Ischemic Heart Disease

III. Ischemic Heart Disease
A. Atherosclerotic coronary artery disease (ASCAD)
1. Definition. ASCAD is the focal narrowing of the coronary arteries as a result of a plaque composed of:
a. Lipids (cholesterol esters and crystals), which are deposited at the center of the plaque and accumulate within macrophages
b. Intimal secretory smooth muscle cells, which proliferate
c. A fibrous cap made of connective tissue
2. Incidence and risk factors. Currently in the United States, the overall incidence of death as a result of ASCAD is 0.5 in 1,000 and decreasing. However, ASCAD differs in frequency in subpopulations with the following risk factors:
a. Age. The incidence of ASCAD increases progressively with age. The risk of death is 1.5 in 1,000 individuals at age 50.
b. Gender. ASCAD is more prevalent in men than in women. This difference is most marked in premenopausal women compared with men of similar age. By the time men reach the age of 50 years, they are affected five times more often than women of the same age. This difference declines as age increases.
c. Serum cholesterol. The incidence of ASCAD increases with increasing total serum cholesterol levels (Online Figure 1-5).


ONLINE FIGURE 1-5 Graph showing the effect of increasing serum cholesterol concentration on the incidence of atherosclerotic coronary artery disease in men age 30–49 years. (Adapted from Cohn PF: Diagnosis and Therapy of Coronary Artery Disease. Boston: Little, Brown, 1979:27.)






(1) Total serum cholesterol is carried in the blood by low-density lipoprotein (LDL), very low-density lipoprotein (VLDL), and high-density lipoprotein (HDL).
(a) The higher the percentage of total cholesterol carried by LDL in relation to HDL, the higher the risk of ASCAD. High levels of HDL seem to be protective.
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(b) Total cholesterol level should be less than 200 mg/dL.
(i) The LDL cholesterol level should be less than 130 mg/dL; in patients with known coronary disease, it should be less than 100 mg/dL. In high-risk patients, consider lowering to 70 mg/dL.
(ii) The HDL cholesterol level should exceed 40 mg/dL.
(2) Several types of hyperlipidemia exist, and many are associated with an increased incidence of coronary artery disease. Online Table 1-2 presents an overview of the hyperlipidemias.

ONLINE TABLE 1-2 The Hyperlipidemias
Type of Hyperlipidemia Lipid Lipoprotein Clinical
Abnormality Abnormality Manifestations Therapy
I Lipoprotein lipase deficiency ↑Triglycerides ↑Chylomicrons Pancreatitis
Eruptive xanthomas
Lipemia retinalis Fat-free diet
IIa LDL receptor deficiency ↑Cholesterol ↑LDL Coronary disease
Tendon xanthomas
Xanthelasma Restricted diet
Bile acid binding resins
Nicotinic acid
HMG-CoA reductase inhibitors
IIb Cholesterol
Triglycerides LDL
VLDL Coronary disease Restricted diet
Bile acid–binding resins
Nicotinic acid
Gemfibrozil
HMG-CoA reductase inhibitors
III Dysbetalipoproteinemia Triglycerides
Cholesterol VLDL Remnants
VLDL Palmar fatty streaks
Tuberous xanthomas
Coronary disease
Peripheral vascular disease
Hypothyroidism Gemfibrozil
IV Triglycerides VLDL Eruptive xanthomas
Pancreatitis
Diabetes
Coronary artery disease Restricted diet
Gemfibrozil
V Triglycerides Chylomicrons Eruptive xanthomas
Pancreatitis
Diabetes
Coronary artery disease Restricted diet
Gemfibrozil
HMG-CoA, hydroxy-methylglutaryl coenzyme A; LDL, low-density lipoproteins; VLDL, very-low-density lipoproteins.







d. Smoking. Compared with nonsmokers, cigarette smokers are 60% more likely to develop ASCAD when other risk factors are controlled for statistically. Smoking increases carbon monoxide levels in the blood, which may, in turn, damage the coronary endothelium. Smoking also increases platelet adhesiveness and thus the likelihood of thrombotic coronary occlusion.
e. Hypertension. The higher the systolic or diastolic blood pressure, the more likely the development of ASCAD. This likelihood is apparent in both men and women and becomes more pronounced with advancing age.
f. Diabetes mellitus is associated with a 50% increase in the incidence of ASCAD in men and a 100% increase in women. In light of this, diabetes mellitus should be considered an ASCAD equivalent.
g. Family history. A family history of premature heart disease is considered to be present when coronary artery disease has occurred in a first-degree male relative age 55 or younger or a female first-degree relative age 65 or younger. A familial predisposition to coronary artery disease exists in part due to inheritance of the above risk factors (except smoking). However, family history is the only risk factor in about one-third of individuals with ASCAD.
3. Pathogenesis (Online Figures 1-6 and 1-7). The previously mentioned risk factors do not constitute a known mechanism for ASCAD. The major theory of atherogenesis is the response to injury theory.


