Atherosclerotic Heart Disease (Coronary Artery Disease)
As stated previously, coronary atherosclerotic heart disease is the most common cause of cardiovascular disability and death in the United States. Men are more often affected than women by an overall ratio of 4:1. Before age 40 this ratio is 8:1, but beyond age 70 it is 1:1. In men, the peak incidence of the clinical manifestations is in the fifth decade of life compared to the sixth decade for women.3
Atherosclerotic heart disease (ASHD), also known as coronary artery disease (CAD), is a progressive disease process characterized by irregularly distributed lipid deposits in the intimal layer of medium and large coronary arteries. Although the mechanisms of atherogenesis are still under investigation, epidemiological studies have identified several risk factors associated with an increased likelihood of developing premature CAD. Risk factors classified as modifiable characteristics, nonmodifiable characteristics, and lifestyle preferences are shown in Box 6-2. Alterable risk factors are the focus of interventional risk-factor reduction studies and cardiac rehabilitation. Blood homocysteine levels and hypoestrogenemia in women are two important risk factors under investigation. Several retrospective studies have identified mild-to-moderate increases in homocysteine, an amino acid, as a strong and independent risk factor for CAD, stroke, and peripheral vascular disease.42–45 However, some prospective studies46–48 have failed to show this association. In these patients, elevated plasma homocysteine appears to be more closely linked to thrombus-mediated coronary events (ie, MI) than to coronary atherosclerosis seen on angiography.49 Elevated homocysteine is also linked to venous thrombosis. The exact mechanisms remain unclear but may include endothelial toxicity, accelerated oxidation of cholesterol, an impairment of endothelial-derived relaxing factor, and a reduction in flow-mediated arterial vasodilation.50–53 As previously mentioned, chronic infections may also be involved and remain under investigation as causal risk factors for atherosclerosis.13
Box 6-2 Characteristics and Lifestyles Associated with Increased Risk of Future Coronary Artery Disease ||Download (.pdf)
Box 6-2 Characteristics and Lifestyles Associated with Increased Risk of Future Coronary Artery Disease
Personal Characteristics (Nonmodifiable)
Family history of CAD or other atherosclerotic vascular disease before age 55 in men, before age 65 in women
Personal history of CAD or other atherosclerotic vascular disease (eg, cerebrovascular or occlusive peripheral vascular disease)
Biochemical or Physiologic Characteristics (Modifiable)
Blood lipid abnormalities
Elevated blood total cholesterol
Elevated LDL cholesterol or VLDL cholesterol
Low HDL cholesterol
Elevated blood triglycerides
Diet high in saturated fat, cholesterol, and calories
Excess alcohol consumption
Recent research has also focused on abnormalities of lipid metabolism. Risk increases progressively with higher levels of low-density lipoprotein (LDL) cholesterol and declines with higher levels of high-density lipoprotein (HDL) cholesterol. The ratio of LDL to HDL cholesterol provides a composite marker of risk. Ratios below 3:1 indicate lower risk, whereas ratios above 5:1 indicate a higher risk.54 There is further evidence that other abnormalities of lipid metabolism may also play a role in the pathogenesis of CAD. Patterns associated with increased atherosclerosis include elevated levels of apolipoprotein (A) and small, dense LDL lipoprotein particles. These lipoproteins and their accompanying lipids appear more likely to pass into the vessel wall and may be more difficult to clear. Although elevated triglyceride levels often occur in association with other lipid abnormalities, accumulating evidence suggests that hypertriglyceridemia is an independent risk factor for CAD.54–57 A more thorough review of the epidemiological evidence for the risk factors associated with cardiovascular disease can be found in Chapter 15.
The Atherosclerotic Lesion
Our knowledge of the pathophysiology of atherosclerosis and the clinical presentations of CAD continue to accumulate rapidly. Abnormal lipid metabolism and/or the excessive intake of cholesterol and saturated fats, especially when superimposed on genetic predisposition, initiate the atherosclerotic process and development of atherosclerotic plaque.5,10
Atherosclerotic plaque consists of accumulated intracellular and extracellular lipids, connective tissue, smooth muscle cells, and glycosaminoglycans (eg, several sulfates and hyaluronic acid). The earliest detectable lesion of atherosclerosis is the fatty streak. The fatty streak consists of lipid-laden foam cells, which are macrophages that have migrated as monocytes from the circulation into the subendothelial layer of the intima. Later, the fatty streak evolves into fibrous plaque that is made up of intimal smooth muscle cells surrounded by connective tissue and intracellular and extracellular lipids.
Pathogenic Mechanisms of Plaque Formation
Although the exact mechanism of plaque formation remains under study, many hypotheses have been developed. The most pervasive include the lipid hypothesis and the chronic endothelial injury hypothesis. Both are described in the following sections.
The lipid hypothesis states that elevation in plasma LDL levels results in penetration of LDL into the arterial wall, leading to lipid accumulation in smooth muscle cells and in macrophages (foam cells) (see Fig. 6-1). LDL also augments smooth muscle cell hyperplasia and migration of cells into the subintimal and intimal regions in response to growth factors. LDL is modified or oxidized in this environment and is rendered more atherogenic. Small, dense LDL cholesterol particles are also susceptible to modification and oxidation. The modified or oxidized LDL is chemotactic to monocytes, which promotes their migration into the intima, their early appearance in the fatty streak, and their transformation and retention in the subintimal compartment as macrophages. Scavenger receptors on the surface of macrophages facilitate the entry of oxidized LDL into these cells, transforming them into lipid-laden macrophages and foam cells. Oxidized LDL is also cytotoxic to endothelial cells and may be responsible for their dysfunction or loss from the more advanced lesion.58–60
Characteristics of “stable” and “vulnerable” coronary atherosclerotic lesions. Initially, vulnerable plaques grow outward. The vulnerable plaque has a substantial lipid core and thin fibrous cap separating the thrombogenic macrophages from the blood. At sites of lesion disruption, smooth muscle cells (SMC) are activated and detected by the presence of human leukocyte antigen-DR (HLA-DR). The stable plaque has a relatively thick fibrous cap protecting the lipid core from contact with the blood. Stable plaques often cause luminal narrowing.
