Pathophysiology of Glaucoma

The major mechanism of visual loss in glaucoma is retinal ganglion cell atrophy, leading to thinning of the inner nuclear and nerve fiber layers of the retina and axonal loss in the optic nerve. The optic disk becomes atrophic, with enlargement of the optic cup (see below). The iris and ciliary body also become atrophic, and the ciliary processes show hyaline degeneration.

The pathophysiology of intraocular pressure elevation—whether due to open-angle or to angle-closure mechanisms—will be discussed as each disease entity is considered (see below). The effects of raised intraocular pressure are influenced by the time course and magnitude of the rise in intraocular pressure. In acute angle-closure glaucoma, the intraocular pressure reaches 60–80 mm Hg, resulting in acute ischemic damage to the iris with associated corneal edema and optic nerve damage. In primary open-angle glaucoma, the intraocular pressure does not usually rise above 30 mm Hg and retinal ganglion cell damage develops over a prolonged period, often many years. In normal-tension glaucoma, retinal ganglion cells may be susceptible to damage from intraocular pressures in the normal range or the major mechanism of damage may be optic nerve head ischemia

Mycrobiology of sinusitis

A.Acute sinusitis
The most commonly identified organisms in children with acute sinusitis are Streptococcus pneumoniae in 30% to 40%, Haemophilus influenzae in 20% to 25%, and Moraxella catarrhalis in 20%. In adults, S. pneumoniae and H. influenzae are the two leading causes of acute sinusitis, whereas Moraxella is unusual. Anaerobic organisms are primarily identified in cases of acute sinusitis originating from dental root infections, but are otherwise uncommon. Hospital-acquired sinusitis is most often seen as a complication of nasogastric tube placement, and is typically caused by gram-negative enteric organisms, such as Pseudomonas and Klebsiella species.

B.Chronic sinusitis
1.Bacteria cultured from children with persistent symptoms are usually the same as those seen in acute disease. In children with more severe and protracted symptoms, anaerobic species (such as Bacteroides) and staphylococci are cultured more frequently. In adults with refractory symptoms, Staphylococcus epidermidis is frequently cultured from intraoperative specimens. The exact role of this species in the pathogenesis of chronic sinusitis is unclear. Although anaerobic organisms were once implicated in adults with chronic sinus disease, more recent evidence casts doubt upon those data.

2.Fungi, such as Aspergillus species, are a common cause of sinus disease in immunocompromised hosts, including diabetics and patients who have defective cell-mediated immunity. Increasingly, fungi have been identified as causes of sinusitis in patients who are otherwise healthy and should, therefore, be considered in cases of refractory sinusitis. Allergic fungal sinusitis is a syndrome that occurs in adults with asthma and has been attributed to Aspergillus, Bipolaris, and Curvularia species. It is characterized by severe, hyperplastic sinusitis and nasal polyposis, and is associated with significant eosinophilia of sinus tissue and blood.

Indications for Anticoagulation in Patients With Prosthetic Heart Valves

All patients with mechanical valves require warfarin therapy. The risk of embolism is greater with a valve in the mitral position (mechanical or biological) than in the aortic position. With either type of prosthesis or valve location, the risk of emboli is higher in the first few days and months after valve insertion. Low-dose aspirin is recommended for all patients with prosthetic valves (see Table 1. For patients with mechanical valves, the addition of low-dose aspirin (80 to 100 mg/d) to warfarin therapy (INR 2.0 to 3.5) not only further decreases the risk thromboembolism but also decreases mortality due to other cardiovascular diseases. A slight increase in risk of bleeding with this combination should be kept in mind.
Recommendations for Antithrombotic Therapy in Patients With Prosthetic Heart Valves
Class I
1.First 3 months after valve replacement: Warfarin- INR 2.5 to 3.5
2.3 or more months after valve replacement:
A. Mechanical valve
AVR and no risk factor*:
Bileaflet valve or Medtronic Hall valve, Warfarin- INR 2 to 3
Other disk valves or Starr-Edwards valve, Warfarin- INR 2.5 to 3.5
AVR and risk factor,* Warfarin- INR 2.5 to 3.5
MVR, Warfarin- INR 2.5 to 3.5

B. Bioprosthesis
AVR and no risk factor,* Aspirin- 80 to 100 mg/d
AVR and risk factor,* Warfarin- INR 2 to 3
MVR and no risk factor,* Aspirin- 80 to 100 mg/d
MVR and risk factor,* Warfarin- INR 2.5 to 3.5

Class IIa
1.Addition of aspirin to warfarin: Aspirin- 80 to 100 mg daily
2.High-risk patients for whom aspirin cannot be used: Warfarin- INR 3.5 to 4.5
Class IIb
Starr-Edwards AVR and no risk factor,* Warfarin, INR 2 to 3

Class III
1.Mechanical valve, no warfarin therapy.
2.Mechanical valve, aspirin therapy only.
3.Bioprosthesis, no warfarin and no aspirin therapy.

Symptom and Sign Diabetes

SYMPTOMS AND SIGNS

Type 1 diabetes
Increased urination is a consequence of osmotic diuresis secondary to sustained hyperglycemia. This results in a loss of glucose as well as free water and electrolytes in the urine. Thirst is a consequence of the hyperosmolar state, as is blurred vision, which often develops as the lenses are exposed to hyperosmolar fluids.
Weight loss despite normal or increased appetite is a common feature of type 1 when it develops subacutely. The weight loss is initially due to depletion of water, glycogen, and triglycerides; thereafter, reduced muscle mass occurs as amino acids are diverted to form glucose and ketone bodies.
Lowered plasma volume produces symptoms of postural hypotension. Total body potassium loss and the general catabolism of muscle protein contribute to the weakness.
Paresthesias may be present at the time of diagnosis, particularly when the onset is subacute. They reflect a temporary dysfunction of peripheral sensory nerves, which clears as insulin replacement restores glycemic levels closer to normal, suggesting neurotoxicity from sustained hyperglycemia.
When absolute insulin deficiency is of acute onset, the above symptoms develop abruptly. Ketoacidosis exacerbates the dehydration and hyperosmolality by producing anorexia and nausea and vomiting, interfering with oral fluid replacement.
The patient's level of consciousness can vary depending on the degree of hyperosmolality. When insulin deficiency develops relatively slowly and sufficient water intake is maintained, patients remain relatively alert and physical findings may be minimal. When vomiting occurs in response to worsening ketoacidosis, dehydration progresses and compensatory mechanisms become inadequate to keep serum osmolality below 320–330 mosm/L. Under these circumstances, stupor or even coma may occur. The fruity breath odor of acetone further suggests the diagnosis of diabetic ketoacidosis.
Hypotension in the recumbent position is a serious prognostic sign. Loss of subcutaneous fat and muscle wasting are features of more slowly developing insulin deficiency. In occasional patients with slow, insidious onset of insulin deficiency, subcutaneous fat may be considerably depleted.

Type 2 diabetes
While many patients with type 2 diabetes present with increased urination and thirst, many others have an insidious onset of hyperglycemia and are asymptomatic initially. This is particularly true in obese patients, whose diabetes may be detected only after glycosuria or hyperglycemia is noted during routine laboratory studies. Occasionally, type 2 patients may present with evidence of neuropathic or cardiovascular complications because of occult disease present for some time prior to diagnosis. Chronic skin infections are common. Generalized pruritus and symptoms of vaginitis are frequently the initial complaints of women. Diabetes should be suspected in women with chronic candidal vulvovaginitis as well as in those who have delivered large babies (> 9 lb, or 4.1 kg) or have had polyhydramnios, preeclampsia, or unexplained fetal losses.
Obese diabetics may have any variety of fat distribution; however, diabetes seems to be more often associated in both men and women with localization of fat deposits on the upper segment of the body (particularly the abdomen, chest, neck, and face) and relatively less fat on the appendages, which may be quite muscular. Standardized tables of waist-to-hip ratio indicate that ratios of "greater than 0.9" in men and "greater than 0.8" in women are associated with an increased risk of diabetes in obese subjects. Mild hypertension is often present in obese diabetics. Eruptive xanthomas on the flexor surface of the limbs and on the buttocks and lipemia retinalis due to hyperchylomicronemia can occur in patients with uncontrolled type 2 diabetes who also have a familial form of hypertriglyceridemia.

PATHOLOGY OF ACUTE PANCREATITIS

PATHOLOGY
Detailed histological studies of pancreatic tissue are available from a limited number of cases of human acute pancreatitis. A histological spectrum of acute pancreatitis is recognized ranging from mild, interstitial disease to coagulation necrosis. 3 Interstitial pancreatitis may lead to local and systemic complications but is rarely fatal; necrotizing pancreatitis may be fatal in up to 30% of cases.

Interstitial
In interstitial pancreatitis the gland is edematous, but its gross architecture is preserved. Parenchymal inflammatory cells are present together with interstitial edema. Disruption of the normal acinar cell architecture is common and may contribute to the reduced enzyme secretion characteristic of acute pancreatitis. Zymogen granules are displaced from their fusion site in the apical domain of the cell and become dispersed throughout the cell, and the apical membrane appears contracted and microvilli disappear. 4 Zymogen granules fuse with each other instead of the apical membrane. Similar to animal models of pancreatitis, a distinct form of cell necrosis is observed in which the apical domain of the acinar cell is shed into the lumen, resulting in intact zymogen granules within the lumen. This pattern of partial cell necrosis may allow the acinus to regenerate rapidly after injury.

Necrotizing
Macroscopically, marked tissue necrosis and hemorrhage are apparent. Surrounding areas of fat necrosis are also prominent. These chalky areas of dead adipose tissue are found within the peripancreatic tissue and throughout the abdomen. Large hematomas often are located in the retroperitoneal space. The microscopic appearance of the pancreas parallels the gross changes, with marked fat and pancreatic necrosis. Vascular inflammation and thrombosis are common.

TREATMENT OF ACUTE MYOCARD INFARCTION

Treatment

Because myocardial damage progresses rapidly during the early hours, efforts during this critical period must be directed toward reducing myocardial oxygen demand and improving coronary blood supply to diminish the extent of myocardial damage. To be maximally effective, these interventions must be initiated as soon as possible: The reduction in benefit is very time-dependent, and patients who are treated within an hour fare significantly better than those treated later. Thus, prompt reperfusion therapy via primary angioplasty or thrombolytic therapy should be initiated in the absence of contraindications as early as possible in patients with ST elevation acute infarctions. It is now becoming clear that urgent treatment also reduces the morbidity associated with non-Q wave infarctions as well, especially if followed by definitive intervention on the infarct related artery.