ONLINE FIGURE 1-6 Diagrammatic representation of an atherosclerotic plaque, showing its composition. The fibrous cap of the plaque is linked to clinical events because of its tendency to fracture and ulcerate. The necrotic core of the plaque has clinical consequence as a result of its size, consistency, and thromboplastic components. (Adapted from Braunwald E: Heart Disease. 2nd ed. Philadelphia: WB Saunders, 1984:1186.)


ONLINE FIGURE 1-7 Schematic evolution of the atherosclerotic plague. 1, Lipoprotein particles accumulate in the intima. The modification of these lipoproteins is depicted by the darker color. 2, Oxidative stress (including products found in modified lipoproteins) induce local cytokine elaboration. 3, The cytokines induce increased expression of molecules that direct their migration into the intima. 4, Blood monocytes enter the artery wall in response to chemoattractant cytokines such as monocyte chemoattractant protein 1 (MCP-1). They encounter stimuli such as macrophage colony stimulating factor (M-CSF) that augment their expression of scavenger receptors. 5, Scavenger receptors mediate the uptake of modified lipoprotein particles and promote development of foam cells. Foam cells produce cytokines and effector molecules including hypochlorous acid, superoxide anion (O2-), and matrix metalloproteinases. 6, Smooth muscle cells in the intima proliferate and other smooth muscle cells migrate into the intima from the media. 7, The smooth muscle cells elaborate extracellular matrix, promoting its accumulation in the growing atherosclerotic plaque. The fatty streak evolves into a fibrofatty lesion. 8, In later stages, calcification can occur (not depicted) and fibrosis continues, sometimes accompanied by smooth muscle cell death. The result is a relatively acellular capsule surrounding a lipid-rich core that may also contain dying or dead cells and their debris. LDL, low-density lipoprotein; IL-1, interleukin-1. (Modified from Zipes D, Libby P, Bonow RO, Braunmwald Ed, eds. Braunwald's Heart Disease: A Textbook of Cardiovascular Medicine. 7th ed. Philadelphia: Elsevier Saunders, 2005:925.)

a. This theory states that some injurious stimulus (e.g., hypertension or hypercholesterolemia) causes endothelial damage, resulting in the release of various growth factors. These growth factors cause smooth cell proliferation and migration of macrophages into the vessel wall. At the same time, the now injured endothelium becomes more permeable, admitting lipid and cholesterol into the intima.
b. These changes result in plaque formation, which may eventually compromise the vessel lumen enough to impede blood flow. If the plaque is disrupted, platelets are activated, leading to thrombus formation and worsening obstruction.
4. Pathophysiology of ischemia
a. Supply–demand relationship. As wall stress and heart rate increase (e.g., with exercise), myocardial oxygen consumption rises. Autoregulated increases in coronary blood flow normally meet this increased demand. However, if demand exceeds supply, ischemia results. The product of heart rate and left ventricular systolic pressure or wall stress roughly approximate the oxygen needs of the myocardium (see I B 1 b).
(1) Increased demand. In patients with ASCAD, stenosis of the coronary artery prevents the increase in coronary blood flow needed to compensate for an increased demand, resulting in an oxygen demand that exceeds the oxygen supply. Myocardial ischemia is the result of this imbalance.
(2) Reduced supply. Atherosclerotic stenosis was once viewed as a fixed obstruction to coronary blood flow. In fact, the diseased area of the coronary artery often remains dynamic, and the effective lumen of the artery undergoes constant change. Changes are produced by vasoconstriction of the coronary artery, by production and degradation of local thrombi at the site of stenosis, and by progressive enlargement of the atherosclerotic plaque. Acute changes in lumen diameter may reduce the supply of coronary blood flow and, thus, produce ischemia without an increase in demand.
b. Myocardial infarction (MI). The necrosis of myocardial tissue occurs as a result of prolonged ischemia. The rapidity and extent of the infarction process are determined by the extent of reduction of blood flow to the area. In some cases, collateral flow from other coronary arteries may supply enough blood flow to prevent infarction despite a total coronary occlusion.
(1) ST-segment elevation myocardial infarction (STEMI) is associated with occlusion of a coronary artery by a thrombus. Aggressive lysis of the thrombus with agents such as streptokinase and tissue plasminogen activator (t-PA) or balloon angioplasty can reestablish coronary blood flow, relieve pain, reestablish contractile function of the segment of myocardium supplied by the thrombosed artery, and reduce myocardial damage [see III A 5 b (4) (b) ii].
(2) Non STEMI (NSTEMI) is due to severe coronary artery obstruction without total occlusion.
5. Clinical consequences. Atherosclerotic plaques may produce stable angina or an acute coronary syndrome (ACS) (unstable angina, NSTEMI, or STEMI).
a. Angina pectoris is chest pain or pressure produced by myocardial ischemia.