An atherosclerosis model has been studied in monkeys fed a cholesterol-rich diet.61,62 This study demonstrated that within 1 to 2 weeks of inducing hypercholesterolemia, monocytes attached to the surface of the arterial endothelium through the induction of specific receptors, migrated into the subendothelium, and accumulated lipid in macrophages (ie, foam cells). Proliferating smooth muscle cells also accumulate lipid. As the fatty streak and fibrous plaque enlarge and bulge into the lumen, the subendothelium becomes exposed to the blood at sites of endothelial retraction or tear, and platelet aggregates and mural thrombi form. It is postulated that the release of growth factors from the aggregated platelets may increase smooth muscle proliferation in the intima. The organization and incorporation of the thrombus into the atherosclerotic plaque may contribute to its growth.63
The Chronic Endothelial Injury Hypothesis
The chronic endothelial injury hypothesis states that, through various mechanisms, endothelial injury produces loss of endothelium, adhesion of platelets to subendothelium, aggregation of platelets, chemotaxis of monocytes and T-cell lymphocytes, and release of platelet-derived and monocyte-derived growth factors. This induces migration of smooth muscle cells from the media into the intima, where they replicate, synthesize connective tissue and proteoglycans, and form a fibrous plaque (see Fig. 6-2). Other cells (eg, macrophages, endothelial cells, arterial smooth muscle cells) also produce growth factors that can contribute to smooth muscle hyperplasia and extracellular matrix production.5
The complex interaction of the endothelium, platelet aggregation, and coagulation. Vasorelaxation: nitric oxide (NO), nitric oxide synthase (NOS), C-type natriuretic peptide (CNP), prostaglandin I2 (PGI2), cyclooxygenase (COX). Anticoagulation: antithrombin (ATIII), tissue plasminogen factor (tPA), protein C, protein S (Pr C, Pr S), Coagulation: tissue factor (TF), von Willebrand factor (vWF). Platelet aggregation: serotonin (5-HT), adenosine diphosphate (ADP). Vasoconstriction and growth promotion: platelet-derived growth factor (PDGF), endothelin-converting enzyme (ECE), enthothelin-1 (ET-1), prostaglandin H2, thromboxane A2 (TXA2). (Reproduced with permission from Volta SD. Cardiology. Berkshire, UK: McGraw-Hill; @ 1999.)
Modified LDL is cytotoxic to cultured endothelial cells and may induce endothelial injury, attract monocytes and macrophages, and stimulate smooth muscle growth. Modified LDL also inhibits the mobility of macrophages, so that once they transform into foam cells in the subendothelial space they may become trapped. In addition, regenerating endothelial cells (after injury) are functionally impaired and increase the absorbed LDL from plasma.
The atherosclerotic plaque may grow slowly and over several decades may result in severe arterial stenosis or may progress to total arterial occlusion. With time, the plaque becomes calcified. Some plaques are stable, but others, especially those rich in lipids and inflammatory cells (eg, macrophages) and covered by a thin fibrous cap, may undergo spontaneous fissure or rupture, exposing the plaque contents to flowing blood (see Fig. 6-2). These plaques are believed to be unstable or vulnerable and are more closely associated with the onset of an acute ischemic event.5 The ruptured plaque stimulates thrombosis; the thrombus may (1) embolize, (2) rapidly occlude the lumen to precipitate myocardial ischemia or infarction, or (3) gradually become incorporated into the plaque, contributing to its stepwise growth.
The two hypotheses just described are closely linked and not mutually exclusive. The lipid hypothesis suggests that remnants of triglyceride-rich lipoproteins or modified LDL of hyperlipidemic subjects are absorbed by macrophages to form the early atherosclerotic lesion and that chronic exposure of endothelium to these lipoproteins leads to cell injury. Cell necrosis in turn results in a deposition of lipid in the extracellular space. Injury to the endothelium and progression of atherosclerotic lesions by exposure to chronically elevated levels of remnants and/or modified LDL could be part of the sequence leading to the formation of occlusive plaques and to their clinical sequelae.64,65
As previously introduced, recent studies13,66,67 have validated an old theory that atherosclerosis progresses as the result of an inflammatory response in the vessel wall. The process may be initiated or worsened by an infectious agent as diverse as cytomegalovirus, C. pneumoniae, and H. pylori. A high circulating level of the nonspecific inflammatory marker, C-reactive protein, has been correlated with a higher rate of ischemic events.
Coronary Anastomosis (Collaterals)
Larger caliber collaterals develop below adjacent arteries on the epicardial surface. These are believed to be preexisting smaller arteries altered by flow-induced pressure differentials between different coronary beds. Functionally, these have been considered very important for maintaining blood supply to myocardial cells supplied by stenotic vessels.5Angiographical evidence indicates that coronary artery collaterals form locally at sites of high-grade lesions in response to chronic ischemia.5
Progression and Regression of Atherosclerosis
With sequential angiographical studies, the progression of atherosclerosis is known to be phasic and unpredictable. High-grade lesions do not necessarily appear where low-grade lesions were once found. New lesions of more than 50% can occur between repeated angiograms. Sites of future lesions cannot be identified and the progression cannot be predicted.68–71 Individual plaques may progress at accelerated rates unrelated to their degree of stenosis. We do know that high-grade lesions tend to progress. Chronic total occlusions result from high-grade lesions three times more frequently than in cases of less severe lesions but frequently do not result in infarction because of collateral development.72 Stenotic regression can also be demonstrated angiographically in some but not all cases after either aggressive pharmacologic treatment with statins or very low-fat diets.
