors: Vascular endothelial growth factor (VEGF) and fibroblast growth factor (FGF) are the most important of more than 15 growth factors involved in stimulating arteriogenesis. Tissue hypoxia up-regulates VEGF.
  • Mechanisms inhibiting collateral growth
  • • Inhibitory factors: Angiostatin, endostatin, and thrombospondin are major factors in the inhibition of arteriogenesis.
    • Severity of obstruction: Coronary collaterals do not develop until a coronary stenosis of at least 70% diameter narrowing is present. Beyond this degree of stenosis, growth of collaterals is directly related to severity of stenosis.
    • Coronary risk factors: Diabetic patients have impaired ability to develop collateral blood vessels in the setting of obstructive CAD.
  • Exercise: This has no effect on preexisting collaterals in the absence or presence of coronary occlusions or stenoses.
  • Regulation of collateral tone: Collateral blood flow is regulated by the same vasoactive substances (eg, NO, prostacyclin, vasopressin, serotonin) as native epicardial arteries.
  • At this time, the relative importance of any of these stimuli remains to be characterized in individuals and in general.
  • Coronary collaterals in patients with CAD
  • • Coronary collaterals can mitigate the severity of myocardial ischemia; in acute MI, collateral circulation can contribute a significant amount of blood flow, decrease infarct size, improve LV function, reduce the likelihood of LV aneurysm formation, and improve chance of survival.
    • Quantifying collateral blood flow in conscious humans undergoing coronary angioplasty has recently become possible. Coronary pressure distal to the site of angioplasty balloon occlusion (ie, coronary wedge pressure) can be measured and reflects recruitable collateral perfusion.
    • Patients in whom recruitable collateral blood flow exceeded 28% of normal maximal myocardial blood flow were free of ischemia at the time of coronary occlusion induced by balloon angioplasty. Conversely, ischemia was frequently present at the time of coronary occlusion when recruitable collateral blood flow was less than 28% of normal maximal myocardial blood flow.
    • An important but unresolved issue is whether a defined mechanism(s) underlies differences in recruitable collaterals among different individuals.
    • This approach has shown that collateral circulation rarely provides blood flow increases adequate to meet the myocardial oxygen demands of maximal physical exercise. Collateral circulation is typically limited to less than 50% of maximal CFR.
  • Angiogenesis
  • • Angiogenesis overlaps with arteriogenesis but is confined to the sprouting of new vessels from preexisting blood vessels and usually results in formation of smaller, capillarylike structures. Subendocardial collaterals may be formed in this manner. In therapeutic angiogenesis, exogenous angiogenic growth factors (or genes encoding these growth factors) are administered to stimulate neovascularization of ischemic tissues.
    • Therapeutic angiogenesis has generated much interest and has significant potential as an effective means of improving myocardial perfusion and reducing symptoms of CAD.

Frequency

United States

The prevalence of myocardial ischemia is difficult to ascertain since the actual numbers of ischemic episodes and patients with myocardial ischemia would have to include those with silent ischemia. Silent ischemia is undoubtedly common, but its precise prevalence is unknown. However, the frequency of ischemic heart disease certainly parallels that of CAD and is at least as prevalent. Atherosclerotic coronary heart disease (CHD) causes approximately 500,000 deaths in the United States each year, ie, about 1 in 5 deaths overall.

• Roughly 6.3 million Americans are believed to experience angina. An estimated 350,000 new cases of angina occur every year. More than 12 million Americans had a history of MI and/or angina pectoris in the year 2000.
• About every 29 seconds, an American has a coronary event, and about every minute someone dies from one.
• Approximately 14 million people alive today have coronary disease: 6.5 million males and 7.5 million females.
• Roughly 1.5 million Americans have new or recurrent acute MIs each year, and 40% of these individuals die as a result.
• From 1987-1997, however, the death rate from CHD declined 24.9%.

International

International incidence, especially in the developed countries, echoes that observed in the United States.