(1) Characteristic features
(a) Relation to exertion. The single most important feature of angina pectoris is its precipitation by exertion. Exertion increases myocardial oxygen demand beyond the supply capabilities of diseased coronary arteries, producing ischemia. Other factors that increase myocardial oxygen demand (e.g., emotional upset, eating a meal, or the peripheral vasoconstriction caused by walking in cold weather) also may precipitate angina.
(b) Quality of pain. Although many patients perceive angina as chest pain, others report a feeling of pressure in the chest area or complain of a burning sensation. In some patients, exertional dyspnea may represent an anginal equivalent.
(c) Radiation of pain. Radiation of anginal pain to the left arm is well known. Pain also may radiate to the right arm, jaw, teeth, or throat. Occasionally, these radiation sites may be the only sites of pain, and the chest is free of discomfort; or the chest discomfort, when present, may not radiate at all.
(d) Progression of ischemia and duration of symptoms. Whatever the anginal symptom quality for a given patient, repeated episodes of ischemia usually reproduce that same quality. The symptom complex usually begins at a low intensity, increases over 2–3 minutes, and lasts a total of less than 15 minutes. Episodes longer than 30 minutes suggest that MI may have occurred.
(2) Types of ischemic episodes
(a) Chronic stable angina is angina that recurs under similar circumstances and with a similar frequency over time.
(b) Unstable angina (UA) is a term applied to angina when a change in status occurs (e.g., new-onset angina; angina of increasing severity, duration, or frequency; or angina occurring at rest for the first time). It represents a more serious clinical situation than chronic stable angina because unstable angina indicates a progression of disease and may be an immediate precursor of MI.
(i) Rest angina. Angina at rest is particularly worrisome because it implies that decreased supply, rather than increased demand, is causing the angina. This concept in turn suggests that arterial occlusion and possible infarction may be imminent.
(ii) New-onset angina. In cases of new-onset angina, it is difficult to generalize about clinical outcome. New-onset angina that progresses in frequency, severity, or duration over 1 or 2 months is worrisome. Conversely, some cases of new-onset angina may simply be the first episode in what becomes a chronic stable anginal pattern.
(c) Variant (Prinzmetal's) angina
(i) The hallmark of variant angina is the appearance of transient ST-segment elevation on the ECG during the angina attack. The ST-segment elevation represents transmural ischemia produced by a sudden reduction in coronary blood flow.
(ii) The reduction in flow results from transient coronary spasm, which may or may not be associated with a fixed atherosclerotic lesion. The spasm produces total but transient coronary occlusion.
(iii) Variant angina usually occurs at rest (often at night), and episodes frequently are complicated by complex ventricular arrhythmias.
(3) Diagnosis. When a patient exhibits chest pain characteristic of angina, the diagnosis can be suspected strongly on the basis of patient history alone. The suspicion that coronary disease is present is heightened by the presence of one or more coronary risk factors.
(a) Physical examination. Patients experiencing an episode of angina are usually uncomfortable and anxious. Blood pressure and pulse rate are increased in most cases.
(b) Resting electrocardiography. The ECG taken in the absence of pain in patients with angina pectoris with no history of MI is normal in 50% of cases. Every effort should be made to obtain an ECG while the patient is experiencing chest pain.
(i) The presence of new horizontal or downsloping ST segments on the ECG is highly suggestive of myocardial ischemia. New T-wave inversion also may occur, but this finding alone without ST segment depression is less specific.