Manifestations of Atherosclerotic Heart Disease
The clinical manifestations of ASHD typically evolve after many decades of progressive atherosclerosis and include myocardial ischemia, infarction, congestive heart failure, and sudden death. Each of the possible manifestations and related pathophysiology are presented.
Myocardial ischemia results when there is an imbalance between myocardial oxygen supply and myocardial oxygen demand. It is a reversible phenomenon, which typically comes on with exertion and goes away with rest. The factors affecting the balance between myocardial oxygen supply and demand are illustrated in Fig. 6-3. Increased myocardial oxygen requirements may be provoked by a number of factors including exercise, mental stress, or even spontaneous fluctuations in heart rate and blood pressure. Decreased oxygen supply may result from a reduction in coronary blood flow. (The reader may recall the already-high extraction of oxygen from blood flowing through myocardial tissue, with the resultant dependence on coronary blood flow to meet myocardial demand. See Chapters 3 and 5.) Decreased blood flow may be due to decreased aortic driving pressure or increased coronary vascular resistance, which may be due to coronary vasospasm, platelet aggregation, or partial thrombosis.
Factors influencing myocardial oxygen supply and demand.
It is a commonly held belief that coronary artery occlusion greater than 70% produces myocardial ischemia, which in turn provokes the symptoms that bring the patient to the doctor's office. The patient at this stage of atherosclerotic progression is comfortable at rest but will complain of chest pressure during mild-to-moderate exercise, which is relieved by rest. The diagnosis of ischemic heart disease is usually made on the basis of a formal exercise stress test.
Coronary atherosclerosis and coronary arterial spasm both reduce coronary blood flow and thus reduce myocardial oxygen supply. When this happens, myocardial ischemia and irritability occur, which may produce arrhythmias, impaired myocardial contractility (systolic dysfunction), and impaired myocardial relaxation (diastolic dysfunction). This diastolic dysfunction prolongs systole and reduces ventricular filling time. Ventricular compliance decreases and the ventricular end-diastolic pressure rises, causing aortic driving pressure to be further reduced. Myocardial ischemia often manifests itself on an electrocardiogram (ECG) as ST-segment displacement (see Chapter 11).
The threshold for myocardial ischemia can be either predictable or unpredictable. Abnormal endothelial function appears to play a role in the unpredictable, fluctuating threshold for ischemia. The majority of studies suggest that endothelium-dependent vasodilator mechanisms predominate in nondiseased epicardial coronary arteries. During interventions that normally induce increases in myocardial oxygen consumption and blood flow (eg, exercise, stress, induced tachycardia), epicardial vascular dilation occurs. This dilation is at least partially endothelial dependent. However, the presence of even nonocclusive, early atherosclerosis appears to impair the release of endothelium-relived relaxing factor (nitrous oxide), attenuating this vasodilator mechanism, which results in prevailing, unopposed vasoconstriction. Moderate vasoconstriction in an area of minimal occlusion may be of little hemodynamic consequence; however, the same degree of vasoconstriction in an area of greater occlusion may markedly decrease blood flow and induce ischemia.73–75
The classical symptom of myocardial ischemia is angina pectoris. This discomfort is described as pressure, heaviness, or tightness that may be located in the middle of the chest (substernal); over the heart (precordial); or in the shoulder, arm, throat, or jaw. Angina may be precipitated by exertion, stress, emotions, and heavy meals. Stable angina usually lasts for several minutes and is usually relieved by rest and/or nitroglycerin. The patient is pain free at rest.
Anginal pain arises within the myocardium and is thought to stimulate free nerve endings in or near small coronary vessels. Impulses travel in afferent unmyelinated or small myelinated cardiac sympathetic nerves through the upper thoracic ganglia to dorsal horn cells and through the spinothalamic tract of the thalamus to the cortex.5,76 The cerebral cortex integrates and modifies these impulses. This modulation may contribute to the variability in the perception of angina across patients. Psychosocial and cultural factors may also influence the perception of pain at the cortical level.
The term unstable angina is usually used to denote either a change in the anginal pattern or angina at rest. Unstable angina may occur with less exertion than previously described, may last longer, or become less responsive to medication. Angiography has shown that a high proportion of patients with unstable angina have complex coronary stenoses characterized by plaque rupture, ulceration, or hemorrhage with subsequent thrombus formation. This inherently unstable situation may progress to complete occlusion and infarction, or may heal, with reendothelialization and return to a stable though possibly more severe pattern of ischemia. New-onset angina is sometimes considered unstable, but if it presents in response to exertion and responds to rest and medication, it does not carry the same poor prognosis.
Prinzmetal (Variant) Angina
Prinzmetal angina, also called atypical or variant angina, is an unusual type of cardiac pain due to myocardial ischemia that occurs almost exclusively at rest. Prinzmetal and colleagues77 hypothesized that variant angina was the result of transient increases in vasomotor tone or vasospasm. Vasospasm causes a transient, abrupt, marked decrease in the diameter of the coronary artery that results in myocardial ischemia. In such cases, no preceding increases in myocardial oxygen demand occur. Vasospasm can occur in both normal and diseased coronary arteries. Often the decrease in the diameter can be reversed by nitroglycerin.10 Variant angina is usually not associated with physical exertion or emotional stress and is associated with ST-segment elevation, rather than with depression on ECG.78 This form of angina is often severe and characteristically occurs in the early morning, awakening patients from sleep. It tends to involve the right coronary artery and is likely to be associated with arrhythmias or conduction defects.5 Prinzmetal angina may be associated with acute MIs and severe cardiac arrhythmias, including ventricular tachycardia and fibrillation (see Fig. 6-4).79
Clinical presentation, electrocardiographic, chemical, and arterial changes associated with coronary artery spasm. Note the ST-segment elevation above baseline.