A. EMERGENCY CARE AND PROTOCOLS

More than 85% of patients who present with ST elevation within 4 h of the onset of acute infarction have total thrombotic occlusion, thought to be caused by plaque rupture and subsequent development of an intramural coronary thrombus. The timely reestablishment of nutritive perfusion saves lives. This is best done, if possible, by primary angioplasty but if not available in <60 min (door to balloon time), thrombolytic agents should be used. The time window may not be the same for all patients, however. In some patients, collateral perfusion to the infarct zone extends this window; in others, there is only intermittent occlusion and transient recanalization prior to total occlusion, which may modify the time course of the infarction. It cannot be emphasized enough that the earlier treatment occurs the better (Figure 5–4). Although the magnitude of benefit varies for thrombolytic therapy, patients treated within 1 h of the onset of infarction (an impossibility if treatment requires 90 min to initiate) have up to a 50% reduction in mortality rates; those treated in the second hour have only half that benefit, and there is controversy about whether benefit occurs at all after 6 h. For primary angioplasty, this time dependence, especially after the first hour is less, but treatment during the initial 60–90 min is associated with profound benefit. The mortality rate for patients treated within 60–90 min of the onset of infarction in an outpatient trial of thrombolysis was 1%; for patients receiving identical treatment from 90 min to 3 h, the mortality rate was 10%. Emergency departments and hospitals must facilitate the way in which interventions aimed at coronary recanalization are implemented.

To this end, each hospital should have a plan that addresses each step in the identification, triage, and treatment of the patient who is a potential candidate for coronary recanalization.
It is starting to become clear that such a plan should be expanded, albeit with different therapies for patients with non-Q wave events as well. Such plans should include:
1. Activities that can be initiated by paramedics en route to the hospital— Paramedics can record and transmit 12-lead ECGs to the receiving facility; they can screen patients for indications for and contraindications to treatment with thrombolytic agents. In some emergency medical systems, thrombolytic therapy can safely be implemented by paramedics. Although the cost-effectiveness of initiating therapy in the field is unclear, screening by paramedics and the availability of a diagnostic ECG prior to arrival appear desirable.
2. Emergency room procedures— A triage plan should be developed to identify patients with chest discomfort compatible with ischemia and to facilitate rapid ECGs. Electrocardiograph machines should be available in all emergency facilities, with personnel trained to rapidly record 12-lead ECGs available at all times. The ECG must be read expeditiously by a physician. Although ECG screening by computer algorithms may be a reasonable adjunct, all computer systems do not perform equally well. The ultimate responsibility for interpretation of the ECG therefore resides with the physician. Emergency room physicians without a high level of expertise in this area should have readily available expert consultation (whether on-site or via electronic communications) to minimize delays in interpretation. This step should take no more than 5 min.
The first physician who sees the patient with chest discomfort and appropriate ECG changes should have both the responsibility and the authority to initiate treatment. If there is a prospective plan to use primary angioplasty in patients with ST elevation events, this is the therapy of choice. If not or if there is delay, thrombolytic therapy should be given. For patients with non-Q wave events (those with elevated troponins), treatment with antiischemic agents such as nitrates and b-blockers and the use of heparin (LMWH is better) is called for, and if intervention is likely, IIB/IIIA agents should be initiated. Each hospital should develop a protocol to address the following issues:

How many intravenous (IV) lines are necessary? One line must always be available in the event of an emergency and for infusion of medication to facilitate reperfusion (heparin, lytic agents, or IIB/IIIA agents). An additional line may be necessary for other medicines or for a heparin lock through which to draw blood.

How much oxygen should be used routinely? This should be defined; blood gases are relatively contraindicated in this situation, oximetry is preferred.

If primary angioplasty is the therapy of choice, prospectively detailed lines of communication must be established. If thrombolysis is the choice, the facility should know the thrombolytic agent of choice, and the dose for the routine patient. These should be decided by consensus. Instances in which an exception is necessary should be detailed, as should whom to call for consultation. The agent for routine use should, of course, be available in appropriate doses within the emergency department to facilitate rapid administration.

Which medicines should be used adjunctively? Aspirin, heparin, nitroglycerin, b-blockers, and IIB/IIIA agents for the routine patient should be specified in advance—and should be immediately available in the emergency department.

Which contraindications should preclude treatment?

How will patients be moved rapidly from the treatment area to their ultimate destination in an intensive care unit?
B. GENERAL PROCEDURES

1. Intravenous line— An intravenous line should be placed immediately in any patient who is seriously considered to have suffered acute ischemia; this will provide access for the administration of pharmacologic agents should they be necessary and for emergency treatment should the need arise. The IV line should be large (18 gauge or greater); its patency should be maintained with an infusion of 5% dextrose in water, one-half normal saline, or normal saline solution.
2. Oxygen— Oxygen is appropriate for all patients with suspected AMI. Given the current aggressive approach toward anticoagulation and reperfusion in treating coronary heart disease, which often entails the use of potent anticoagulants or thrombolytic agents, blood gas determinations are not appropriate as a routine measure; oximetry is preferred. The empiric use of oxygen, usually via nasal prongs at 2–4 L/min, is recommended for all patients except those who have both normal oxygen saturations by oximetry or some reason to withhold oxygen (eg, a history of CO2 retention). Even patients with severe chronic obstructive pulmonary disease who may be at risk for CO2 retention should receive oxygen if systemic oxygenation is inadequate. Although supported by experimental data, the concern that supraphysiologic doses of oxygen may induce vasoconstriction and adverse effects has never been convincingly documented clinically.
3. Relief of discomfort— Relief of discomfort is a high priority.
a. Sublingual nitroglycerin— Unless contraindicated by hemodynamic abnormalities, sublingual nitroglycerin can be used to try to relieve chest discomfort and reverse ECG changes. A reversal of ECG changes is found most often in patients with patent infarct-related coronary arteries; it suggests that ischemia rather than infarction is present. Nitroglycerin must be given cautiously, however, especially to patients with inferior MI who may have RV infarction and who are prone to hypotension in response to this agent. A small subset of patients without RV infarction will also develop hypotension and an inappropriately slow heart rate after nitroglycerin. This is a vagally mediated phenomenon that has also been reported with morphine sulfate. Atropine (0.5 mg) is the treatment of choice in such cases.
b. Intravenous nitroglycerin— If patients have a beneficial response to sublingual nitroglycerin, it is reasonable to initiate treatment with IV nitroglycerin at a low dose (5–10 µg/min). Although this may relieve some of the chest discomfort in patients with acute infarction, it does not reduce the need for treatment with analgesics. Furthermore, reductions in blood pressure by more than 10% in normotensive patients are likely to be detrimental. Keeping the dose low and not expecting it to provide total relief of discomfort is recommended. This approach reduces the incidence of tolerance to the agent, which occurs in up to 25% of patients. Some physicians also use more potent vasodilators such as sublingual nifedipine to assess whether chest pain can be relieved and ECG changes reversed. Although these agents are effective, there is an associated incidence of marked hypotension that can cause detrimental cardiovascular effects. Calcium channel blockers are not recommended for routine administration.
c. Morphine sulfate— If the patient does not have a prompt response to sublingual nitroglycerin, morphine sulfate is the drug of choice. An IV dose of 2–4 mg and repeated as necessary and tolerated until chest discomfort is relieved is recommended. In addition to relieving pain, morphine sulfate reduces anxiety and the catecholamine secretion that occurs across the myocardial vasculature during acute infarction. As noted earlier, there is a small incidence of hypotension with an inappropriate heart-rate response that responds to atropine. Other analgesic agents used for the treatment of pain include meperidine and pentazocine.
d. Beta-blockers— Beta-blockers are commonly used to treat the chest discomfort associated with AMI in countries outside the United States. They have been shown to be effective, apparently because of both their membrane-stabilizing effects and their beneficial effects on myocardial oxygen supply and demand. Small doses of metoprolol (generally 5 mg), propranolol (1–3 mg IV) or esmolol (a loading dose of 250 mg/kg followed by 25–50 mg/kg/min, up to a maximum dose of 300 mg/kg/min) can be given as long as hemodynamic and electrical stability can be maintained. Although esmolol’s efficacy in this area is not well established, it is rapidly metabolized by esterases in red cells and is the only agent with a brief duration of action. Beta-blockers may also be useful in reducing the extent of infarction and for secondary prevention (see section d. Adjunctive therapy).
e. Angiotensin-converting enzyme inhibitors— Patients with ST elevation infarction seem to benefit from the early initiation of treatment with angiotensin-converting enzyme inhibitors (ACEI) if blood pressure allows. This strategy improves ventricular remodeling acutely but is even more efficacious over the longer term
4. Activity— Bed rest, except for the patients who require the use of a bedside commode, is mandatory during the first 24 h; autonomic instability, hypotension, and arrhythmias are common. It was believed in years past that strict bed rest was appropriate for 7–10 days and that discharge should occur after approximately 2 weeks. It is now clear that it is less stressful and thus more beneficial medically if hemodynamically stable patients are allowed to sit in a chair and use a bedside commode after 24 h. In general, patients without complications remain in an intensive care unit for 2–3 days, during which time their activities are markedly restricted. On transfer out of the intensive care unit, they can gradually begin ambulation, and most patients without complications can be discharged as early as 4 days after infarction.
5. Diet— It generally has been recommended that patients with acute infarction avoid extremes of hot and cold, have no caffeine, and be maintained initially on a liquid diet. The rationale for this approach includes the presence of autonomic instability, concerns that caffeine might exacerbate arrhythmias, and fear that particulate matter could be aspirated in the event of cardiac arrest (which tends to occur early during the evolution of acute infarction). Although none of these concerns have been strictly validated, such restrictions are considered prudent. After the first day, if patients are stable, their diet can be advanced. Education to facilitate good eating habits and a reduction in fat intake can be initiated at that time.
6. Bowel care— Patients, especially those who are older and are put to bed-rest with a reduced oral intake, have a tendency to constipation. Given the autonomic instability indigenous to AMI, the reduction of straining when bowel movements occur is recommended. In general, the use of stool softeners such as docusate sodium in a once-a-day dose of 100 mg is adequate. Some degree of selection is appropriate; some patients are not in need of this treatment, whereas others require more potent treatment.
7. Sedation— If patients are excessively restless and no physical cause can be determined, sedation with small doses of a sedative-hypnotic agent such as diazepam is recommended. During the initial 24 h, the dosage should be the minimum required to relieve anxiety, and patients should be continually reassessed to ensure that what is being treated is anxiety and not an underlying complication of infarction.
8. Electrocardiographic monitoring— All patients with significant likelihood of AMI should be monitored electrocardiographically. Those with chest pain and ECG changes that are highly likely to be due to infarction should be hospitalized in an intensive care unit. Those deemed at less risk still require ECG monitoring in an environment where defibrillation is readily available. It is recommended that patients with uncomplicated acute infarction be monitored until discharge; patients with complications require longer periods of observation.
9. Heparin— Unless there are contraindications to its use or patients are receiving other anticoagulants, all patients should receive subcutaneous heparin, 5000 units every 12 h. This regimen has been shown to reduce the incidence of deep venous thrombi that occurs in as many as 24% of treated patients; it should reduce the frequency of pulmonary emboli as well. Although the studies documenting these effects were done at a time when long periods of bed rest were mandated, they are most likely still correct—at least in principle—and there is little morbidity associated with the relatively modest doses of heparin. Therefore, despite earlier ambulation, the use of subcutaneous heparin twice daily is still recommended. Most patients with ST segment elevation AMI or with non-Q wave AMI benefit from the use of therapeutic doses of heparin. Many still recommend unfractionated heparin to increase the activated partial thromboplastin time (aPTT) to 1½–2½ times. However, it is now clear that LMWH is mC. RECANALIZATION THERAPY