Mortality/Morbidity

In the United States, approximately 14 million persons have ischemic heart disease and its various complications. CHF, as a result of ischemic cardiomyopathy, has become the most common discharge diagnosis in US hospitals.

• Approximately 1.5 million Americans have acute MI annually, 500,000 of whom die. CAD is the single most common cause of death in the United States, with a rate of almost 1 death per minute. More than half of those who die suddenly from CAD have no previous symptoms. In patients with UA, older studies showed the incidence of death in the early weeks following hospitalization to be approximately 4%, and the incidence of MI approximately 10%. The outcome in patients with abnormal ECG findings, and, in particular, ST-segment depression, approximates that of patients with acute MI. Other predictors of worse long-term outcome in UA include advanced age, underlying LV systolic dysfunction, and more widespread extent of CAD. In the United States, almost 500,000 patients undergo PCIs, and another 400,000 individuals undergo coronary artery bypass surgery (CABS) per year as a result of myocardial ischemia and/or MI.
• Survivors of MI exhibit a poorer prognosis as well. They have a 1.5- to 15-times higher risk of mortality and morbidity than the rest of the population without prior MI and are at higher risk for subsequent MI, as well as for fatal and near-fatal arrhythmias as a result of myocardial ischemia.
• Within a year of MI, 25% of men and 38% of women die. Within 6 years, 18% of men and 34% of women have a second MI, 7% of men and 6% of women experience sudden death, 22% of men and 46% of women are disabled with CHF, and 8% of men and 11% of women have a stroke.

Race

Significant racial variations exist in the incidence, prevalence, presentations, and response to therapy for CAD.

• African Americans appear to have higher morbidity and mortality rates, even when corrected for educational and socioeconomic status. The risk-factor burden experienced by African Americans differs from that experienced by whites. Incidence of hypertension, obesity, dysmetabolic syndrome, and lack of physical activity are much higher, while the incidence of hypercholesterolemia is lower. As documented in recent demographic studies, African Americans present later after the onset of acute MI, are less often subjected to invasive strategies, and suffer a greater overall mortality rate. Similar statistics can be cited for presentation and management of stable CAD as well.
• Indian Asians have 2- to 3-times higher incidence of CAD than whites in the United States. They have greater incidence of hypoalphalipoproteinemia and high lipoprotein(a) (Lp(a)) levels.
• Persons of Mediterranean origin have a lower incidence of CAD and myocardial ischemia. The relative importance of genetics versus environment (especially diet) has yet to be completely elucidated in this population.

Sex

The incidence of ischemic heart disease is equal in men and women, with the onset in women typically delayed by about 10 years. Premenopausal women are generally protected from manifestations of ischemic heart disease because of the protective effects of estrogen, but the presence of diabetes eliminates the protection associated with female sex.

• The mortality rates associated with ischemic heart disease are similar for both men and women, although they are slightly higher in women. This is partially attributable to being older at presentation than men and frequently to having less-than-typical symptoms. Women tend to survive to an older age than men.
• Numerous studies have reported that women tend to present later than men when presenting with acute MI or ischemic episodes, are less often subjected to invasive strategies, and tend to benefit less from these invasive strategies. Earlier studies tended to show women having a greater overall mortality rate during invasive strategies, but this has been contradicted in more recent studies.

Age

Age is one of the strongest independent risk factors for development of CAD and all its presenting manifestations.

• Elderly persons still experience higher mortality and morbidity rates from CAD than younger people. Complications of multiple therapeutic interventions tend to be higher; however, the magnitude of benefit from the same interventions is greater because they form the high-risk subgroup.