Asymptomatic (Silent) Myocardial Ischemia
Many individuals have some episodes of “silent” ischemia (ischemia without symptoms); some patients have only silent ischemia. Asymptomatic ischemic episodes may be present in patients with any of the aforementioned ischemic coronary syndromes or after an MI. Some patients never complain of chest pain with episodes of ischemia; others inconsistently report chest pain with episodes of ischemia. The true prevalence of silent ischemia is undetermined, but it is believed to be high. Important factors include age, the presence and extent of CAD, and other disease processes that include peripheral neuropathy as a component (eg, diabetes mellitus, alcoholic neuropathy).
Some clinicians have attempted to explain silent ischemia as angina that is less noxious than reported angina. The correlation between ECG evidence of ischemia and the report of anginal pain in patients with chronic stable angina is only fair.80,81 Therefore, the most likely explanation is neurologic. Neuropathy with defective sensory efferent nerves occurs commonly in persons with diabetes. The variable expression of ischemic pain may be explained by modification of pain stimuli in the central nervous system. Patients with diabetes have a relatively high incidence of painless MIs and definite silent ischemic episodes as documented by ambulatory ECG recordings and exercise testing.82–85
These include dyspnea, fatigue, lightheadedness, and belching brought on by exercise or stress and relieved by rest or nitroglycerin. We have said that some patients with diabetes may not complain of chest discomfort due to impaired peripheral sensation (eg, silent ischemia). Alterations in neural processing can, by extension, also give rise to anginal equivalents. Ischemic episodes in this group can present as a fullness in the throat and jaw, a desire to cough, or dyspnea. Elderly patients and patients with peripheral neuropathies may also present with anginal equivalents.
The rich variety of radiation patterns associated with angina pectoris is determined by the levels of the spinal cord, which share sensory inputs with somatic structures (eg, gut) and the heart. The precise mechanisms causing angina and anginal equivalents are yet to be defined.
MI results from prolonged myocardial ischemia and is precipitated in most cases by an occlusive coronary thrombus at the site of a preexisting atherosclerotic plaque. Less frequently,3,65,86 infarction may result from prolonged vasospasm, inadequate myocardial blood flow (eg, hypotension), or excessive metabolic demand. Very rarely, MI may be caused by embolic occlusion, aortitis, vasculitis, or coronary artery dissection. Cocaine87 and other similar types of drugs can induce coronary artery vasoconstriction and may lead to myocardial ischemia as well as to infarction.
Regardless of the etiology, an MI results in the complete interruption of blood supply to an area of myocardium, almost always in the left ventricle, and more rarely in the right ventricle. Cells die and tissues become necrotic in an area referred to as the zone of infarction. Within 18 to 24 hours after MI, an inflammatory response occurs in response to necrosis. Leukocytes aid in the removal of dead cells, and fibroblasts form a connective tissue scar within the area of infarction. Visible necrosis is present in 2 to 4 days. During this time, proteolytic enzymes remove debris while catecholamines, lipolysis, and glycogenolysis elevate plasma glucose and increase free fatty acids to assist depleted myocardium recovery from an anaerobic state. By 4 to 10 days the debris is cleared and a collagen matrix is laid down. Between 10 and 14 days, weak, fibrotic scar tissue with beginning revascularization is present. This area remains vulnerable to stress. Usually, the formation of fibrous scar tissue is complete within 6 to 8 weeks.88,89 Inelastic scar tissue replaces the necrotic tissue and the region is unable to contract and relax like healthy myocardial tissue. When a transmural MI occurs with full-thickness necrosis, wall motion may be reduced (hypokinetic), abnormal (dyskinetic), or absent (akinetic). When necrosis is limited to the innermost layer of the heart (ie, subendocardial MI), wall motion will usually appear to be normal.
The completed scar is tough, usually thick, and fibrous and serves to protect the heart from further damage. Current best practice calls for the implementation of low-level exercises designed to maintain function and prevent the deleterious effects of prolonged inactivity during this initial 6- to 8-week period.
Adjacent to the zone of infarction is a less seriously damaged area of injury called the zone of hypoxic injury. This zone is able to return to normal, but may become necrotic if blood flow is not restored. With adequate collateral circulation, this area may regain function within 2 to 3 weeks. Immediately surrounding the zone of injury is another reversible zone known as the zone of ischemia (see Fig. 6-5).
ECG changes associated with the three zones of infarction.
The location and extent of infarction depend on the anatomic distribution of the occluded vessel, the presence of additional stenotic lesions, and the adequacy of collateral circulation. Occlusion in the anterior descending branch of the left coronary artery results in infarction of the anterior left ventricle and the interventricular septum. Occlusion of the left circumflex artery produces anterolateral or posterolateral infarction. Right coronary thrombosis leads to infarction of the posteroinferior portion of the left ventricle and may involve the right ventricular myocardium and interventricular septum. The arteries supplying the atrioventricular node and the sinus node more commonly arise from the right coronary; thus, atrioventricular blocks at the nodal level and sinus node dysfunction occur more frequently during inferior infarctions. A general rule is that the more proximal the lesion, the greater the extent of the infarct. Individual variation in coronary anatomy and the presence of collateral vessels can make it difficult to locate the precise site of the lesion responsible for infarction. The gold standard for identification of the blockage and infarct site remains that of coronary angiography rather than that of ECG. The necrotic, ischemic, and injured myocardial tissue cause characteristic ECG changes as the myocardium heals. These changes are described in the following sections.