Prompt coronary recanalization clearly reduces infarct size and, in the long term, saves lives. The so-called open artery hypothesis also has additional benefits (see section 2. Implemantation of Reperfusion Strategies). At one time, there was legitimate controversy over whether coronary recanalization induced by mechanical means (angioplasty) was better, with lower mortality and morbidity rates, than that induced by thrombolysis in patients presenting with an ST elevation MI. Comparative studies indicate that the greater degree of coronary patency induced by angioplasty produces less residual ischemia and recurrent infarction. It is clear that patients whose vessels are open, with sluggish flow (TIMI II grade), have a substantially worse prognosis than do those whose vessels are widely patent with a normal (TIMI III grade) flow. Thus, because direct reperfusion of a coronary artery via mechanical means is more apt to induce TIMI grade III flow and, thus, better nutritive perfusion, it results in reduced mortality and morbidity. In general, patency rates with primary percutaneous coronary intervention (PCI) are in the range of 85–90%, whereas with thrombolysis, the rates are roughly 65% and recurrent events are more common. With modern advances, direct stenting appears to be by far the best approach. This is clearly the case for patients who present ³1–1½ h after the onset of symptoms. The results with thrombolysis in early (<90 min) patients probably match the results of PCI. If intervention is delayed for more than 60 min, results are far less positive. Thus, unless PCI can be done immediately, treatment with thrombolytic agents should be initiated.
Similar data concerning the advantages of recanalization therapy are starting to emerge for those with non-Q wave infarction as well although the data are still controversial. However, both the FRISC 2 and Tactics TIMI 18 studies strongly suggest that the aggressive use of newer anticoagulants such as IIB/IIIA agents and LMWH along with urgent recanalization improve prognosis. Additional trials in this important area are ongoing.
1. Subsets of patients—
a. Inferior versus anterior myocardial infarction— The mortality rates associated with anterior ST elevation MI are at least twice those for ST elevation inferior MI, and patients with the former should be treated more aggressively. Specifically, recanalization therapy should be considered appropriate for as long as 12 h in patients with anterior MI. This is particularly true when the ST segment elevation is greater than 2 mm or when more than two anterior precordial leads are involved. Data from patients with inferior infarction suggest that those with marked ST elevation and especially those with ST depression in the right-sided anterior precordial leads (V1–V3) are at greatest risk. Such changes are associated with a larger area at risk for infarction and subsequent morbidity and mortality. In addition, patients with RV involvement benefit substantially from recanalization. Therefore, the site of infarction and the ECG changes must be factored in with the patient’s age, hemodynamic stability, and other signs in determining the time during which treatment is appropriate.
b. Elderly patients— Elderly patients with acute ST elevation MI are at high risk for increased morbidity and mortality with thrombolytic agents. Indeed, some studies suggest that these agents have no benefit in this group. On the other hand, PCI is clearly beneficial. However, if PCI cannot be accomplished, individual decisions concerning the risk (which is substantial, especially in regard to intracranial bleeding) and the potential benefits must be balanced. Given the high (20–30%) mortality rate from ST elevation MI in the elderly, some increased risk may be reasonable.
c. Hypertension— Many studies of thrombolysis have been extremely cautious about enrolling patients with concurrent hypertension. In some studies, the presence of hypertension has been a demonstrable risk factor for bleeding; in others, this has not been the case. Although even patients with severe hypertension have been treated with beneficial results and no complications in some studies, definitive data are absent in this area. One important consideration is the ease with which blood pressure can be controlled. Transient hypertension that resolves quickly when pain is treated is less worrisome than that which requires treatment with vasodilators. The use of less aggressive dosing regimens and gentler anticoagulation may help to avoid morbidity when treating hypertensive patients. Again, PCI avoids many of these problems.
d. Prior cerebral vascular accidents— Initially, all patients with a history of cerebral vascular accidents were handled cautiously and were considered to have contraindications to the use of thrombolytic agents. It is now clear that this criterion is too rigid, and only cerebral vascular accidents that have occurred within the past 2 months and those associated with intracranial bleeding should be considered absolute contraindications.
2. Implementation of reperfusion strategies— Once the decision is made to treat a patient, treatment should be initiated promptly and the patient transferred to an intensive care unit. (Contraindications to the use of thrombolytic agents are contained in Table 5–2).

a. Urgent percutaneous coronary intervention— Recent data suggest that stenting with the use of clopidogrel for at least 4 weeks is the preferred modality of therapy. Although in one study, stenting appeared to present a possible initial early hazard, this was not observed in a subsequent study, and the frequency of subsequent ischemia and restenosis is clearly improved. The adjunctive use of LMWH is problematic because the only data concerning its use in this setting are preliminary. However, for enoxaparin, an initial IV dose of 30 mg appears optimal or dalteparin in a dose of 120 IU/kg subcutaneously.
b. Plasminogen activators— Plasmin, the key ingredient in the fibrinolytic system, degrades fibrin, fibrinogen, prothrombin, and a variety of other factors in the clotting and complement systems. This effect inhibits clot formation and can lead to bleeding. Patients with AMI and ST segment elevation have little evidence of spontaneous or intrinsic fibrinolysis, despite the intense thrombotic stimulus present. This may be due in part to increased levels of circulating PAI 1 in plasma or PAI-1 that is elaborated locally from platelets. The pharmacologic administration of plasminogen activators (Table 5–3) to such patients seems reasonable. Plasminogen activators can be administered intravenously or directly into the coronary artery. Although more rapid patency occurs with local administration, and lower doses can be used, given the need for early treatment, plasminogen activators are generally administered intravenously.