CLINICAL

Section 3 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

History

Ischemic heart disease and myocardial ischemia are manifested in a broad spectrum of clinical syndromes. The spectrum of presentation includes symptoms and signs consistent with the following conditions:

• Asymptomatic state (subclinical phase)
• Stable angina pectoris
• Unstable angina (acute coronary syndrome)
• Acute MI
• Chronic ischemic cardiomyopathy
• CHF
• Sudden cardiac arrest

For any of the clinical syndromes described above, the patient may report one or more of the following signs and symptoms:

• Chest discomfort
• Shortness of breath
• Fatigue and reduced exertional capacity due to ischemia-mediated cardiac dysfunction
• Palpitations and dizziness from arrhythmias that occur as a result of myocardial ischemia
• Leg swelling and weight gain from heart failure
• Symptoms related to the risk factors for CAD
• Silent myocardial ischemia

Silent myocardial ischemia, which occurs in a significant number of individuals, deserves special consideration. Included in this category are individuals who truly have no symptoms whatsoever and those with subtle evidence of CHD manifested as decreased endurance or energy. The following considerations are important:

• Silent myocardial ischemia is indicated by lack of symptoms in the presence of documented ECG or nuclear imaging evidence of myocardial ischemia. It occurs frequently in patients with CAD, particularly frequently in patients with diabetes and in patients who have undergone cardiac transplantation. Silent myocardial ischemia occurs in 20% of patients with asymptomatic type 2 diabetes mellitus.
• The prognostic importance and significance and the mechanisms of silent ischemia have been the subject of considerable interest for almost 30 years. Patients with silent ischemia have been stratified into 3 categories by Cohn.
• • Type 1 silent ischemia
  • • Type I is the least common form of silent ischemia.
    • It occurs in totally asymptomatic patients with obstructive CAD (which may be severe), and these patients do not experience angina at any time. Some patients with type I silent ischemia do not experience pain even in the course of MI.
    • Epidemiological studies of sudden death, as well as clinical and postmortem studies of patients with silent myocardial ischemia and studies of patients with chronic angina pectoris, suggest that many patients with extensive coronary artery obstruction never experience angina pectoris in any of its recognized forms (ie, stable, unstable, variant).
    • These patients with type I silent ischemia may be considered to have a defective anginal warning system.
  • Type II silent ischemia is the form that occurs in patients with documented previous MI.
  • Type III silent ischemia
  • • Type III is the most frequent form of silent ischemia.
    • It occurs in patients with the usual forms of chronic stable angina, UA, and variant angina.
    • When monitored, patients with this form of silent ischemia exhibit some episodes of ischemia that are associated with chest discomfort and other episodes that are not, ie, episodes of silent (asymptomatic) ischemia. The total ischemia burden in these patients refers to the total period of ischemia, both symptomatic and asymptomatic.
• Ambulatory ECG in silent myocardial ischemia
• • The extensive use of ambulatory ECG monitoring has led to a greater appreciation of the high frequency of type III silent ischemia. That angina pain is a poor indicator and underestimates the frequency of significant cardiac ischemia has become apparent. Exercise-induced hemodynamic changes indicative of myocardial ischemia, such as increasing LV end-diastolic pressure and decreasing LV ejection fraction, occur in patients with CAD regardless of the development of ischemic discomfort.
  • The role of myocardial oxygen demand in the genesis of myocardial ischemia has been evaluated by measuring heart rate and blood pressure changes preceding silent ischemic events during ambulatory studies. These studies show that a large percentage (>90%) of all episodes of ischemia were silent and that most were preceded by significant increases in heart rate or blood pressure. Circadian variations in heart rate and blood pressure also paralleled the increase in silent ischemic events.
  • Numerous studies suggest that increases in myocardial oxygen demand also have a significant role in the genesis of silent ischemia; in some patients, however, reduction in myocardial oxygen supply may make an important contribution to the initiation of both symptomatic and asymptomatic episodes. The mechanisms underlying development of ischemia, as detected by ambulatory ECG and exercise testing, may be different in different patients; in patients in the Asymptomatic Cardiac Ischemia Pilot (ACIP) study, concordance between ambulatory ECG and single-photon emission computed tomography (SPECT) imaging was only 50%.
  • Transient ST-segment depression of 0.1 millivolt (mV) or more that lasts longer than 30 seconds is a rare finding in healthy subjects. Patients with known CAD show a strong correlation between such transient ST-segment depression and independent measurements of impaired regional myocardial perfusion and ischemia determined by rubidium 82 uptake, as measured by PET.