As mentioned previously, MIs are classified as either transmural (full-thickness) or subendocardial (partial-thickness) infarctions. Transmural MIs are characterized by electrocardiographic evolution of ST-segment elevation with significant Q waves. Subendocardial MIs are characterized by ST-T wave changes but without the development of significant Q waves (see Chapter 11). On pathologic examination, however, most infarctions involve the subendocardium initially, and some transmural extension is common even in the absence of Q waves. Thus, some cardiologists prefer the classification of Q wave or non–Q-wave infarction. The non–Q-wave infarction generally results from incomplete occlusion or spontaneous lysis of the thrombus and signifies the presence of additional jeopardized myocardium; non–Q-wave infarctions are associated with a higher incidence of reinfarction and recurrent ischemia.90,91
Because of this high incidence of reinfarction, patients with subendocardial MIs are considered less stable than those with transmural MIs. Indeed, many of these patients will be referred to surgery for surgical management. For this reason, physical therapy interventions tend to be more conservative than those directed toward patients with full-thickness MIs.
The size and anatomic location of the infarction strongly influence the acute course, the early complications, and the long-term prognosis. Hemodynamic stability is related to the extent of necrosis. In small infarctions, cardiac function may be normal, whereas with more extensive damage, early heart failure and cardiogenic shock92 may appear. Prevention of infarct extension by reducing both the zones of injury and ischemia is a major goal of early intensive care unit management.
Diagnosis of an MI relies upon the presentation of classical symptoms, elevation of specific enzymes, and an acute injury pattern on ECG with evolutionary ECG changes over time.93–95 Because of the multiple neural innervation levels, pain presentation with MI may vary (see CD-ROM). It has been estimated that up to 25% of MIs occur without any symptoms.96 These silent MIs present a challenge to the clinician who must utilize other monitoring techniques and instruct patients about symptom recognition and provide activity guidelines. These alternative methods of therapeutic intervention are described in Chapter 10.
Diagnosis and Laboratory Findings
Diagnosis of an acute MI requires that at least two of the following three elements be present: (1) a history of ischemic-type chest discomfort, (2) evolutionary changes on serially obtained ECG tracings, and (3) a rise and fall in serum cardiac enzymes.97 With respect to these three elements, there is considerable variation in presentation.
Clinical Presentation of Myocardial Infarction
The most notable symptom of an MI is the sudden sensation or onset of chest discomfort that is often described as “crushing chest pain or pressure,” which occasionally radiates to the arms, neck, throat, and back. This pain is usually constant, lasts for 30 minutes or more, and may be associated with pallor and shortness of breath. The pain of MI is qualitatively different from the pain of angina. The former is usually more severe and prolonged and unrelieved by rest. Patients who are prescribed nitroglycerin are instructed to report to the hospital if their angina is unrelieved after three doses, because of the likelihood of an evolving MI.
The chest pain of an MI is accompanied by a dramatic surge in sympathetic nervous system activity. The release of catecholamines results in sympathetic stimulation, which may produce diaphoresis and peripheral vasoconstriction that may cause the skin to become cool and clammy to touch. Reflex stimulation of vomiting centers may cause nausea and vomiting. In the first 24 hours, fever may develop and persist for up to a week because of the inflammatory responses within the myocardium. If cardiac output is compromised, the patient may complain of lightheadedness due to a reduction in blood pressure. The patient experiencing an acute MI may also be in denial and not seek care for several days following the event. It should be noted that patient denial of symptoms will result in the delay of medical care. This delay does not only affect diagnosis and treatment—it can also have tragic consequences. Indeed, the sooner the patient presents to the hospital, the better the chances of survival. “Time is muscle” is a phrase that can save a patient's life!
Electrocardiographic changes are almost always present in patients experiencing acute infarctions. A normal tracing obtained during an MI is rare. The extent of the electrocardiographic abnormalities provides only a rough estimate of the magnitude of infarction. The earliest signs are usually peaked or “hyperacute” T waves, followed by ST-segment elevation, Q-wave development, and finally T-wave inversion. This sequence of events may develop over a few hours or over several days. The evolution of new Q waves (>30 ms in duration and one-third the height of the R wave) is diagnostic for transmural MI. Q waves do not develop in 30% to 50% of acute infarctions, representing subendocardial MI. If these patients have a typical clinical presentation (ie, elevated cardiac enzymes and ST-segment changes, usually depression or T-wave inversion lasting at least 48 hours), they are classified as having non–Q-wave infarctions.93,94 Some of these changes are shown in acute and subacute tracings for an anterior and lateral wall infarction (Fig. 6-6). Further discussion of electrocardiography can be found in Chapter 11.
Twelve-lead electrocardiogram showing an acute anterolateral wall myocardial infarction. Note the ST-segment elevations in V2–V6, coupled with deep Q waves in V1–V5, representing areas of myocardial injury and necrosis, respectively.
As myocytes become necrotic, the integrity of the sarcolemmal membrane is compromised and serum cardiac markers diffuse into the cardiac interstitium. These markers eventually reach the microvasculature and lymphatics in the region of the infarct.98 Intracellular location, molecular weight, local blood and lymphatic flow, and the rate of elimination from the blood are all factors that determine the rate of appearance of the markers.99–101 Markers currently monitored include creatine kinase (CK), myoglobin, and the cardiac-specific troponins (troponin T, and troponin I). Lactic dehydrogenase (LDH) and serum glutamic–oxaloacetic transaminase (SGOT) are also enzymes that are frequently used to rule in an MI.
CK is released when cells die. Three isoenzymes of CK have been identified by electrophoresis: The MM band is specific to skeletal muscle death, the BB band is specific to brain cell death, and the MB band is specific to myocardial cell death. Rapid assays are now available for CK-MB isoforms. A ratio of CK-MB2/CK-MB1 greater than 2.5 has a sensitivity for the presence of myocardial cell necrosis of 46.4% at 4 hours and 91.5% at 6 hours.62Serum CK levels exceed the normal range within 4 to 8 hours after the onset of an acute MI and returns to normal within 2 to 3 days.10 Peak CK occurs on average at approximately 24 hours. Although the elevation of CK is considered a sensitive detector of an acute infarction, false positives are found in many patients including those with muscle disease, diabetes mellitus, skeletal muscle trauma, pulmonary embolism, and alcohol intoxication.99,101,102
Myoglobin is a protein released into circulation from injured myocardial cells and can be detected within a few hours after the onset of infarction. Peak levels of myoglobin are reached within 1 to 4 hours. Myoglobin is excreted into the urine. Its measurement has been suggested as a useful index of successful reperfusion.103 Patients presenting with ST-segment elevation less than 6 hours from symptoms and a diagnosis of MI are at increased risk of mortality when myoglobin is elevated.