In addition to invoking fibrinolysis and inhibiting clotting by degrading clotting factors, all activators enhance clot formation. These effects seem greater with nonspecific activators such as streptokinase and urokinase and could partly explain why fibrin-specific activators such as t-PA open arteries more rapidly.
The enhancement of coagulation by plasminogen activators suggests an important role for the concomitant use of antithrombotic agents.
(1) Streptokinase— Streptokinase is derived from streptococcal bacteria and activates plasminogen indirectly, forming an activator complex with a slightly longer half-life than streptokinase alone (23 min versus 18 min after a bolus). Because it activates both circulating plasminogen and plasminogen bound to fibrin, both local and systemic effects occur; that is, circulating fibrinogen degrades substantially (fibrinogenolysis as well as fibrinolysis occurs).
Because antibodies to the streptococci exist in many patients, allergic reactions can occur; anaphylaxis is rare, however, and the use of steroids to avoid allergic reactions is no longer recommended. When streptokinase is administered intravenously, a large dose is necessary to overcome antibody resistance. Because a dose of 250,000 units will suffice in 90% of patients, the recommended dose of 1.5 million units over a 1-h period is generally more than adequate to overcome resistance. Patients who are known to have had a severe streptococcal infection or to have been treated with streptokinase within the preceding 5 or 6 months (or longer) should not receive the agent.
Rapid administration of streptokinase, even at the recommended dose, can cause a substantial reduction in blood pressure. Although this might be considered a potential benefit of the agent, it may also be detrimental. The rate of the infusion should therefore be reduced in response to significant hypotension, and the blood pressure should be monitored closely. Because streptokinase is more procoagulant than other thrombolytic agents, it should not be surprising that patients benefit to a greater extent from the concomitant use of potent antithrombins such as hirudin. However, in combination with IIB/IIIA agents, streptokinase seems to be associated with markedly increased bleeding rates.
(2) Urokinase— Urokinase is a direct activator of plasminogen. It has a shorter half-life than streptokinase (14 ± 6 min) and is not antigenic. Its effects on both circulating and bound-to-fibrin plasminogen are similar to those from streptokinase. It is therefore difficult to understand why IV doses of urokinase (2.0 million units as bolus or 3 million over 90 min) seem to induce coronary artery patency more rapidly than does streptokinase. There is substantial synergism between urokinase and t-PA.
(3) Tissue plasminogen activator— The initial human t-PA was made by recombinant DNA technology. The half-life in plasma was short (4 min) as a bolus but longer (46 min) with prolonged infusions. Despite the short half-life lytic activity persisted for many hours after clearance of the activator. Although t-Pas are considered “fibrin-specific,” no activator is totally fibrin-specific, and fibrin specificity is lost at higher doses. At clinical doses, however, less fibrinogen degradation took place than with nonspecific activators. Tissue plasminogen activator clearly opened coronary arteries more rapidly than nonspecific activators and this is likely why its use improved mortality rates. Bleeding was not less and there was a slight increase in the number of intracranial bleeds which was in part due to the need for dosage adjustment for lighter-weight patients.
The original regimen for the use of t-PA was 100 mg over 3 h: 10 mg as a bolus, followed by 50 mg over the first hour and 40 mg over the next 2 h. Patients who weighed less than 65 kg received 1.25 mg/kg over 3 h with 10% of the total dose given as a bolus. An alternative front-loaded regimen was found to be more effective and included an initial bolus of 15 mg, followed by 50 mg over 30 min and 35 mg over the next 60 min. Doses higher than 100 mg are associated with a higher incidence of intracranial bleeding.
(4) Reteplase— Over time a variety of t-PA variant molecules have been developed. This mutant, called reteplase, lacks several of the structural areas of the parent molecule (the finger domain, kringle 1, and the epidermal growth factor domain). It is less fibrin-specific (causes more systemic degradation of fibrinogen) than the parent molecule, and has a longer half-life. Accordingly, it is used as a double bolus of 10 units initially followed by a second bolus 30 min later. Initial studies suggested that such a regimen used with unfractionated heparin opened more coronary arteries faster than did t-PA. This led to a large trial (GUSTO III) that compared the activators and found no difference. If anything, the minor trends that were present, favored the parent molecule. Nonetheless, many have elected to use reteplase because of the convenience of the double bolus administration.
(5) Tenecteplase— Tenecteplase is also a mutant form of t-PA. It has substitutions in the kringle 1 and protease domains to increase its half-life, increase its fibrin specificity, and reduce its sensitivity to its native inhibitor (PAI-1). These effects were substantiated in clinical trials and initially it appeared that the agent might be substantially superior to the parent molecule. However, in a direct comparison trial (Assent 2), using a 40-mg dose of tenecteplase, no differences in patient outcomes were observed with the possible exception of the group treated more than 4 h after the onset of symptoms. Nonetheless, because of the convenience of a single bolus dose, this agent is generally being used in preference to the parent molecule.
c. Combined thrombolysis and percutaneous coronary intervention— This combination approach has substantial promise. The early experience with coronary interventions after thrombolysis suggested substantial morbidity. Recent data using a half dose of thrombolytic agent (PACT) and studies using IIB/IIIA agents have suggested that now rapid serial thrombolysis and PCI can be accomplished without detriment and may in the long run permit the benefits of both modalities to be combined. This may be an important strategy for those patients living in areas where transport times or logistics make timely PCI impossible. Trials are ongoing to further test these strategies.
d. Adjunctive therapy—
(1) Aspirin— The ISIS II study showed that the combination of aspirin and streptokinase produced a greater reduction in mortality rates than did streptokinase or aspirin alone. Aspirin alone, however, in a dose of 162.5 mg, reduced mortality from acute infarction to almost the same extent as did streptokinase alone. These impressive data have led to the use of aspirin in all patients with AMI. Such a posture is supported by strong experimental evidence that aspirin inhibits platelet aggregation and facilitates fibrinolysis. In general, chewable aspirin in a dose of 162.5–325 mg is recommended initially because its effects on platelets occur within 20 min.
(2) Heparin— Intravenous heparin, used with plasminogen activators, improves the rapidity with which patency is induced; it is essential for maintaining coronary patency, especially with t-PA type agents. Its use is less necessary after treatment with streptokinase, probably because of the anticoagulant effects of fibrinogen depletion and degradation products.
The standard dose of unfractionated heparin is usually a bolus of 5000 units, followed by a 1000-unit-per-hour infusion until the partial thromboplastin time (PTT) can be used to titrate a dose between 1.5 and 2 times the normal range. It has become clear that optimal titration of unfractionated heparin is problematic and that if the activated PTT is either too high or too low, some benefit is lost. For this reason, the use of LMWH is recommended. With the exception of patients with renal failure, a dose of 1 mg/kg for enoxaparin and 120 unit/kg for dalteparin provides for consistent reduction in anti-Xa levels and thus consistent anticoagulation. This is probably the reason that recent studies suggest it is more effective for the treatment of patients with AMI. In addition, because LMWH inhibits Xa activity predominantly, there is some suggestion that discontinuing it may be less problematic than is the case for unfractionated heparin, which has fewer effects on Xa and more direct effects (when combined with antithrombin 3) on thrombin itself. The ability to use the agent intravenously in the catheterization laboratory has not been a problem in regions where this strategy has been embraced.
(3) Beta-blockers— If given early, IV b-blockers have been shown to lower the risk of reinfarction in low-risk patients treated with thrombolytic agents. This provides a rationale for their use (metoprolol, 5 mg IV every 5 min for 3 doses, followed by 25–50 mg every 12 h orally; or propranolol, 0.1 mg/kg initially (IV), followed by 20–40 mg every 6 h) in patients receiving thrombolytic therapy. It is presumed but has not been proven that similar benefits accrue to patients treated with primary PCI. Contraindications to the use of b-blockers include rales more than one-third of the way up the posterior lung fields, systolic blood pressure of less than 100 mm Hg, a heart rate of less than 60 bpm, conduction disturbances, a history of chronic obstructive pulmonary disease or asthma, or a history of an adverse responses to b-blockers. Tachycardia should not be considered the result of increased adrenergic tone and should be treated with b-blockers until all possible physiologic causes can be excluded. This is particularly important with diabetic patients, in whom autonomic neuropathy can at times cause tachycardia. Once treatment with b-blockers has been initiated, there will be some reason to discontinue the drug during the first 2–3 days for 20–30% of patients. This may be due to the evolution of infarction with the development of heart failure or to unanticipated complications of the drug (Table 5–4).

Table 5–4. Standard intravenous doses of commonly used agents in patients with acute myocardial infarction.

In general, b-blockers appear to induce most benefit in patients who reduce their degree of ST segment elevation in response to treatment. This is thought to be the marker of a patent infarct-related vessel and probably permits the agent to reach the infarct zone.
(4) Nitroglycerin— Sublingual nitroglycerin is usually administered immediately to patients with suspected AMI to assess resolution of ST elevation and relief of pain (discussed earlier). Intravenous nitroglycerin has been shown to reduce infarct size in patients not receiving reperfusion and to improve survival in patients with infarction and CHF. Its use during thrombolysis was presumed to induce similar benefit; however, the ISIS 4 trial failed to show any effect on subsequent morbidity and mortality. Therefore, the routine use of IV nitroglycerin is not recommended.
(5) Intravenous magnesium— Several small studies have documented a reduction in mortality rates after administration of IV magnesium (1–2 g over 1 h, followed by 8 g over 24 h) to patients presenting during the initial 24 h of acute infarction. ISIS 4, however, failed to demonstrate any benefit in morbidity or mortality with the routine use of IV magnesium. Therefore, because IV magnesium induces mild hypotension and bradycardia, its use cannot be recommended unless serum magnesium levels are shown to be low or other indications, such as torsade de pointes, are present.
(6) Calcium channel blockers— Dihydropyridine calcium channel blockers have shown to be detrimental in patients with AMI, probably because of a small but important incidence of severe hypotension. The data are inadequate to assess the risk or benefit of other calcium channel blockers. Although it is hoped that IV preparations may avoid adverse effects, allowing achievement of some of the benefits seen in experimental models, the use of calcium channel blockers cannot be recommended at this time.
(7) Lidocaine— Lidocaine was initially administered to patients receiving thrombolytic agents because of concern that coronary recanalization might exacerbate arrhythmias; However, recanalization reduces the incidence of such arrhythmias. In addition, recent analyses suggest the routine use of lidocaine may actually increase mortality rates. Accordingly, the use of prophylactic lidocaine is not recommended. The agent should be used if ventricular tachycardia (VT) or ventricular fibrillation (VF) occurs.
(8) IIB/IIIA agents— These agents bind to the platelet fibrinogen receptor and prevent platelet aggregation and activation. The initial agent in this group was abciximab, which is a chimeric antibody fragment to the receptor. Now both small peptide and nonpeptide competitive inhibitors of the receptor are available. These agents markedly inhibit hemostasis by both inhibiting hemostatic plug formation and reducing subsequent coagulation. They have not as yet been shown to be of benefit in patients with ST elevation AMI but are clearly efficacious in patients with non-Q wave events, especially if they undergo PCI. This is a group with an adverse long-term prognosis without intervention.
e. Complications— The most serious complication of treatment with thrombolytic agents is bleeding, particularly intracranial hemorrhage. Reduction in this dreaded complication is one of the very substantial benefits of catheter-based interventions. The mechanism of bleeding with thrombolytic agents is unclear but has been related to the efficacy of the agent, the concomitant use of antithrombotic agents such as heparin and aspirin, and the degree of hemostatic perturbation induced by the plasminogen activators. In most studies, the incidence of stroke and intracerebral bleeding has been slightly higher with t-PA type activators. This may be in keeping with the greater efficacy and rapidity of their effects. Although most bleeding occurs early during treatment, some can occur 24–48 h later, and vigilance even after the first few hours is important.
Bleeding may be of several types. Intracranial bleeding is by far the most dangerous because it is often fatal. For most activators, the incidence of intracranial hemorrhage is less than 1%; it may be as high as 2–3% in elderly patients. Risk factors for intracranial bleeding include a history of cerebral vascular disease, hypertension, and age. These factors must be taken into account when determining whether a thrombolytic agent has an appropriate benefit-to-risk relationship. Changes in mental status require an immediate evaluation—clinical and computed tomography or magnetic resonance imaging. If bleeding is strongly suspected, heparin should be discontinued or reversed with protamine.
There also is a substantial incidence of nonhemorrhagic, probably thrombotic, stroke that may be partly due to dissolution of thrombus within the heart, followed by migration. The exact mechanisms of this phenomenon are unclear. In some studies, the excess of strokes with t-PA has been found to be related to this phenomenon and in others it has been due to an apparent increase in intracranial bleeding.
Bleeding outside the brain can occur in any organ bed and should be prevented whenever possible. The puncture of noncompressible arterial or venous vessels is relatively contraindicated in all cardiovascular patients: those with unstable angina one day may be candidates for thrombolytic treatment on the next. Blood gas determinations should therefore be avoided if possible and oximeters used instead in cardiovascular patients. It should be understood that central lines placed in cardiovascular patients pose a substantial risk should there be a subsequent need for a lytic agent. Foley catheters and endotracheal (especially nasotracheal) intubation can also predispose to significant hemorrhage. Bleeding should be watched for assiduously. If severe bleeding occurs while heparin is in use, it should be antagonized with protamine. In general, this and supportive measures are all that can be done. In some studies, there appears to be a slightly higher incidence of extracranial bleeding with nonspecific activators than with t-PA; this finding has not been consistent. In an occasional patient, who begins to bleed shortly after receiving the plasminogen activator, epsilon amino caproic acid, which changes the activation of plasminogen, may be useful. Otherwise, discontinuation of the drug and conservative local measures are all that can done. If volume repletion is necessary, red blood cells are preferred to whole blood, and cryoprecipitate is preferred to fresh frozen plasma because they do not replenish plasminogen.
Allergic reactions related to the use of streptokinase are unusual but should be identified when they occur. Mild reactions such as urticaria can be treated with antihistamines; more severe reactions such as broncho-spasm may require glucocorticoids or epinephrine.
Bleeding after primary PCI whether for ST elevation of non-Q wave AMI can also be substantial, particularly if IIB/IIIA agents are administered. The use of newer closure devices are touted by some but close observation is the key to minimizing bleeding from the catheter site. On occasion, platelet transfusions may be necessary.
3. Subsequent early management— Aggressive monitoring can help determine which patients have coronary recanalization in response to treatment and which do not. Conventional ECG monitoring for ST segments and arrhythmias and consideration of the presence or absence of chest pain are not particularly reliable for this purpose. In fact, increasing degrees of ST segment elevation during the first hour after treatment appear to be a sign of incipient recanalization.
Emergency cardiac catheterization and angioplasty are not indicated for the routine patient who has been successfully thrombolysed. However, patients with non-Q wave AMI who have been stabilized pharmacologically and who are candidates for intervention should have it performed promptly. Patients who suffer continuing or persistent chest discomfort, who have recurrent segment change, or who have difficult-to-treat hypotension and heart failure should be considered for cardiac catheterization.
D. OTHER INTERVENTIONS