  • In patients with type III silent ischemia, perfusion defects occur in the same myocardial regions during symptomatic and asymptomatic episodes of ST-segment depression. Other methods of detecting silent ischemia include measurement of LV ejection fraction with a nuclear vest or presence of regional wall-motion abnormalities and perfusion defects on ECG or radionuclide scintigraphy.
  • Type III silent ischemia is extremely common. Analysis of ambulatory ECG recordings among patients with known CAD who had both symptomatic and silent myocardial ischemia found that 85% of ambulant ischemic episodes occur without chest pain, and 66% of angina reports were unaccompanied by ST-segment depression. The frequency of silent ischemic episodes has elicited the suggestion that overt angina pectoris is merely the "tip of the ischemic iceberg."
  • Among patients with stable CAD enrolled in one study 1-6 months after hospitalization for an acute ischemic event, only 15% had angina with exercise, yet 28% had ST-segment depression, and 41% had reversible myocardial perfusion defects on thallium scintigraphy. Episodes of silent ischemia have been estimated to occur in at least half of all patients with angina, and an even higher prevalence has been postulated in patients with diabetes mellitus.
  • Episodes of ST-segment depression, both symptomatic and asymptomatic, exhibit a circadian rhythm and are more common in the morning. Asymptomatic nocturnal ST-segment changes are almost invariably an indicator of 2- or 3-vessel CAD or left main coronary artery stenosis.
  • Pharmacologic agents that abolish or reduce episodes of symptomatic ischemia (ie, nitrates, beta-blockers, calcium antagonists) also reduce or abolish episodes of silent ischemia.
• Mechanisms of silent ischemia: The mechanism or mechanisms that elicit silent ischemia are unknown. Investigations into the causes of silent ischemia have focused primarily on the following 5 areas:
• • The association of diabetes with both silent ischemia and painless infarction has been attributed to an autonomic neuropathy.
  • Patients with silent ischemia have a high threshold for other forms of pain, such as that resulting from electric shock, limb ischemia, cutaneous application of heat, or balloon inflation in the coronary artery.
  • Hypertensive patients who demonstrated a higher incidence of silent ischemia have been shown to have higher pain thresholds and lower reactions to tooth-pulp stimulation than normotensive patients. Some investigators have suggested that these patients produce an excessive quantity of endogenous opioids (and endorphins) that raise the pain threshold, but the existence of such a mechanism is debated.
  • In patients with type III silent ischemia, the asymptomatic episodes may result from a less severe ischemia than the symptomatic episodes. In some of these patients, shorter periods of ischemia on Holter ECG tend to be asymptomatic, whereas longer periods are accompanied by angina. That the pain receptors are not stimulated by the milder episodes of ischemia has been postulated.
  • A more recent area of investigation suggests that silent ischemia in some patients may not be due to peripheral nerve dysfunction but instead is the result of a defect in the cerebral cortex. Frontal cortical activation appears necessary to experience cardiac pain, and some evidence indicates that, in patients with silent ischemia, afferent pain messages from the heart are subject to abnormal neural processing.
• Prognosis of silent myocardial ischemia
• • In asymptomatic patients, the presence of exercise-induced ST-segment depression predicts a 4- to 5-fold increase in cardiac mortality rate compared to patients without this finding. On the other hand, in some subsets of patients (eg, hemodynamically stable patients with previous MI), the presence of painless exercise-induced ischemia has not been shown to provide additional prognostic information.
  • The presence of myocardial ischemia on ambulatory ECG, whether silent or symptomatic, is associated with a worse cardiac outcome, particularly if the episodes are frequent or accelerating. What is not clear is whether detection of asymptomatic episodes of ischemia on ambulatory ECG adds independent prognostic information over and above that provided by the results of the stress test and the frequency and severity of symptoms.
  • • In the ACIP study, among patients treated medically, myocardial ischemia detected by ambulatory ECG and by an abnormal treadmill test result were each independently associated with adverse cardiac outcomes. Moreover, ischemia detected by ambulatory ECG monitoring did not correlate with the presence and extent of ischemia as quantified by stress SPECT scintigraphy, which suggests that these techniques detect different pathophysiological manifestations of ischemia.
    • Patients with ischemia on ambulatory ECG were more likely to have multivessel CAD, severe proximal stenoses, and a greater frequency of complex lesion morphology (including intracoronary thrombus, ulceration, and eccentric lesions), as observed on angiography, than patients without evidence of ischemia on ambulatory monitoring. The presence of severe and complex CAD may explain the apparent independent effect of silent ischemia during ambulatory monitoring on prognosis.