(ii) In the presence of variant angina, an acute current of injury indicated by transient ST segment elevation is diagnostic. The ST segment elevation normalizes as the pain wanes and no Q waves appear.
(c) Stress electrocardiography. Recording the ECG during exercise substantially increases the sensitivity and specificity of electrocardiography. In addition, a formal exercise test permits quantification of the patient's exercise tolerance and observation of the effects of exercise on the patient's symptoms, heart rate, and blood pressure.
(i) The appearance of horizontal or downsloping ST-segment depression of 1 mm or more during exercise has a sensitivity of approximately 70% and a specificity of 90% for the detection of coronary disease.
(ii) The ST criteria for positivity are less accurate in women than in men. An abnormal ST segment on a resting ECG, as seen in left bundle branch block, left ventricular hypertrophy, or the use of digoxin by the patient all reduce the accuracy of this test.
(d) Stress scintigraphy, when used in combination with the stress ECG, has yielded increased sensitivity (80%) and specificity (92%) over the standard stress ECG alone. Therefore, it is a particularly useful diagnostic tool when the standard stress ECG is expected to be of low yield (e.g., in women and in patients with bundle branch block) and in patients in whom a previous stress ECG has produced equivocal results.
(i) Method. When the radioactive isotope thallium 201 (201TI) or the technetium-based isonitrile sestamibi is injected into the peripheral venous blood, the myocardial distribution of the substance is affected by blood flow and ischemia, with areas of less blood flow and ischemia taking up less 201TI or sestamibi than areas of normal blood flow. With exercise, blood flow increases, but in patients with coronary artery disease, those parts of the myocardium supplied by diseased coronary arteries and areas of MI take up less 201TI or sestamibi than normal areas, as shown in the scintigram in Online Figure 1-8. In patients who are unable to exercise, infusion of dobutamine (to increase oxygen demand) or dipyridamole or adenosine (to cause coronary vasodilation) are used to alter coronary flow.


ONLINE FIGURE 1-8 Single Photon Emission Computed Tomography (SPECT) images of myocardial perfusion utilizing a radio-labeled tracer were obtained at peak stress (top rows) and at rest (matched bottom rows). Tomographic “slicesâ€‌ of the heart were obtained in three axes (from top to bottom): short axis images “slicingâ€‌ from apex to base; vertical long-axis images “slicingâ€‌ from septum to lateral wall; and horizontal long axis images “slicingâ€‌ from posterior to anterior. The image in (A) demonstrates matched perfusion of all segments at both peak stress and at rest. This would be considered an example of a “normalâ€‌ myocardial perfusion stress test. The image in (B) demonstrates a relatively photopenic region on the peak stress images involving the interventricular septum, anterior wall and apex. This defect normalizes on the rest images, and would be termed a â€کreversible’ defect, which is characteristic of ischemia. The patient had severe proximal left anterior descending stenosis on angiography.