The cardiac troponins are the newest markers. The troponin complex consists of three subunits that regulate the calcium-mediated contractile processes of striated muscle. Troponin C binds Ca2+; troponin I binds to actin and inhibits actin–myosin interactions; and troponin T binds to tropomyosin. Troponin T and troponin I are highly cardiac selective and are released into the blood during an MI. These regulatory proteins rise within 4 to 6 hours of the onset of cell necrosis and remain elevated for several days after the infarction.10
Because of the rapid elevation and decline in CK-MB assays, patients who are in denial and who delay presentation to the emergency room may show normal CK-MB values. However, troponin levels remain elevated for a longer period of time and may “salvage” a diagnosis (see Fig. 6-7).
Evolution of three major serum markers (CK-MB, myoglobin, and troponin T) after myocardial infarctions in patients in whom (A) reperfusion with thrombolytics was successful and (B) not achieved. (Reprinted with permissions of Chapelle JP. Diagnosticum. 1993;93(1):8-15).
Treatments and Complications
Management of patients with MI can be divided into medical and surgical interventions. Medical interventions include the use of pharmacological agents aimed at reducing myocardial oxygen demand (eg, β-blockade, calcium channel blockade), increasing myocardial oxygen supply (eg, coronary artery vasodilators), and improving/maintaining myocardial function (eg, digitalis glycosides). These medical interventions are covered in some detail in Chapter 8. Current surgical interventions for patients with MI include thrombolysis, intra-aortic balloon pump, angioplasty, and stent placement104–106 (see Table 6-1).
Table 6-1 Current Treatment of Myocardial Infarction ||Download (.pdf)
Table 6-1 Current Treatment of Myocardial Infarction
Early initiation of emergency services
CPR, defibrillation, aspirin, nitroglycerin, oxygen, etc
Cardiovascular stabilization, maintaining myocardial oxygen supply, decreasing myocardial oxygen demand
Administration of clot-dissolving drugs (eg, streptokinase, tPA)
Salvage of jeopardized myocardium
Intra-aortic balloon pump (IABP)
Placement of balloon-tipped catheter in aorta distal to the aortic arch
Increases ejection of blood from left ventricle during systole; improves coronary artery perfusion during diastole
Percutaneous transluminal coronary angioplasty (PTCA)
Inflation of balloon-tipped catheter in coronary artery at the site of occlusion
Restoration of myocardial blood flow via plaque compression
PTCA with stent placement
Placement of a cylindrical wire mesh at the site of occlusion in coronary artery
Restoration and maintenance of myocardial perfusion via plaque compression
Intracoronary radiation therapy (brachytherapy)
Local ionizing g- or b-radiation is delivered to the site of coronary stenosis
Reduction of restenosis via plaque irradiation
Coronary artery bypass graft (CABG)
Use of select veins or arteries obtained from the patient, which bypasses atherosclerotic lesions
Restoration of myocardial blood flow via revascularization
Left ventricular assist devices (LVAD)
Mechanical device that surrounds the ventricles and assists in ventricular ejection
Improves stroke volume and cardiac output, used as either bridge to transplantation or destination therapy
Replacement of heart from a suitable donor
Improves cardiac performance
Enhanced external counterpulsation (EECP)
Pneumatic cuffs applied to the lower extremities that alternately inflate and deflate
Increases collateral blood flow to ischemic areas of the myocardium
Some of the surgical interventions in Table 6-1 deserve comment. Drugs that have the potential to dissolve (“lyse”) a thrombus within a coronary artery are called thrombolytic agents and are introduced surgically by way of a catheter whose tip is placed in the coronary artery at the site of the blockage. Thrombolytic agents such as streptokinase and tissue plasminogen activator (tPA) are then administered, usually within a few hours of an acute MI in hope of dissolving a thrombus and improving blood flow to areas of myocardium in the zones of injury and ischemia.
Coronary artery stents were first introduced into clinical practice in the mid-1980s. These are cylindrical wire-mesh devices that are placed at the site of vascular occlusion via balloon angioplasty. Stents are now used in 80% of all percutaneous cardiac interventions.107 However, their propensity to restenosis has led to the recent development in drug-eluting “coated stents.” These devices are coated with antiproliferative substances, most notably rapamycin. Early results show extremely low restenosis rates averaging between 0% and 9% after 6 and 12 months,107 respectively.
The use of intracoronary radiation therapy (brachytherapy) is a relatively recent addition to management options of patients with MI and/or residual ischemia. It was developed to address the relatively high rate of restenosis in patients following stent placement.108–110 This technique involves the use of radiation delivered either via a stent or a catheter-based system. It is believed that this radiation inhibits smooth muscle cell mitosis and proliferation of adventitial myofibroblasts.111
The use of enhanced external counterpulsation (EECP) devices demonstrates early promise in the treatment of ischemia.112–116 It is a noninvasive outpatient series of treatment sessions that consists of total 35 hours, divided into one or two 60-minute treatment sessions 5 days a week. A series of pneumatic compressive cuffs is wrapped around the calves and thighs. Inflation of the cuffs is synchronized with the cardiac cycle such that inflation occurs during diastole and deflation occurs during systole (see Table 6-1). The benefits of enhanced external counterpulsation have been shown to last up to 5 years following initial treatment.
With all these interventions, it is important to remember that early recognition and prompt intervention provide the most options and increased chance of salvaging injured myocardium.