Physical

Physical examination may reveal the following findings in various combinations:

• Heart rate, during episodes of myocardial ischemia, is variable. Patients may present with tachycardia driven by increased catecholamine levels, or they may present with bradycardia when ischemia involves the sinus node and/or atrioventricular node.
• Patients with myocardial ischemia may present with normal blood pressure, elevated pressure, or hypotension, depending on cardiac performance during the episode of myocardial ischemia and the vasoactive neurohormonal effects present at the time of myocardial ischemia.
• Cardiac auscultation findings may be unremarkable, or it may reveal the following:
• • S₃ gallop in patients with decompensated heart failure due to ischemic cardiomyopathy or acute myocardial ischemia with LV systolic dysfunction
  • S₄ gallop due to elevated LV diastolic filling pressures as a consequence of myocardial ischemia or the chronic consequences of myocardial ischemia
  • The murmur of mitral regurgitation may be heard because of ischemic papillary muscle dysfunction.
• Auscultation of the lungs may yield normal findings, or it may reveal rales as a manifestation of acute pulmonary edema caused by ischemic myocardial dysfunction or acute valvular heart disease caused by myocardial ischemia.
• A careful vascular examination is critical in patients with possible CHD. Carotid or abdominal bruits, abdominal aortic enlargement suggestive of an abdominal aortic aneurysm, or diminished peripheral pulses suggest the presence of a vasculopathy that may include the coronary circulation. Moreover, the presence of peripheral vascular disease, especially of an abdominal aortic aneurysm, is of prognostic significance in these patients.

Causes

See Pathophysiology.

• Risk factors for coronary atherosclerosis
• • Family history of premature CAD
  • Hyperlipidemia, including hypercholesterolemia (elevated low-density lipoprotein [LDL] level), low high-density lipoprotein (HDL) cholesterol level, and elevated triglyceride level
  • Hypertension
  • Cigarette smoking
  • Diabetes mellitus
  • Hypoalphalipoproteinemia
  • Dysmetabolic syndrome
• Nontraditional risk factors
• • Hyperhomocystinemia
  • High Lp(a) level
  • High iron level
  • Clinical depression
• Syndromes of accelerated atherosclerosis
• • Graft atherosclerosis
  • Postcardiac transplant CAD
  • Restenosis
• Infections implicated in development of atherosclerosis
• • Chlamydia pneumoniae
  • Helicobacter pylori
  • Herpes simplex virus

DIFFERENTIALS

Section 4 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

WORKUP

Section 5 of 11  

• Authors and Editors
• Introduction
• Clinical
• Differentials
• Workup
• Treatment
• Medication
• Follow-up
• Miscellaneous
• Multimedia
• References