(e) Stress echocardiography. Two-dimensional echocardiography can detect regional ischemia by identifying areas of wall motion abnormalities that occur with stress and are not present at rest. This regional dysfunction indicates that the area involved is not receiving adequate blood flow. The sensitivity is similar to radionucleotide imaging.
(f) Cardiac catheterization with coronary arteriography allows for direct visualization of the coronary arteries by selective injection of radiographic contrast material. This procedure is the most sensitive and specific test commonly used for coronary artery disease.
(i) Risk. Unlike the previously mentioned tests, cardiac catheterization is an invasive procedure that carries a small but finite risk. The overall risk of mortality during coronary arteriography is approximately 0.2%.
(ii) Applications. Cardiac catheterization should be reserved for cases in which the diagnosis is uncertain after noninvasive testing, when more information is needed to help determine whether medical or surgical therapy is most appropriate for the patient's coronary disease, or when intervention is necessary, as in patients with acute STEMI or UA. If surgery is contemplated, the arteriograms obtained at catheterization guide the surgeon's placement of the bypass grafts.
(g) Cardiac computed tomography (CT). An emerging and potentially powerful tool for detecting coronary artery disease is cardiac CT. The role of this modality has not yet been clearly established.
(4) Therapy. Treatment of angina pectoris is directed either at reducing myocardial oxygen demand to compensate for impaired flow through diseased coronary arteries or at increasing myocardial oxygen supply (i.e., blood flow).
(a) Nitrates. This class of drugs produces venodilation and, to a lesser extent, arteriolar vasodilation. They may increase coronary blood flow and decrease myocardial oxygen demand by decreasing preload and afterload.
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(b) خ²-Adrenergic blocking agents. خ²-Adrenergic receptor stimulation results in an increase in heart rate and in the force of myocardial contraction. Both events increase myocardial oxygen demand. خ²-blockers counteract these effects and reduce myocardial oxygen demand.
(c) Calcium channel blockers. Calcium regulates the contraction of smooth muscle, which is present in the walls of the coronary and peripheral arteries. Calcium channel blockers are particularly effective in preventing the coronary spasm that causes variant angina. They are also useful in treating cases of typical angina, in which they act as coronary and peripheral arterial vasodilators. The nondihydropyridine calcium channel blockers, diltiazem and verapamil, also reduce heart rate and all calcium channel blockers may decrease blood pressure.
(d) Percutaneous coronary intervention (PCI). Removing or reducing the obstructive coronary atherosclerotic lesion can alleviate the angina.
(i) During angioplasty, a small balloon is inserted into a femoral or brachial artery and guided to the obstruction of the affected coronary artery. The balloon is inflated, dilating the stenosis and reducing the obstruction.
(ii) The initial success rate of simple balloon angioplasty approaches 90%, although there is a 33% restenosis rate after 6 months, making it necessary to repeat the procedure in some patients. Placement of small wire stents reduces the rate of restenosis and now accompanies the majority of angioplasties. Today some stents are coated with sirolimus or paclitaxel, which reduces the restenosis rate to approximately 5%. Co-administration of abciximab, a IIb–IIIa platelet receptor antibody, or eptifibatide, a IIb–IIIa receptor antagonist, also enhances short- and long-term patency. The use of a thienopyridine, such as clopidogrel, is essential after stenting to prevent acute thrombosis.
(e) Coronary artery bypass grafting (CABG). CABG extends survival in patients with severe left main coronary artery disease or patients with severe three-vessel disease and depressed left ventricular function. There is continued debate regarding the role of CABG versus multivessel PCI in patients with severe multivessel disease and normal left ventricular function. CABG may be preferable in diabetic patients with multivessel disease that includes the left anterior descending artery.
(f) Refractory angina. Several new therapies have emerged for treatment of refractory angina including transmyocardial laser revascularization, enhanced extracorporeal counter pulsation, and ranolazine. These methods can be considered in patients who continue to experience angina despite maximal treatment on conventional medical therapy and revascularization.






b. Myocardial infarction (MI) occurs when the myocardium is deprived of its blood supply (and therefore, oxygen) for a significant amount of time.
(1) Pathogenesis. An abrupt change in the atherosclerotic plaque seems to be one of the events precipitating an MI. Plaque rupture attracts platelets that trigger thrombus formation, leading to severe stenosis or total occlusion of the vessel.
(2) Symptoms. The patient usually experiences severe, oppressive chest pain or pressure that persists for more than 30 minutes and is unrelieved by nitroglycerin. The pain radiates in a pattern similar to that of angina pectoris.
(a) Frequently, nausea, vomiting, diaphoresis, and shortness of breath accompany the pain.
(b) An unusually large number of infarctions occur between 6 A.M. and 10 A.M., when catecholamine levels increase on awakening.
(3) Diagnosis
(a) Physical examination. The patient experiencing MI is in obvious pain, is quite apprehensive, and often appears ashen. If the infarction is extensive, hypotension and tachycardia may be present. There also may be signs of CHF (e.g., elevation of the neck veins, pulmonary rales, and a cardiac gallop rhythm). The new murmur of mitral regurgitation may be present.
(b) Electrocardiography. The ECG is diagnostic in approximately 85% of cases. The remaining 15% of patients may experience MI without manifesting clear-cut evidence on the ECG.
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(i) STEMI is demonstrated by ST-segment elevation in those leads reflecting the area of the MI. As the ST segments fall, Q waves appear, and the T waves become inverted (online Figure 1-9).
Online Figure 1-9 Sequence of ECG changes during the evolution of a myocardial infarct.
A. Smoothing of ST segment and T waves, making it difficult to see where one ends and the other begins.

B. Straightening of the ST segment, losing the upward concavity.
C. Elevation of the straightened ST segment.
D. ST elevation may also occur without loss of the upward concavity.
E. Inversion of the T waves with concave downward ST segments.
F. Development of Q waves with inverted T waves. The ST segment remains elevated and concave downward.