A variety of other interventions have been suggested throughout the years. These include the use of glucose, insulin, potassium, and hyaluronidase. Intraaortic balloon pumps have also been suggested, especially in patients with anterior infarction who might be deemed at risk for the development of severe heart failure. In general, none of these are recommended as routine measures. Perhaps the most promising of these is in the area of tight glucose control in diabetes. The DIGAMI study suggested an impressive benefit in early and late mortality and morbidity. With the availability of accurate glucose monitoring for point of care use, implementation of a strategy using rapid adjustments of IV insulin guided by hourly glucose measurements is likely to emerge as an important additional strategy.

DIANNOSTIC ACUTE MYOCARD IINFARCTION

Clinical Findings
The clinical presentations of patients with AMI vary. Although most patients have had chest discomfort prior to the onset of infarction, 20% or more have infarction as a first manifestation of ischemic heart disease; in 20–30% of patients, infarction may go unrecognized. Nonetheless, symptoms are generally present.
A. SYMPTOMS AND SIGNS

The most common and best symptom on which to base a consideration of MI is chest discomfort, usually described as “pressure,” “dull,” “squeezing,” “aching,” or “oppressive,” although it may be described differently because of individual variability, differences in articulation or verbal abilities, or concomitant disease processes. The discomfort is usually in the center of the chest and may radiate to the left arm or the neck. In general, patients with ischemic chest pain tend to be still, but patients with infarction can be restless as well. The nature of the pain may lead patients to place a hand over the sternum (Levine’s sign). These clinical signs and symptoms were originally defined in groups of males. It is now clear that women often have more disease symptoms or more atypical symptoms.
Patients with diabetes or hypertension also may have atypical presentations; a classic presentation in a diabetic is with abdominal pain that mimics the discomfort commonly associated with gallstones. Elderly patients often present with heart failure: by age 85, only 40% of patients will present with chest discomfort. Patients who present with symptoms compatible with ischemia, (paroxysms of dyspnea, for example) or atypical chest discomfort should have the diagnosis of MI considered. Patients can also present with discomfort that is sharper or that radiates to the back. These patients can have pericarditis alone, pericarditis induced by infarction, or a dissecting aortic aneurysm—with or without concomitant infarction.
Much has been made of the presence of associated symptoms and findings such as dyspnea, diaphoresis, nausea and vomiting, and the response of chest discomfort to antianginal agents. Although positive findings should evoke increased consideration of a diagnosis of ischemic heart disease, their absence is not definitive.
B. PHYSICAL EXAMINATION

The physical examination may vary tremendously, from markedly abnormal, with signs of severe congestive heart failure (CHF), to totally normal. In general, an S4 sound is heard in patients with ischemic heart disease. Dyskinesis can be palpated in patients with larger infarctions. Signs of heart failure, such as neck vein distention, S3 sounds, and rales, should be looked for specifically.
C. DIAGNOSTIC STUDIES

The diagnosis of infarction in patients with suspected acute ischemic heart disease requires evidence of myocardial necrosis. This finding usually depends on elevated molecular markers of cardiac injury.
1. Troponins are the markers of choice— They are significantly more sensitive than CK2, and now with second- and third-generation assays, they have nearly absolute cardiac specificity. Absent analytic false-positives, one can be sure that the release of troponin is indicative of cardiac injury. However, because they are so sensitive, they detect cardiac insults that are nonischemic in nature (Table 5–1). Thus, the diagnosis of AMI requires clinical, electrocardiographic (ECG), or other (eg, coronary angiographic) evidence of acute ischemia (see Table 5–1). Troponin is elevated between 4 and 6 h after onset of an AMI and remains elevated for 8–12 days. Thus, the late or retrospective diagnosis of AMI can be made with this marker, making the use of lactate dehydrogenase isoenzymes superfluous. Troponin elevations in patients with ST elevation at the time of admission presage a lower rate of recanalization regardless of reperfusion modality used and a worse prognosis. This may be, at least in part, because patients with elevations present later than those without elevations. Patients who present with ST depression also have a worse prognosis if troponin is elevated to any extent. Even minor elevations are of significance (Figure 5–2). This group also has a unique beneficial response to LMWH and IIb/IIIa agents. Patients at low risk for ischemic heart disease who present with chest pain have a high frequency of coronary artery disease if troponin is elevated. Because increases in troponin persist for up to 2 weeks after an acute event, if the initial troponin value is elevated, it may be of value to define a shorter-lived marker (eg, CK2) if the cardiac injury is acute or has occurred in the days or weeks prior to presentation.

Table 5–1. ESC/ACC definition of myocardial infarction.

Figure 5–2. Prognosis in patients with acute coronary syndrome (ACS), elevated troponin, and no elevation of CK2 (isoenzyme of creatinine kinase), Peto odds ratio (OR), and 95% confidence interval (fixed). Adapted, with permission, from Am Heart J 2000;140:917.

Coronary recanalization, whether spontaneous or induced pharmacologically or mechanically, alters the timing of all markers’ appearance in the circulation. Because it increases the rapidity with which the marker is washed out from the heart, leading to rapid increases in plasma, the diagnosis of infarction can be made much earlier—generally within 2 h of coronary recanalization. Although patency can be approximated from the marker rise, distinguishing between thrombolysis in myocardial infarction (TIMI) II and TIMI III flow is not highly accurate. It should also be understood that peak elevations are accentuated, which must be taken into account if one wants to use peak values as a surrogate for infarct size.
2. Other molecular markers— The diagnosis of infarction requires increases in molecular markers of myocardial injury. Myoglobin release from injured myocardium occurs quite early and is very sensitive for detecting infarction. Unfortunately, it is not very specific because minor skeletal muscle trauma also releases myoglobin. Myoglobin is cleared renally, so even minor decreases in glomerular filtration rate lead to elevation. The other early marker advocated by some are isoforms of CK2. This marker has comparable early sensitivity to myoglobin, but because it uses such sensitive criteria, it also has nearly similar specificity as well. The marker of choice in past years was the MB isoenzyme of creatine kinase (CK2). A typical rising-and-falling pattern of CK2 alone (in the proper clinical setting) was sufficient for the diagnosis of acute infarction. In the typical pattern of CK2 release after infarction, the enzyme marker level exceeds the upper bound of the reference range within 6–12 h after the onset of infarction. Peak levels occur by 18–24 h and generally return to baseline within no more than 48 h. However, elevations can occur due to release of the enzyme from skeletal muscle. The lack of a rising-and-falling pattern should raise the suspicion that the release is from skeletal muscle, which is usually due to a chronic skeletal muscle myopathy. Elevations of CK2 in patients with hypothyroidism (where clearance CK2 is retarded) and those with renal failure (where clearance is normal because CK2 is not cleared renally) have elevations caused, in part, by myopathy. The percentage of CK2 with respect to total CK2 is an unreliable criterion for the diagnosis of infarction.
3. Electrocardiography— Only a few ECG patterns have high specificity for infarction (Figure 5-3). In general, an upwardly concave elevation of the ST segment is considered diagnostic of acute myocardial injury, with a high degree of specificity. Patients with inferior infarction should all be evaluated with right-sided chest leads to determine if right ventricular (RV) infarction is present by detecting ST elevation in V3R or V4R. Patients with ST segment depression in V1 and V2 may have total circumflex occlusions, which can be unmasked by the findings of ST segment elevation in the so-called posterior leads (V7–V9). The Q waves that tend to develop mark these patients as potential candidates for strategies designed to reduce the extent of infarction (discussed in the section on Implementation Reperfusion Strategies). Reperfusion accelerates the appearance of the Q waves often associated with this type of infarction. The electrocardiogram may not show typical changes, however, because of concomitant conduction disturbances (eg, left bundle branch block [LBBB]) that may mask the findings or because only ST depression, which is considered more nonspecific, is present. Without acute ST segment elevation or the development of new Q waves, no other ECG changes can be considered highly specific—and even these findings are not 100% specific. The ECG can even be totally normal. In the absence of an old ECG for comparison, any changes present should be presumed to be new. Although persistent or fixed changes are more characteristic of infarction, labile changes have a greater predictive value for the presence of ischemia for patients with elevated biomarkers thought to have non-Q wave MI, the presence of ST depression is a negative prognostic sign.

Figure 5–3. Typical evolution of the electrocardiographic changes of acute myocardial infarction. A: Anterior infarction. B: Inferior infarction. Reproduced, with permission, from Lipman BS, Dunn MI, Massie E: Clinical Electrocardiography. St. Louis: Mosby, 1984.

4. Imaging— Imaging can also be used to confirm the presence or absence of acute infarction, but it is rarely used in modern practice. Infarct-avid imaging with technetium 99m pyrophosphate indium-111-labeled myosin or 99m sestamibi can be used. These techniques detect large AMIs well. With smaller infarctions, however, sensitivity is lost. In addition, with larger infarctions, a significant number (20–30%) of images will remain persistently positive for at least 6 months.
Echocardiography also may be helpful in detecting an AMI. Some researchers argue that the absence of regional abnormalities on the ECG is strong evidence against the presence of acute infarction. The sensitivity of echocardiography, however, is critically dependent on the quality of the views obtained; the absence of an abnormal ECG should not of itself be used to exclude the presence of ischemic heart disease. Furthermore, echocardiography cannot distinguish acute infarction from a persistent defect caused by an old myocardial injury. At present, therefore, it is diagnostically useful for AMI when the ECG and clinical history are equivocal. It is valuable in defining the presence of the complications of AMI.