Lab Studies

• CBC count is usually within reference ranges, but anemia can contribute to myocardial ischemia, particularly in patients with severe CAD or reduced LV systolic function. WBC count can be elevated during acute MI, but abnormalities of the WBC count are not typically found in patients with myocardial ischemia.
• Chemistry profile findings are usually within reference ranges in patients with myocardial ischemia. Serum glucose levels may be mildly elevated in nondiabetic patients during myocardial ischemia, but they are usually within reference ranges and are not helpful in confirming the diagnosis. In diabetic patients, however, elevated serum glucose levels, often markedly elevated, can be a clue to the diagnosis of myocardial ischemia, particularly in those with silent ischemia.
• Thyroid function tests are not routinely ordered but should be performed in patients for whom the diagnosis of thyrotoxicosis is suspected as a cause of myocardial ischemia.
• Lipid profile, including total cholesterol, LDL cholesterol, HDL cholesterol, and triglyceride levels, should be performed in all patients with suspected CAD as part of the risk-factor assessment. If necessary, specific lipid studies include the small, dense Lp(a) study and the VAP (apoprotein) profile.
• Homocysteine level is an uncommon but significant risk factor for CAD if elevated.
• Serum cardiac markers are useful in diagnosing MI or myocardial necrosis, and they also may be useful as a prognostic tool in patients with UA who do not meet ECG or laboratory criteria for acute MI. When troponin (I or T) or creatine kinase - myocardial band (CK-MB) level is elevated, but below the diagnostic threshold for a definitive diagnosis of MI, they identify patients at high risk for subsequent ST-elevation MI (STEMI) or non–ST-elevation MI (NSTEMI) in the next 6-12 months and thus identify a group of patients who should be immediately referred for invasive diagnostic testing via coronary angiography, and if necessary, coronary revascularization.
• • Troponins (I or T)
  • CK-MB
  • Myoglobin
  • Ischemia-modified albumin (IMA): The combination of IMA with myoglobin-CK-MB-troponin has been found to increase the sensitivity for detecting ischemia to 97%, with a negative predictive value of 92%. IMA is highly sensitive and has a high negative predictive value.
• C-reactive protein (CRP) is an inflammatory marker that is thought to have reliable prognostic significance in identifying patients at high risk of acute coronary syndromes within the near future. Although not routinely used now, CRP levels (especially in combination with serum HDL and LDL measurements) are among the best predictors of future cardiac risk. Note that of the various CRP measures currently available, high-sensitivity CRP (hsCRP) is far more reliable and predictive than other measures.
• B-type natriuretic peptide (BNP) level and its N-terminal fragment (NT-proBNP) level are elevated in patients with acute coronary syndromes and are closely linked to prognosis. In a multivariate analysis, NT-proBNP was an independent predictor for CAD. NT-proBNP level is elevated in patients with stable angina pectoris and has a close correlation to disease severity. When combining the measurement of NT-proBNP level with exercise testing, the test accuracy for predicting severe CAD can be improved.