(ii) NSTEMI will have less specific findings, such as ST depression or T-wave inversion.
(c) Cardiac enzyme studies
(i) As myocardial necrosis occurs, the myocardium releases creatine kinase (CK), including the MB isoform, and troponins, thereby increasing serum concentrations of these enzymes.
(ii) CK and troponin elevation appear 3 hours after infarction. CK and CK-MB usually return to baseline within 2 days, but troponin may remain elevated for up to 10 days following an MI.
(4) Therapy
(a) Initial medical therapy. For patients presenting with either an STEMI or NSTEMI, several medical therapies should be initiated, providing there are no contraindications.
(i) Aspirin should be given immediately to block platelet aggregation.
(ii) Oxygen should be delivered to ensure adequate oxygenation of tissues.
(iii) Nitroglycerin can alleviate pain by vasodilation, which increases blood flow, thereby decreasing oxygen demand and coronary vasospasm.
(iv) Heparin should be started intravenously to decrease further clot formation. IV heparin is preferred for STEMI, when an early intervention is planned, as it can easily be turned off. LMWH may be preferable in NSTEMI, when intervention can be delayed, as there is no need for dose adjustment, and the mortality risk may be slightly lower.
(v) خ²-blockers reduce ventricular arrhythmias and the risk of reinfarction and decrease the workload and oxygen demand of the heart. They should be used with caution in patients with severe CHF, bradyarrhythmias, or bronchospasm.
(b) STEMI. In STEMI, persistent thrombotic occlusion is present in the majority of patients, leading to necrosis of myocardial tissue that is not being perfused. Mortality and morbidity are decreased with the establishment of early reperfusion of the occluded vessels, restoring blood flow to the myocardium.
(i) PCI. If the patient presents within 12 hours of symptom onset and is able to undergo PCI within 90 minutes of presentation or is in cardiogenic shock, PCI is the preferred method of treatment for an STEMI as it offers the best chance for reperfusion and has improved outcomes compared to fibrinolysis.
(ii) Fibrinolysis. If PCI is not readily available, fibrinolysis to dissolve the thrombus and promote reperfusion should be considered. Fibrinolytic agents (streptokinase, t-PA, and urokinase) should be administered within 30 minutes of presentation. There is a significant risk of bleeding with thrombolytic therapy and contraindications need to be ruled out before administration.
(c) UA/NSTEMI. In NSTEMI or UA, there is severe coronary obstruction usually without total occlusion of the coronary artery, and thus treatment is focused at stabilizing the plaque and treating residual ischemia.
(i) PCI. Immediate PCI is not indicated in most patients, and is associated with worsened outcomes in UA/NSTEMI. Angiography and possible PCI are performed after stabilization in high-risk patients, patients who continue to have pain despite anti-ischemic therapy, or in low-risk patients with evidence of ischemia on noninvasive stress testing.
(ii) Additional antiplatelet agents are administered with aspirin and have been shown to decrease the mortality and morbidity associated with UA/NSTEMI. Clopidogrel further inhibits platelet activity by blocking adenosine diphosphate (ADP) receptors and preventing aggregation. A loading dose should be given followed by daily oral dosing. Glycoprotein IIb/IIIa inhibitors such as eptifibatide, tirofiban or abciximab prevent the final pathway of platelet aggregation and are administered via IV infusion.