Even when treatment is initiated promptly, a variety of complications can occur following an MI (Box 6-3). Approximately 10% of patients experience a recurrent infarction in the first 10 to 14 days.3 Infarct extension is at least twice as common in non–Q-wave infarcts when compared to Q-wave infarcts. The recurrent infarct may be relatively silent or associated with prolonged or intermittent chest pain. Abnormalities of rhythm and conduction are common. Myocardial dysfunction is proportionate to the extent of necrosis. A large MI will destroy a large portion of myocardium and likely result in extensive myocardial dysfunction. Extensive myocardial dysfunction is likely to produce acute heart failure, hypotension, and possibly shock, all of which are indicative of a poor prognosis after an acute MI.95
Box 6-3 Complications Following Myocardial Infarction ||Download (.pdf)
Box 6-3 Complications Following Myocardial Infarction
Infarct extension and postinfarction ischemia
Acute left ventricular failure
Hypotension and shock
Right ventricular infarction
Mechanical defects (partial or complete rupture of a papillary muscle or interventricular septum)
Left ventricular aneurysm
In this chapter, heart failure is presented as one of the possible manifestations of ASHD. Further information about heart failure can be found in Chapter 18. Heart failure exists when the heart is unable to pump sufficient cardiac output to meet the body's metabolic demands. Clinically, heart failure is defined as a syndrome with a variety of interrelated pathophysiologic phenomena, of which impaired ventricular function is the most important. This results in a reduction of exercise capacity and other characteristic clinical manifestations.64 Many of the signs and symptoms are related to systolic dysfunction.
Systolic function of the heart is determined by four major determinants: (1) the end-diastolic volume and the resultant fiber length of the ventricles prior to onset of the contraction (preload), (2) the impedance to left ventricular ejection (afterload), (3) the contractile state of the myocardium (contractility), and (4) the rate of contraction, or heart rate (chronotropy).3
Heart function may be impaired as a result of alterations in any of these four determinants. The most common problem is depression of myocardial contractility, caused either by a loss of functional muscle due to infarction or by processes diffusely affecting the myocardium. The heart may fail as a pump because of excessive preload (eg, valvular regurgitation) or when afterload is excessively elevated, as occurs in severe hypertension. Pump function may also be inadequate when the heart rate is too slow or too rapid. The normal heart is capable of handling considerable variation in preload, afterload, and heart rate; however, the diseased heart often has limited reserve for handling such challenges.
Cardiac pump function may be normal or even supranormal at rest, but inadequate when metabolic demands or requirements for blood flow are in excess. This situation is termed high-output heart failure. Hyperthyroidism, beriberi, severe anemia, arteriovenous shunting, osteitis deformans (Paget disease), and sepsis may result in high-output heart failure.117
Cardiac failure may also occur as a result of isolated or predominant diastolic dysfunction of the heart. In these cases, filling of the left or right ventricle is impaired because of excessive hypertrophy or changes in the composition of the myocardium. Contractility may be preserved; however, diastolic pressures are elevated and cardiac output may be reduced.10,118
A number of cardiac and systemic adaptations occur when the heart fails. If the stroke volume of either ventricle is reduced by depressed contractility or excessive afterload, end-diastolic volume and pressure in that chamber will rise. This increases end-diastolic myocardial fiber length, resulting in a greater systolic shortening in the normal heart; but in the failing heart, Starling's law is less applicable. If the condition is chronic, ventricular dilatation will occur. Although this may restore resting cardiac output, the resulting chronic elevation of diastolic pressures will be transmitted back up to the atria and to the pulmonary and systemic venous circulation. Ultimately, increased pulmonary capillary pressure may lead to transudation of fluid, with resulting pulmonary or systemic edema. Reduced cardiac output will also activate several neural and humoral systems. Increased activity of the sympathetic nervous system will stimulate myocardial contractility, heart rate, and venous tone. This change results in a rise in central blood volume, which serves to further elevate preload. Although these adaptations are designed to increase cardiac output, tachycardia and increased contractility may result and cause ischemia in patients with underlying CAD. The rise in preload may worsen pulmonary congestion. Sympathetic nervous system activation also increases peripheral vascular resistance. Because peripheral vascular resistance is also a major determinant of left ventricular afterload, excessive sympathetic activity may further depress cardiac function. Lower cardiac output causes a reduction in renal blood flow and glomerular filtration rate, which leads to sodium and fluid retention. The renin–angiotensin–aldosterone system is also activated, leading to further increases in peripheral vascular resistance and left ventricular afterload as well as sodium and fluid retention. Heart failure is also associated with increased circulating levels of arginine vasopressin, a vasoconstrictor and inhibitor of water excretion.118,119
Myocardial failure is characterized by two hemodynamic alterations. The first is a reduction in the ability to increase cardiac output in response to increased demands imposed by activity or exercise (cardiac reserve). The second major abnormality is the elevation of ventricular diastolic pressure. This is considered a result of compensatory processes.
Heart failure may be left sided or right sided, or involve both sides of the heart (biventricular failure). Patients with left heart failure have symptoms of low cardiac output and elevated pulmonary and venous pressures. In right-sided heart failure, signs of fluid retention predominate. Many patients exhibit signs and symptoms of both right- and left-sided failure. Left ventricular failure is the most common cause of right-sided failure. The pathophysiology and manifestations for left- and right-sided heart failure are listed in Table 6-2.