Imaging Studies

• Echocardiography (echo): Transthoracic echo is useful in assessing LV regional wall-motion abnormalities at baseline and during acute ischemic episodes.
• • Stress echo
  • • Exercise echo is useful in evaluation of patients with chronic CAD because it can assess global and regional LV function in the absence and presence of ischemia, and it can detect LV hypertrophy and associated valve disorders. Exercise echo, in which imaging is performed at rest and immediately after exercise, is relatively inexpensive and safe and allows detection of regional ischemia by identifying new areas of wall-motion disorders.
    • Adequate images can be obtained in more than 85% of patients, and the test is highly reproducible. The inability to image at peak exercise is only a minor disadvantage because most wall-motion abnormalities do not normalize immediately on exercise.
    • Detection of ischemic myocardium has been enhanced by development of systems that allow side-by-side display of rest and postexercise images. Numerous studies have shown that exercise echo can detect the presence of CAD with an accuracy similar to that of stress myocardial perfusion imaging and superior to that of exercise echo alone. Exercise echo is also valuable in localizing and quantifying ischemic myocardium. Published results in more than 3200 patients with angiographic confirmation of the presence or absence of CAD yielded an average sensitivity of 85% and a specificity of 86%.
    • The indications for exercise echo are similar to those discussed for exercise myocardial perfusion imaging. It is an excellent alternative to nuclear cardiology procedures. Although less expensive than nuclear perfusion imaging, it is more expensive and less available than exercise stress testing. A regular exercise stress test should always be considered first for screening and detection of CAD in patients with a normal resting ECG result who are capable of performing treadmill exercise. That said, studies on the prognostic accuracy of treadmill demonstrate extreme variability, some showing a predictive accuracy of only 50%. Many cardiologists consequently favor exercise imaging studies as the first level of screening.
  • Pharmacologic stress echo
  • • Alternative approaches are available for patients unable to exercise, those unable to achieve adequate heart rates with exercise, and those in whom the quality of the echo images during or immediately after exercise is poor.
    • The most well-studied and clinically available method is dobutamine stress echo, in which constant echo imaging is performed during the infusion of dobutamine, beginning at 5-10 mcg/kg/min with graded increases to a maximum of 40-45 mcg/kg/min. Dobutamine increases both heart rate and contractility and produces diagnostic changes in regional wall motion and systolic wall thickening as ischemia develops.
    • Low-dose dobutamine infusion (5-10 mcg/kg/min) is also valuable for assessing contractile reserve in regions with hypokinetic or akinetic wall motion at rest, as a means of identifying viable myocardium that may improve in function after revascularization. Administration of atropine increases the accuracy of dobutamine stress echo in patients with inadequate heart-rate responses, especially in those taking beta-blockers and those in whom second-degree heart block develops at higher atrial rates.
    • Dobutamine stress imaging achieves diagnostic accuracy comparable to that of exercise echo; as with myocardial perfusion imaging, however, exercise stress imaging is preferable in patients capable of performing adequate exercise. An exception to this general policy is the patient with LV dysfunction who is undergoing dobutamine echo to assess myocardial viability. Dobutamine stimulation is safe, especially if the test is terminated at the onset of the first ischemic regional wall-motion abnormalities.
    • An alternative form of pharmacologic stress echo is infusion of high-dose dipyridamole or adenosine infusion, but exercise and dobutamine stress appear to have greater sensitivity than vasodilator stress in detecting CAD and are superior in assessing the extent of CAD. All forms of stress echo have similar high specificities, because a new wall-motion abnormality in a patient with normal resting LV function is a highly specific finding for reversible ischemia.
    • Transesophageal dobutamine stress echo has been shown to be feasible, safe, and accurate for detection of myocardial ischemia. Although it is not readily available for large numbers of patients, it may allow extension of dobutamine stress testing to patients whose results on transthoracic echo imaging are inconclusive.
    • Stress echo and stress nuclear perfusion imaging provide similar accuracy in detecting CAD. In studies in which the same patients were tested with both techniques and with coronary angiography, nuclear myocardial perfusion imaging had slightly greater sensitivity, and stress echo had greater specificity. Stress echo is associated with lower cost and easier implementation in the physician's office, but this depends on local expertise and available facilities.
  • Contrast echo
  • • Contrast echo is a rapidly evolving field in noninvasive testing for diagnosis and assessment of CAD.
    • A major objective is development of intravenous ultrasonic contrast agents for noninvasive myocardial perfusion imaging.