(d) Long-term secondary prevention therapy. In addition to modifying risk factors through smoking cessation and control of hypertension, diabetes, and hyperlipidemia,
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several classes of medications have been shown to have a mortality benefit when used post-MI.
(i) Aspirin. Long-term aspirin therapy increases the likelihood of patency of the affected arteries. If patients have an aspirin allergy, clopidogrel may be substituted.
(ii) خ²-blockers. Long-term mortality benefit is likely due to a combination of an antiarrhythmic effect and neurohormonal modulation.
(iii) 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins). Decreasing LDL is essential in lowering the risk of coronary heart disease. Statin therapy also has an anti-inflammatory effect that benefits mortality independently of lipid reduction.
(iv) Inhibition of the renin–angiotensin–aldosterone system with ACE- inhibitors or ARBs prevents remodeling and decreases the risk of ischemic events, and should be used in patients with anterior MI or systolic dysfunction.
(v) Clopidogrel added to aspirin improves outcomes after hospitalization in patients with NSTEMI, regardless of in-hospital treatment approach.
(e) Automated implantable cardioverter-defibrillator (AICD). Patients with prior MI and a left ventricular ejection fraction (LVEF) of ≤40% or patients who have survived resuscitation after cardiac collapse not associated with acute infarction should be evaluated by a cardiac electrophysiologist. Such patients may be candidates for insertion of an AICD. AICDs monitor the heart rhythm and defibrillate the heart if a lethal rhythm is detected. Patients who receive frequent shocks may be candidates for the addition of antiarrhythmic drugs or catheter-based ablation.
(5) Prognosis. Following an MI, a patient's prognosis is largely determined by pump function and residual ischemic burden.
(a) Pump function. LV function should be assessed following an MI by left ventriculography, multiple gated acquisition scan (MUGA), or echocardiogram. Prognosis is markedly worse for patients with an LVEF of ≤40%.
(b) Residual ischemic risk. All patients who have an MI should be evaluated by cardiac catheterization or stress testing to determine the risk of recurrent ischemia or infarction.
(6) Complications. An MI can occur with little clinical consequence; indeed, many are silent. The complications of MI, however, produce clinically significant events.
(a) Arrhythmias. A patient having an acute MI is subject to acute, lethal ventricular arrhythmias (i.e., ventricular tachycardia or ventricular fibrillation), as well as less serious atrial arrhythmias (e.g., atrial fibrillation, atrial flutter). The risk for a lethal arrhythmia is greatest within the first 48 hours, requiring close monitoring.
(b) Acute conduction system abnormalities. The specialized conducting system of the heart is itself myocardium, which may become ischemic or infarcted during an MI. This may lead to bradyarrhythmias, heart block, or both.
(i) Inferior MI usually occurs when the right coronary artery is diseased. Because this artery supplies the SA node in 55% of patients and the AV node in 85% of patients, sinus bradycardia and varying degrees of AV nodal block can occur. Heart block occurring during inferior infarction is almost always transient.
(ii) Anterior MI usually occurs from occlusion of the anterior descending coronary artery, which supplies the interventricular septum. Because the bundle branches course through the septum, acute right or left bundle branch block may occur during anterior MIs. Complete heart block also may occur due to dysfunction of both bundle branches or the bundle of His.
(c) Pump failure. When 30% of the myocardium is infarcted from one or more MIs, CHF is likely to ensue. If more than 40% of the myocardium becomes infarcted, cardiogenic shock is likely to develop.
(d) Mitral regurgitation. The papillary muscles, which are projections of the myocardium, tether the mitral valve. Dysfunction or infarction of the papillary muscles together with ventricular dilatation may lead to systolic prolapsing of the mitral valve into the left atrium, causing varying degrees of mitral regurgitation. This may lead to a precipitous rise in the left ventricular filling pressure that is transmitted to the lungs, resulting in pulmonary edema.






(e) Ventricular septal defect. The left ventricular septum may become infarcted in either anterior or inferior MI, leading to rupture of the septum. This occurs in approximately 2% of patients, usually 2–5 days after infarction.
(f) Cardiac rupture. MI of the free wall may lead to eventual perforation of the heart. This complication, which results in overwhelming cardiac tamponade, is nearly always fatal. Rarely, rupture may be contained by adherent pericardium forming a pseudoaneurysm. Surgical correction is necessary.
(g) Left ventricular aneurysm. The infarcted zone of the myocardium may evaginate and heal with fibrous connective tissue, forming an aneurysm. Left ventricular aneurysms may produce cardiac failure and angina, and they also may be the source of severe left ventricular arrhythmias and systemic emboli.
(7) Treatment of complications