PHATOPHYSIOLOGI ACUTE MYOCARD INFARCTION

It is generally accepted that a prolonged imbalance between myocardial oxygen supply and demand leads to the death of myocardial tissue. Coronary atherosclerosis is an essential part of the process in most patients. Ischemic heart disease seems to progress through a process of plaque rupture that transiently increases the amount of luminal impingement by the stenotic lesion. Infarction may occur when the plaque ruptures and leads to thrombosis, erosion of the plaque causes thrombosis, or when cardiac work exceeds the ability of the narrowed coronary artery to supply nutritive perfusion. Recent work suggests that inflammation may play a pivotal role in the genesis of plaque rupture.
Greater numbers of acute infarctions occur during the early morning hours (from 6:00 AM to 12:00 noon) than any other time of the day, suggesting that perhaps the increased catecholamine secretion associated with awakening or circadian changes in coagulation common in the early morning (eg, increases in type-1 plasminogen activator inhibitor [PAI-1]) may induce platelet aggregation and lead to thrombus formation. Beta-blockers reduce this propensity and psychiatric depression shifts this pattern back 6 h—as it does with other circadian patterns. In keeping with this pattern, most infarctions do not appear to be induced by exertion. When severe exertion or severe emotional distress does occur, it appears to induce a window of vulnerability for roughly an hour or two after the acute event in susceptible individuals.
In general, patients with acute infarction tend to be males in their 50s and 60s, although infarction in elderly women in their 70s and older is now equally common. Indeed, acute infarction is now equal in incidence between women and men. Most often, those individuals have risk factors for the development of coronary artery disease, such as an increased cholesterol, diabetes, hypertension, cigarette smoking, a sedentary life-style, or a family history of early coronary artery disease. These risks are not present in all patients, however, and the absence of risk factors does not eliminate the possibility of infarction. This is especially true with the increasing prevalence of drug abuse. In patients who have AMI without apparent risk factors, an evaluation for the presence of novel risk factors, such as homocysteine, lipoprotein(a), small dense low-density lipoprotein (LDL), and markers of inflammation such as C-reactive protein and phospholipase A2 is warranted.
A. TOTAL THROMBOTIC OCCLUSION

In many patients (roughly 50%), total thrombotic occlusion is superimposed on the atherosclerotic plaque. The occlusion is thought to develop in response to plaque rupture when the luminal diameter of the coronary artery is sufficiently reduced to initiate clot formation or if erosion of the plaque causes exposure of procoagulant factors. Procoagulant factors (such as tissue factor) reside within the plaque itself and the absence of counterbalancing antithrombotic factors (eg, heparin, tissue-factor-inhibitor) and fibrinolytic activities (tissue plasminogen activator [t-PA] and single-chain urokinase-type plasminogen activator) within the endothelial cells of the coronary artery can cause thrombosis. Total thrombotic occlusion occurs most commonly in proximal coronary arteries; its presence has been documented during the first 4 h after infarction in more than 85% of patients who present with ST segment elevation (Figure 5–1). Most patients who present in this manner subsequently develop Q waves. A similar type of myocardial insult occurs occasionally despite angiographically normal coronary arteries and is caused by emboli (eg, in patients with prosthetic valves or those with endocarditis), dissection of the coronary artery (most commonly in pregnant women), or on rare occasions, coronary vasospasm. It can also be caused by thrombosis in situ, the probable mechanism by which patients who have variant angina or who abuse cocaine can suffer acute infarction. In these cases, vasoconstriction secondary to endothelial dysfunction and a propensity to thrombosis is of sufficient magnitude and duration to cause thrombus formation. Oxygen consumption and possibly direct myocyte toxicity also increase with cocaine use. In addition, thrombosis in situ can apparently cause infarction among women who take estrogens (especially if they smoke).

Figure 5–1. Incidence of total occlusion in patients with acute myocardial infarction. Reproduced, with permission, from DeWood MA, Spores J, Notske R et al: Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897.

B. NON-Q WAVE INFARCTION

The remainder of infarctions occur generally in the absence of total thrombotic occlusion. The term non-Q wave infarction is used because the infarction is not associated with the development of new Q waves on the electrocardiogram. (This term is preferred to nontransmural infarction because no correlation has been found between Q waves and the presence of infarction through all levels of the ventricle). The frequency of this type of infarction is increasing because of the use of newer more sensitive and specific markers such as the troponins to detect small events.
Although, overall, the coronary anatomy of patients with non-Q wave infarctions is virtually identical to that of patients with Q wave infarctions, the incidence of documented total thrombotic occlusion during the initial 24 h after presentation with non-Q wave infarctions is only 29%.
Some clinicians believe that non-Q wave infarction is caused by small clots that dissolve prior to investigation, leaving only an open artery to be detected. Evidence for this includes an early rise in both the total and the MB isoenzyme of creatine kinase (CK2) and the finding of contraction-band necrosis (a sign of calcium overload commonly seen after reperfusion). The rapidity of the rise and fall of marker proteins and the presence of contraction bands are related to coronary blood flow, however, and continued antegrade flow could also be responsible. Because smaller infarctions also tend to have earlier times to peak CK concentrations, early enzyme peaking could represent a small infarction or the presence of antegrade coronary flow rather than spontaneous coronary recanalization.
Nonetheless, abundant data confirm that thrombosis is common in such patients if diagnosed by an elevated troponin level, especially if concomitant ST depression is present. There are other pathophysiologic possibilities for non-Q wave infarctions. An imbalance of myocardial oxygen supply and demand could be the result of a prolonged increase in myocardial work and oxygen consumption in the distribution of a coronary artery unable to increase its blood flow because of atherosclerosis or endothelial dysfunction. The coronary artery could also constrict abnormally and cause a similar imbalance. Small amounts of vasoconstriction can cause major changes in the cross-sectional area of a vessel since A = pr2.
Patients with non-Q wave infarction and partial coronary occlusion are at increased risk for subsequent total occlusion and recurrent infarction during the hospital course and in the weeks and months following the event. After the first few days, although these infarctions are smaller, mortality rates increase more rapidly than in patients with Q wave infarctions because of the greater number of recurrent events. By 6 months, mortality rates are similar to those for patients with Q wave infarctions. However, it is now clear that invasive interventions such as stenting with the assistance of potent anticoagulant modalities such as IIB/IIIA antiplatelet agents and low-molecular-weight heparins (LMWH) can reduce these subsequent events.
Non-Q wave infarction is often seen when other medical illnesses coexist with ischemic heart disease. Pulmonary embolism, septic shock, severe anemia, or even great emotional distress can increase myocardial oxygen demand, reduce coronary perfusion pressure, or evoke paradoxical coronary artery responses and lead to non-Q wave infarction.
Regardless of the cause, the process of myocyte death occurs as a wavefront. It is clear that by 20 min after occlusion (in animal models and likely in humans) some myocytes have died. Then the infarction spreads, usually from the subendocardium toward the epicardium. In experimental animals, infarction is complete in 3–4 h, and it is difficult to save myocardium after that time. In human patients, the time window for myocardial salvage is less clear because the time of onset is more difficult to delineate. Some antegrade flow may occur in many coronary arteries from subtotal occlusion or transient constriction and relaxation of the affected vessel, or myocyte viability may be sustained by collateral perfusion from other vessels. There appears to be some time (in general, perhaps as long as 12 h, and in some patients possibly even longer) during which it may be possible to modify the extent of the myocardial injury by increasing blood flow to the infarct area.

treatment chronic myiocard ischemic

A. GENERAL APPROACH

Because myocardial ischemia is produced by an imbalance between myocardial oxygen supply and demand, in general, treatment consists of increasing supply or reducing demand—or both. Heart rate is a major determinant of myocardial oxygen demand, and attention to its control is imperative. Any treatment that accelerates heart rate is generally not going to be efficacious in preventing myocardial ischemia. Therefore, care must be taken with potent vasodilator drugs, which may lower blood pressure and induce reflex tachycardia. Furthermore, because most coronary blood flow occurs during diastole, the longer the diastole, the greater the coronary blood flow; and the faster the heart rate, the shorter the diastole.
Blood pressure is another important factor: Increases in blood pressure raise myocardial oxygen demand by elevating left ventricular wall tension, and blood pressure is the driving pressure for coronary perfusion. A critical blood pressure is required that does not excessively increase demand, yet keeps coronary perfusion pressure across stenotic lesions optimal. Unfortunately, it is difficult to tell in any given patient what this level of blood pressure should be, and a trial-and-error approach is often needed to achieve the right balance. Consequently, it is prudent to reduce blood pressure when it is very high, and it may be important to allow it to increase when it is very low. It is not uncommon to encounter patients whose myocardial ischemia has been so vigorously treated with a combination of pharmacologic agents that their blood pressure is too low to be compatible with adequate coronary perfusion. In such patients, withholding some of their medications may actually improve their symptoms. Although myocardial contractility and left ventricular volume also contribute to myocardial oxygen demand, they are less important than heart rate and blood pressure. Myocardial contractility usually parallels heart rate. Attention should be paid to reducing left ventricular volume in anyone with a dilated heart, but not at the expense of excessive hypotension or tachycardia because these factors are more important than volume for determining myocardial oxygen demand.
It is important to eliminate any aggravating factors that could increase myocardial oxygen demand or reduce coronary artery flow (Table 3–3). Hypertension and tachyarrhythmias are obvious factors that need to be controlled. Thyrotoxicosis leads to tachycardia and increases in myocardial oxygen demand. Anemia is a common problem that increases myocardial oxygen demand because of reflex tachycardia; it reduces oxygen supply by decreasing the oxygen-carrying capacity of the blood. Similarly, hypoxia from pulmonary disease reduces oxygen delivery to the heart. Heart failure increases angina because it often results in left ventricular dilatation, which increases wall stress, and in excess catecholamine tone, which increases contractility and produces tachycardia.

Table 3–3. Factors that can aggravate myocardial ischemia.