    • With greater spatial resolution than nuclear perfusion imaging, echo has the potential for evaluating transmural distribution of flow heterogeneity and detecting changes in subendocardial perfusion. Although this goal has not been fully realized with intravenous administration of ultrasonic contrast agents, early work is promising.
• Nuclear cardiology techniques - Stress myocardial perfusion imaging
• • Exercise perfusion imaging incorporates all the components of the exercise ECG with images of myocardial blood flow by using either a technetium 99m or thallium 201 perfusion tracer. The radionuclide is injected intravenously at peak exercise or at a symptom-limited end point such as angina or dyspnea; the patient is encouraged to exercise for another 45-60 seconds to ensure that initial myocardial uptake of the tracer reflects the perfusion pattern at peak stress.
  • The stress images are acquired several minutes after the patient finishes exercising (see Image 1). At rest images are acquired separately to compare the stress images with images of resting perfusion. Reversible perfusion defects between stress and rest indicate exercise-induced myocardial ischemia, whereas irreversible defects usually represent regions of myocardial fibrosis.
  • Exercise perfusion imaging with simultaneous ECG is superior to exercise ECG alone in detecting CAD, in identifying multivessel disease, in localizing disease vessels, and in determining the magnitude of ischemia and infarcted myocardium. The published results of exercise SPECT imaging show that it yields average sensitivity and specificity of greater than 90%. The results with thallium 201 are comparable to those obtained with technetium 99 sestamibi or technetium 99 tetrofosmin, so these agents can generally be used interchangeably for the diagnosis of CAD.
  • Perfusion imaging is valuable for detecting myocardial viability in patients with regional or global LV dysfunction, with or without Q waves. Stress perfusion imaging also provides important information in regard to prognosis.
  • Stress myocardial perfusion scintigraphy is particularly helpful in diagnosis of CAD in patients with abnormal resting ECG findings and those in whom ST-segment responses cannot be accurately interpreted, such as patients with left bundle-branch block or LV hypertrophy and repolarization abnormalities, or those receiving digitalis glycosides. Because stress myocardial perfusion imaging is a relatively expensive test (3-4 times the cost of exercise ECG), the following issues should be considered:
  • • A regular exercise ECG should always be considered first in patients with chest pain and a normal resting ECG finding for screening and detection of CAD.
    • Stress myocardial perfusion scintigraphy should not be used as a screening test in patients in whom the prevalence of CAD is low because a false-positive result is the most common abnormal test finding.
    • Stress perfusion imaging is more sensitive than exercise ECG in detecting CAD, especially in patients with single-vessel CAD.
    • Perfusion imaging is more accurate than exercise ECG in patients with resting ECG abnormalities and in those receiving digitalis.
    • Perfusion imaging is more accurate in localizing and quantifying regions of myocardial ischemia (which is of particular importance in patients who previously underwent revascularization) and in determining the extent of viable myocardium in patients with LV dysfunction.
• Nuclear cardiology techniques - Pharmacologic nuclear stress imaging
• • For patients unable to exercise adequately, especially the elderly and patients with peripheral vascular disease, pulmonary disease, arthritis, or previous cerebrovascular accident, pharmacologic vasodilator stress may be induced with dipyridamole or adenosine. These individuals currently account for about 40% of all patients referred for nuclear perfusion imaging. While adverse effects occur more often with adenosine than with dipyridamole, the adverse effects attributed to dipyridamole are more difficult to manage and necessitate longer monitoring time, as well as fairly frequent intravenous administration of aminophylline for reversal.
  • Although the diagnostic accuracy of pharmacologic vasodilator stress perfusion imaging is comparable to that achieved with exercise perfusion imaging, a treadmill test is preferred for patients who are capable of exercising, because the exercise component of the test provides additional diagnostic information about ST-segment changes, effort tolerance, symptomatic response, and heart rate and blood pressure responses. In some studies, furthermore, exercise perfusion imaging has a lower false-positive rate than pharmacologic vasodilator stress perfusion imaging.
  • Noninvasive measurement of coronary flow reserve
  • • As already mentioned, radionuclide stress myocardial perfusion imaging (technetium 99 sestamibi, thallium 201) is widely used to quantify CFR. Some laboratories are using PET and nuclear MRI for the same purpose. Flow reserve is typically assessed by these techniques during exercise or with pharmacologic coronary vasodilators such as dipyridamole, adenosine, or dobutamine.
    • In contrast to invasive techniques that measure an index of absolute flow reserve, these noninvasive cardiac imaging techniques assess relative CFR