Table 6-2 Clinical Manifestations of Heart Failure ||Download (.pdf)
Table 6-2 Clinical Manifestations of Heart Failure
Left Ventricular Failure
Right Ventricular Failure
Progressive dyspnea (on exertion first)
Dyspnea and orthopnea
Paroxysmal nocturnal dyspnea
Anorexia, nausea, bloating
S3 heart gallop
Right-sided S3 or S4
Possible functional mitral and tricuspid regurgitation RV lift of sternum
Murmurs with pulmonary or tricuspid valve insufficiency
S/S of pulmonary edema
Jugular venous distension
Right upper quadrant (liver) pain
Cyanosis (nail beds)
Decreased urine output
Left Ventricular Failure (Congestive Heart Failure)
Intrinsic myocardial disease (eg, ASHD, cardiomyopathy), excessive workload on the heart (eg, hypertension, valvular disease, congenital defects), and cardiac arrhythmias or iatrogenic damage (eg, drug toxicity, irradiation) can result in the development of left ventricular failure. Systolic ventricular dysfunction results in a reduced stroke volume and increased end-diastolic volume with a resultant drop in the ejection fraction (stroke volume/end-diastolic volume). Increased left ventricular end-diastolic volume (LVEDV) decreases left ventricular compliance and causes the left atrial volume to expand, which results in left atrial dilatation. The elevated end-diastolic volume will produce higher end-diastolic pressure, which will be reflected back to the left atria, and pulmonary vessels and their pressures will be elevated. If pulmonary pressures rise high enough to cause transudation of intravascular fluid from the pulmonary capillaries (and if the rate of transudation exceeds the rate of lymphatic drainage), then dyspnea and possibly pulmonary edema will develop. In addition, the diastolic dysfunction or delayed ventricular relaxation resulting from left ventricular hypertrophy causes an even greater left ventricular end-diastolic pressure (LVEDP). Elevated LVEDP inhibits diastolic coronary blood flow to the endocardium and thus increases the risk of subendocardial ischemia. Finally, marked left ventricular dilatation can stretch the mitral valve annulus, resulting in functional mitral regurgitation.
Left heart failure may cause a reduction in physical exercise capacity. Systolic dysfunction may result in a marked decrease in stroke volume and ejection fraction, producing an elevated end-diastolic pressure, which causes blood to be reflected backward into the lung fields. The lungs become soggy and difficult to move, resulting in premature exercise-induced shortness of breath. Redistribution of blood flow due to reduced cardiac output during exercise will also cause a reduction of blood flow to the kidneys and skin initially and later to the brain, gut, and skeletal muscle. However, during exercise, peripheral arteriovenous oxygen extraction will increase, which may compensate for reduced blood flow.
Right Ventricular Failure
Elevated pulmonary artery pressures caused by left ventricular failure, mitral valve regurgitation, or chronic or acute pulmonary disease can result in an increased pressure load on the right ventricle, with resultant right ventricular dilatation. Right ventricular hypertrophy may or may not develop, depending on the acuteness and severity of the pressure load. If the pressure rises acutely (eg, massive pulmonary embolism or acute mitral regurgitation), there will be right ventricular dilatation and failure without right ventricular hypertrophy. If pulmonary hypertension is a chronic problem (eg, COPD), the right ventricle will undergo hypertrophy in response to chronically increased right ventricular afterload.
Prolonged pulmonary hypertension causes irreversible anatomic changes in the walls of the small pulmonary arteries so that the hypertension becomes chronic, with resultant right ventricular dilatation and right ventricular hypertrophy. Hypoxia, hypercapnia, and/or acidosis cause further pulmonary vasoconstriction, resulting in an even greater degree of pulmonary hypertension. The workload on the right ventricle is subsequently increased. Eventually the right ventricular end-diastolic pressure increases, which will be reflected back to the right atrium and the venous system with resultant jugular venous distension, liver engorgement, ascites, and peripheral edema. Also, right ventricular hypertrophy reduces right ventricular compliance that may interfere with right ventricular filling and further reduce cardiac output. If there is a reduction in blood flow to the pulmonary vascular bed, or an increase in cardiac output, heart rate, or blood volume, then pulmonary hypertension will worsen, producing increased signs and symptoms of right ventricular failure. The manifestations of left- and right-sided heart failure are summarized in Table 6-2.
When possible, the treatment of heart failure targets the underlying cause (eg, ischemia, hypertension, valvular disease, arrhythmias).120,121 Pharmacologic therapy includes a wide variety of agents that attempt to improve contractility, reduce preload, promote vasodilation, impede the stimulation of the sympathetic nervous system, or relieve hypoxia. See Chapter 8. Nonpharmacologic, surgical, and therapeutic interventions for the management of heart failure are presented in Chapter 18.
Sudden death is characterized by a loss of consciousness and absence of an arterial pulse without prior circulatory collapse. It is the result of a fatal cardiac arrhythmia, which is typically due to CAD in the middle-aged and elderly adult. In as many as 25% of patients, sudden death may be the first clinical manifestation of coronary disease.122 Sudden death is a multifactorial problem and is more likely to occur in patients with prior infarct and moderate to severe left ventricular dysfunction. Ischemic heart disease is most often the underlying cause, but cardiomyopathy, valvular heart disease, electrophysiologic abnormalities, and idiopathic ventricular fibrillation may also cause sudden death. Triggering factors include physical or mental stress, ionic or metabolic disorders, an acceleration of sinus rhythm, or the appearance of a supraventricular arrhythmia. Other factors are the arrhythmogenic effect of certain drugs and the interaction of electrical instability with ischemia and/or left ventricular dysfunction due to multiple causes.64 Approximately 20% of patients with acute MI die before reaching a hospital.3 Most of these deaths are caused by ventricular fibrillation. Transient ischemia is rarely the cause of sudden death. Most patients who die suddenly have a vulnerable myocardium. The risk of sudden death in postinfarction patients is strongly related to the presence of electrical instability and its interaction with left ventricular dysfunction and residual ischemia. Patients at high risk of sudden death are those with a history of malignant ventricular arrhythmias (sustained ventricular tachycardia or out-of-hospital arrest), heart disease with markers of a vulnerable myocardium for malignant ventricular arrhythmias (depressed contractility, ischemia, electrical instability), and severe bradyarrhythmias.64