The long-term outlook for patients with coronary atherosclerosis must be addressed by reducing their risk factors for the disease. Once a patient is known to have atherosclerosis, risk-factor reduction should be fairly vigorous: If diet has not reduced serum cholesterol, strong consideration should be given to pharmacologic therapy because it has been shown to reduce cardiac events. Patients should be encouraged to exercise, lose weight, quit smoking, and try to reduce stress levels. Daily low-dose aspirin is important for preventing coronary thrombosis. The use of megadoses of vitamin E, b-carotene, and vitamin C should be discouraged in the patient with known coronary atherosclerosis because clinical trials have not demonstrated efficacy.
B. PHARMACOLOGIC THERAPY

1. Nitrates—Nitrates, which work on both sides of the supply-and-demand equation, are the oldest drugs used to treat angina pectoris (Table 3–4). These agents are now available in several formulations to fit the patient’s lifestyle and disease characteristics. Almost all patients with known coronary atherosclerosis should carry sublingual nitroglycerin to abort acute attacks of angina pectoris. Nitrates work principally by providing more nitrous oxide to the vascular endothelium and the arterial smooth muscle, resulting in vasodilation. This tends to ameliorate any increased coronary vasomotor tone and dilate coronary obstructions. As long as blood pressure does not fall excessively, nitrates increase coronary blood flow. Nitrates also cause venodilation, reducing preload and decreasing left ventricular end-diastolic volume. The reduced left ventricular volume decreases wall tension and myocardial oxygen demand.

Table 3–4. Common oral antianginal drugs.

Sublingual nitroglycerin takes 30–60 s to dissolve completely and begin to produce beneficial effects, which can last up to 30 min. Although most commonly used to abort acute attacks of angina, the drug can be used prophylactically if the patient can anticipate its need 30 min prior to a precipitating event. Prophylactic therapy is best accomplished, however, with longer acting nitrate preparations. Isosorbide dinitrate and mononitrate are available in oral formulations; each produces beneficial effects for several hours. Large doses of these agents must be taken orally to overcome nitrate reductases in the liver. Liver metabolism of the nitrates can also be avoided with cutaneous application. Nitroglycerin is available as a topical ointment that can be applied as a dressing; it is also available as a ready-made, self-adhesive patch that delivers accurate continuous dosing of the drug through a membrane. Although the paste and the patches produce similar effects, the patches are more convenient for patients to use.
Sublingual nitroglycerin tablets are extremely small and difficult for patients with arthritis to manipulate. A buccal preparation of nitroglycerin is available, which comes in a larger, more easily manipulable tablet that can be chewed and allowed to dissolve in the mouth, rather than being swallowed. This achieves nitrate effectiveness within 2–5 min and lasts about 30 min, as do the sublingual tablets. An oral nitroglycerin spray, which may be easier to manipulate and more convenient for some patients, is also available.
The major difficulty with all long-acting nitroglycerin preparations is the development of tolerance to their effects. The exact reason for tolerance development is not clearly understood, but it may involve liver enzyme induction or a lack of arterial responsiveness because of local adaptive factors. Regardless of the mechanism, however, round-the-clock nitrate administration will lead to progressively increasing tolerance to the drug after 24–48 h. Because of this, nitroglycerin is usually taken over the 16-h period each day that corresponds to the time period during which most of the ischemic episodes would be expected to occur. For most patients, this means not taking nitrate preparations before bed and allowing the ensuing 8 h for the effects to wear off and responsiveness to the drug to be regained. This timing would have to be adjusted for patients with nocturnal angina. The difficulty with the 8-h overnight hiatus in therapy, however, is that the patient has little protection during the critical early morning wakening period—when ischemic events are more likely to occur. Patients should therefore take the nitrate preparation as soon as they arise in the morning. For this reason, the nitroglycerin patches have a small amount of paste on the outside of the membrane that delivers a bolus of drug through the skin, which quickly elevates the patient’s blood level of the drug. It is important that the patient be careful not to wipe this paste off the patch before applying it.
Nitrates, which are effective in preventing the development of angina as well as aborting acute attacks, are helpful in both patients with fixed coronary artery occlusions and those with vasospastic angina. Their potency, compared with other agents, is limited, however, and patients with severe angina often must turn to other agents. In such patients, nitrates can be excellent adjunctive therapy.
2. Beta-blockers—Beta-adrenergic blocking agents are highly effective in the prophylactic therapy of angina pectoris. They have been shown to reduce or eliminate angina attacks and prolong exercise endurance time in double-blind, placebo-controlled studies. They can be used around the clock because no tachyphylaxis to their effects has been found. Beta-blockers mainly work by lowering myocardial oxygen demand through decreasing heart rate, blood pressure, and myocardial contractility. As mentioned earlier, however, they also increase myocardial oxygen supply by increasing the duration of diastole through heart rate reduction. Currently, several b-blocker preparations are available, with one or more features that may make them more—or less—attractive for a particular patient.
Among these features is the agent’s pharmacologic half-life, which ranges from 4 to 18 h. Various delivery systems have been developed to slow down the delivery of short-acting agents and prolong the duration of drug activity through sustained release or long-acting formulations. Note that the pharmacodynamic half-life of b-adrenergic blockers is often longer than their pharmacologic half-life, and drug effects can be detected for days after discontinuation of chronic b-blocker therapy.
Ideally, b-blockers should be titrated against the heart rate response to exercise because blunting of the exercise heart rate response is the hallmark of their efficacy. Adverse effects of b-blockers include such expected pharmacologic effects as excessive bradycardia, heart block, hypotension, and—in susceptible individuals—bronchospasm. This is less commonly found in the b1-selective agents. Blocking b2-peripheral vasodilatory actions may aggravate claudication in patients with severe peripheral vascular disease. Beta-adrenergic stimulation is also important for the gluconeogenic response to hyperglycemia in severely insulin-dependent diabetics. Although b-blockers may impair this response, the major problem with their use in insulin-dependent diabetics is that they block the warning signals of hypoglycemia (sweating, tachycardia, piloerection) to the patient. Because of their negative inotropic properties, b-blockers may also precipitate heart failure in patients with markedly reduced left ventricular performance.
Other side effects of b-blockers are less predictably related to their anti-b-adrenergic effects. Adverse central nervous system effects are especially troublesome and include fatigue, mental slowness, and impotence. These side effects are somewhat less common with agents that are less lipophilic, such as atenolol and nadolol. Unfortunately, it is these side effects that make many patients unable to tolerate b-blockers.
3. Calcium channel antagonists—Calcium channel antagonists theoretically work on both sides of the supply-and-demand equation. By blocking calcium access to smooth muscle cells, they produce peripheral vasodilatation and are effective antihypertensive agents. In the myocardium, they block sinus node and atrioventricular node function and reduce the inotropic state. They dilate the coronary arteries and increase myocardial blood flow. The calcium blockers available today produce a variable spectrum of these basic pharmacologic effects. The biggest group is the dihydroperidine calcium blockers, which are potent arterial dilators and thereby cause reflex sympathetic activation, which overshadows their negative chronotropic and inotropic effects.
A second major group of calcium blockers are the heart rate-lowering calcium blockers. Because these drugs have less peripheral vasodilatory action in individuals with normal blood pressure, they produce little reflex tachycardia. The average daily heart rate is usually reduced with these agents because their inherent negative chronotropic effects are not suppressed; negative inotropic effects are also more common with these agents. Hypertensive and normotensive individuals seem to have a different vascular responsiveness to calcium blockers; interestingly, in hypertensive individuals, they lower the blood pressure as well as do the dihydroperidine agents. The two most commonly used drugs in this class are diltiazem and verapamil. Diltiazem is more widely used because of its low side effect profile. Verapamil, which is an excellent treatment for patients with supraventricular arrhythmias, has potent effects on the arteriovenous (AV) node; this can cause excessive bradycardia and heart block in patients with angina pectoris. Verapamil is also more likely than diltiazem to precipitate heart failure, and it often produces troublesome constipation, especially in elderly individuals. All the calcium blockers can produce peripheral edema. This is due not to their negative inotropic effects but rather to an imbalance between the efferent and afferent peripheral arteriolar tone, which increases capillary hydrostatic pressure. Other adverse effects of these drugs are idiosyncratic and include gastrointestinal and dermatologic effects.
Calcium blockers are titrated to the patient’s symptomatology because no physiologic marker of their effect corresponds well to the heart rate response to exercise with b-blockers. This makes choosing the appropriate dosage difficult, and many physicians increase the dose until some side effect occurs, and then they reduce it. The most common side effects are related to the pharmacologic effects of the drugs. With the dihydroperidines, vasodilatory side effects such as orthostatic hypotension, flushing, and headache, occur. Hypotension is less common with the heart rate-lowering calcium blockers, and their side effects are more related to cardiac effects such as excessive bradycardia. These drugs are very useful because they are excellent for preventing angina pectoris, lowering high blood pressure, and, in the case of the heart rate-lowering agents, controlling supraventricular arrhythmias.
4. Combination therapy—Although monotherapy is desirable for patient convenience and cost considerations, many patients, especially those with severe inoperable coronary artery disease, require more than one antianginal agent to control their symptoms. Because all antianginal agents have a synergistic effect in preventing angina, the initial choices should be for agents with complementary pharmacologic effects. For example, nitrates can be added to b-blocker therapy: Nitrates have an effect on dilating coronary arteries and increasing coronary blood flow, and their peripheral effects may increase reflex sympathetic tone and counteract some of the negative inotropic and chronotropic effects of the b-blockers. This has proved to be a highly effective combination. Similarly, combining a b-blocker with dihydroperidine drugs, when the b-blockers suppress the reflex tachycardia produced by the dihydroperidine, has also proved to be highly effective. Combinations of the heart rate-lowering calcium blockers and nitrates have also proved efficacious. Extremely refractory patients may respond to the combination of a dihydroperidine calcium blocker and a heart rate-lowering calcium blocker.
Combining a dihydroperidine calcium blocker and nitrates makes little sense, however, because of the high likelihood of producing potent vasodilatory side effects. This combination may excessively lower blood pressure to the point that coronary perfusion pressure is compromised and the patient’s angina actually worsens. In fact, in as many as 10% of patients with moderately severe angina, both the nitrates and the dihydroperidine calcium blockers alone have been reported to aggravate angina. Although few corroborative data exist, this percentage is certainly higher with the combination of the two agents.
The most difficult cases often involve triple therapy, with a calcium blocker, a b-blocker, and a nitrate. Although there are few objective data on the benefits of this approach, it has proven efficacious in selected patients. The major problem with triple therapy is that side effects, such as hypotension, are increased, which often limits therapy.
Gibbons RJ, Chaterjee K, Daley J et al: ACC/AHA/ACP-ASIM Guidelines for the management of patients with chronic stable angina: A report of the American College of Cardiology/American Heart Association task force on practice guidelines (Committee on Management of Patients with Chronic Stable Angina). J Am Coll Cardiol 1999;3:2092.
Opie LH: Calcium channel antagonists in the treatment of coronary artery disease: fundamental pharmacological properties relevant to clinical use. Prog Cordiovasc Dis 1996;38:273.
Pitt B, Waters D, Brown WV et al. Aggressive lipid-lowering therapy compared with angioplasty in stable coronary artery disease. N Engl J Med 1999;341:70–76.
Thadani U: Management of stable angina pectoris. Prog Cardiovasc Dis1999;14:349–358.
C. REVASCULARIZATION

1. Catheter-based methods—The standard percutaneous coronary intervention (PCI) is balloon dilatation with placement of a metal stent. Such treatment is limited to the larger epicardial arteries and can be complicated by various types of acute vessel injury, which can result in myocardial infarction unless surgical revascularization is immediately employed. Smaller arteries may be amenable to plain old balloon angioplasty (POBA), and large arteries with complicated lesions may be candidates for other forms of PCI. PCI requires intense antiplatelet therapy usually with aspirin and clopidogrel for a month to prevent stent thrombosis. After the stent has been covered with endothelium this risk is much less.
In the absence of acute complications, initial success rates for significantly dilating the coronary artery are > 85%, and the technique can be of tremendous benefit to patients—without their undergoing the risk of cardiac surgery. The principal disadvantage to PCI is restenosis, which occurs in about one-fourth of patients during the first 6 months. Repeat PCI can be as effective as initial PCI, but, again, the restenosis rate remains around one fourth; however, a second PCI can result in a long-term success. Although many agents are under intense investigation, there is currently no pharmacologic approach to preventing restenosis.
PCI is ideal for symptomatic patients with one or two discrete lesions in one or two arteries. In patients with more complex lesions or those with three or more vessels involved bypass surgery is preferable for several reasons. First, the restenosis risk is the same for each lesion treated by PCI, so that if enough vessels are worked on the risk of restenosis in one of them will approach 100%. Second, the ability to completely revascularize patients with multivessel disease is less with PCI compared with bypass surgery. Finally, clinical trials have shown that diabetics have better outcomes after bypass surgery relative to PCI.
2. Coronary artery bypass graft surgery—Controlled clinical trials have shown that coronary artery bypass graft (CABG) surgery can successfully alleviate angina symptoms in up to 80% of patients. These results compare very favorably with pharmacologic therapy and catheter-based techniques and can be accomplished in selected patients with less than 2% operative mortality rates. Although the initial cost of surgery is high, studies have shown it can be competitive with repeated angioplasty and lifelong pharmacologic therapy in selected patients.
The standard surgical approach is to use the saphenous veins, which are sewn to the ascending aorta and then, distal to the obstruction, in the coronary artery, effectively bypassing the obstruction with blood from the aorta. Although single end-to-side saphenous-vein-to-coronary-artery grafts are preferred, occasionally surgeons will do side-to-side anastomoses in one coronary artery (or more) and then terminate the graft in an end-to-side anastomosis in the final coronary artery. There is some evidence that although these skip grafts are easier and quicker to place than multiple single saphenous grafts, they may not last as long. The major problem with saphenous vein grafts is recurrent atherosclerosis in the grafts, which is often quite bulky and friable, and ostial stenosis, probably from cicatrization at the anastomotic sites. Although these problems can be approached with PCI and other interventional devices, the success rate of catheter-delivered devices to open obstructed saphenous vein grafts is not as high as that seen with native coronary artery obstructions, and many patients require repeat saphenous vein grafting after an average of about 8 years. It is believed that meticulous attention to a low-fat diet, cessation of smoking, and the ingestion of one aspirin a day (80–325 mg) will retard the development of saphenous vein atherosclerosis; some patients do well for 20 years or more after CABG.
There is now considerable evidence that arterial conduits make better bypass graft materials. The difficulty is finding large enough arteries that are not essential to other parts of the body. The most popular arteries used today are the internal thoracic arteries. Their attachment to the subclavian artery is left intact, and the distal end is used as an end-to-side anastomosis into a single coronary artery. If a patient requires more than two grafts, some surgeons, rather than using a saphenous vein, have employed the radial artery or abdominal vessels, such as the gastroepiploic. There are less data on these alternative conduits, but theoretically they would have the same advantages as the internal thoracic arteries in terms of graft longevity. Efforts at preventing bypass graft failure are worthwhile because the risk of repeat surgery is usually higher than that of the initial surgery. There are several reasons for this, including the fact that the patient is older, the scar tissue from the first operation makes the second one more difficult, and finally, any progression of atherosclerosis in the coronary arteries makes finding good-quality insertion sites for the graft more difficult.
D. SELECTION OF THERAPY

Pharmacologic therapy is indicated when other conditions may be aggravating angina pectoris and can be successfully treated. For example, in the patient with coexistent hypertension and angina, it is often prudent to treat the hypertension and lower blood pressure to acceptable levels before pursuing revascularization for angina, because lowering the blood pressure will often eliminate the angina. For this purpose, it is wise to use antihypertensive medications that are also antianginal (eg, b-blockers, calcium channel blockers) rather than other agents with no antianginal effects (eg, angiotensin-converting enzyme (ACE) inhibitors, centrally acting agents). The presence of heart failure can also produce or aggravate angina, and this should be treated. Care must be taken in choosing antianginal drugs that they do not aggravate heart failure. For this reason, nitrates are frequently used in heart failure and angina because these drugs may actually benefit both conditions. Calcium channel blockers should be avoided if the left ventricular ejection fraction is below 35%, unless it is clear that the heart failure is episodic and is being produced by ischemia. In this situation, however, revascularization may be a more effective strategy. Beta-blockers can be effective, but they must be started at low doses and uptitrated carefully. Although beta blockers are now part of standard therapy for heart failure, there is little data on their use in patients with angina and reduced left ventricular performance. Finally, the presence of ventricular or supraventricular tachyarrhythmias may aggravate angina. Rhythm disorders also afford an opportunity for using dual-purpose drugs. The heart rate-lowering calcium blockers may effectively control supraventricular arrhythmias and also benefit angina. Beta-blockers can often be effective treatment for ventricular arrhythmias in patients with coronary artery disease and should be tried before other, more potent antiarrhythmics or devices are contemplated. Keep in mind that digoxin blood levels may be increased by concomitant treatment with calcium blockers. In addition, the combination of digoxin and either heart rate-lowering calcium blockers or b-blockers may cause synergistic effects on the AV node and lead to excessive bradycardia or heart block.
The major indication for revascularization of chronic ischemic heart disease is the failure of medications to control the patient’s symptoms. Drug-refractory angina pectoris is the major indication for revascularization. Note that myocardial ischemia should be established as the source of the patient’s symptoms before embarking on revascularization, lest one find out after revascularization that the symptoms were actually due to gastroesophageal reflux. Consequently, some form of stress testing that verifies the relationship between demonstrable ischemia and symptoms is advisable before performing any revascularization procedure.
In some other instances—patient preference, for example—revascularization therapy might be considered before even trying pharmacologic therapy. Some patients do not like the prospect of lifelong drug therapy and would rather have open arteries. Although this is a valid reason to perform revascularization, the physician must be careful that his or her own enthusiasm for revascularization as treatment does not pressure the patient into such a decision. Other candidates for direct revascularization are patients with high-risk occupations who cannot return to these occupations unless they are completely revascularized (eg, airline pilots).
Revascularization is preferred to medical therapy in managing certain types of coronary anatomy that are known (through clinical trials) to have a longer survival if treated with CABG rather than medically. Such lesions include left main obstructions of more than 50%, three-vessel disease, and two-vessel disease in which one of the vessels is the left anterior descending artery. Currently, left main stenoses are not effectively treated with catheter-based techniques, but two- and three-vessel coronary disease could potentially be treated by PCI. Clinical trials have shown equivalent long-term outcomes between PCI and CABG in patients with multivessel disease.
CABG is also recommended for patients with two- or three-vessel coronary artery disease and resultant heart failure from reduced left ventricular performance, especially if viable myocardium can be demonstrated. Because the tests for viable myocardium are not perfect, however, many physicians believe that all these patients should be revascularized in the hope that some myocardial function will return. This seems a prudent approach, given that donor hearts for cardiac transplantation are difficult to obtain—and many patients with heart failure and coronary artery disease improve following bypass surgery.
Surgery is also recommended when the patient has a concomitant disease that requires surgical therapy, such as significant valvular heart disease, heart failure in the presence of a large left ventricular aneurysm, or mechanical complications of myocardial infarction, such as a ventricular septal defect. In the presence of hemodynamic indications for repairing these problems, any significant coronary artery disease that is found should be corrected with bypass surgery at the same time.
The risk of bypass surgery in a given individual must also be considered because several factors can increase the risk significantly and might make catheter-based techniques or medical therapy more desirable. Age is always a risk factor for any major surgery, and CABG is no exception. Also, female gender tends to increase the risk of CABG, possibly because women are, on the average, smaller and have smaller arteries than men. Some data indicate that if size is the only factor considered, gender disappears as a risk predictor with CABG. Other medical conditions that may complicate the perioperative period (eg, obesity, lung disease, diabetes) also raise the risks of surgery. Another factor (discussed earlier) is whether this is a repeat bypass operation. The technical difficulties are especially troublesome when a prior internal thoracic artery graft has been placed because this artery lies right behind the sternum and can be easily compromised when opening the chest.
The choice between catheter-based techniques and CABG surgery is based on several considerations: Is it technically feasible to perform either technique with a good anticipated result? What does the patient wish to do? The patient may have a strong preference for one technique over the other. Again, the physician must be careful not to unduly influence the patient in this regard, lest it give the appearance of a conflict of interest. Consideration must also be given to factors that increase the risk of surgery. The most difficult decision involves the patient who is suitable for either surgery or a catheter-based technique. The few controlled, randomized clinical trials that have been done on such patients have shown equivalent clinical results with PCI and surgery in terms of mortality and symptom relief. Note that this is accomplished by PCI at the cost of repeated procedures in many patients. Despite the necessity for these repeated procedures, the overall cost of bypass surgery is higher over the short term. Unfortunately, the trials do not leave us with clear guidelines for choosing PCI or CABG in the patient who is a good candidate for either treatment; this continues to be a decision to be made by the physician and the patient on a case-by-case basis.