(a) Antiarrhythmic therapy. If serious ventricular arrhythmias occur, amiodarone or lidocaine is infused. Additional drugs may be necessary to control arrhythmias if lidocaine is ineffective. Bretylium tosylate, procainamide, and intravenous خ²-blockers may be useful in controlling acute recalcitrant arrhythmias. These agents are given intravenously with caution.
(b) Correction of serious conduction disturbances. As noted, high-degree AV nodal block may occur during acute MI, producing significant bradycardia and hypotension. Therapies for restoring heart rate include:
(i) Atropine (1 mg intravenously) may restore conduction and increase heart rate, especially in inferior infarctions. If this fails, an infusion of a positive chronotropic agent such as isoproterenol (or use of a transcutaneous electronic pacemaker) increases heart rate. These therapies are directed at maintaining heart rate until temporary transvenous pacemaking can be performed.
(ii) In cases of severe left ventricular dysfunction, atrial systole must be preserved to maintain cardiac output, and AV sequential pacemaking is the preferred treatment.
(iii) The occurrence of new bundle branch block—particularly the combination of right bundle branch block and left anterior hemiblock—may be an indication for temporary prophylactic pacemaking because these disturbances may presage the occurrence of complete heart block; however, this tactic is controversial and obviated by the availability of transcutaneous pacing.
(c) Treatment of heart failure
(i) Mild CHF in patients with MI can be treated with diuretics.
(ii) The use of digitalis during acute MI is safe but of limited efficacy.
(iii) In more advanced cases of CHF, vasodilators may be useful in reducing cardiac afterload, allowing increased cardiac output.
(d) Treatment of cardiogenic shock. Shock in the presence of MI usually is attributable to inadequate left ventricular filling, severe muscle damage, or a mechanical complication of the MI. When shock ensues, an echocardiogram is performed to assess ventricular function, and a Swan-Ganz catheter should be placed to measure left ventricular filling pressure.
(i) If the pulmonary capillary wedge pressure is less than 18 mm Hg, volume is infused to maximize left ventricular filling and cardiac output. In addition, if a new cardiac murmur is detected, the echocardiogram and the Swan-Ganz catheter are useful in making the diagnosis of acute mitral regurgitation or acute ventricular septal defect.
(ii) Alternatively, if cardiogenic shock is caused by severe muscle damage, inotropic agents (e.g., dobutamine, milrinone) and intra-aortic balloon pumping may be used to stabilize the patient until coronary arteriography and reestablishment of coronary blood flow by PCI are carried out. However, the prognosis for such patients remains very poor despite therapy.
(e) Treatment of mitral regurgitation and acute ventricular septal defect
(i) Arteriolar vasodilator therapy to lower systemic vascular resistance is the mainstay of medical therapy for these complications. Reduction of systemic vascular resistance preferentially increases forward cardiac output and reduces nonproductive cardiac output, either into the left atrium (in the case of mitral regurgitation) or through the ventricular septal defect.
(ii) Intra-aortic balloon pumping, which also increases forward cardiac output and reduces nonproductive cardiac output, is useful in stabilizing patients with mitral regurgitation or acute ventricular septal defect, especially in hypotensive patients, where the use of vasodilators is contraindicated.
(iii) Surgical correction of mechanical complications often is required.
c. Sudden death in patients with coronary artery disease is common; in fact, approximately one-third of patients with coronary disease experience sudden death without antecedent angina or MI.






(1) Precipitating causes. It is believed that most patients die of acute ventricular arrhythmias precipitated by ischemia. Although sudden death may be the result of an MI secondary to coronary artery disease, most patients who die suddenly and are resuscitated do not have an acute MI documented. It is likely that in these patients, ischemia produces heterogeneous depolarization of the ventricle, which leads to ventricular tachycardia and ventricular fibrillation.
(2) Acute therapy
(a) Cardiopulmonary resuscitation (i.e., mouth-to-mouth resuscitation and external chest compression) must be initiated in the euthermic patient within 4 minutes of the cessation of effective ventricular contraction to preserve neurologic and myocardial function.
(b) Electrical defibrillation and drug support should be provided as soon as possible.
B. Nonatherosclerotic coronary artery disease
Although the majority of cardiac ischemic events are caused by atherosclerotic coronary disease, nonatherosclerotic disease also may produce clinical ischemia.
1. Coronary embolism occurs in infective endocarditis, from mural thrombus formation following MI, and in the presence of atrial fibrillation. Coronary embolism frequently produces MI.
2. Collagen vascular disease. The collagen vascular diseases that affect medium-sized arteries, including the coronary arteries, are: polyarteritis nodosa, Wegener's granulomatosis, systemic lupus erythematosus (SLE), and, occasionally, rheumatoid arthritis.
3. Radiation therapy. Tumor irradiation, in which the field of radiation includes the heart, damages the coronary arteries and leads to nonatherosclerotic coronary artery disease.






4. Transplantation. The development of coronary disease following cardiac transplantation is a major factor in limiting the success of this therapy. Post-transplantation coronary disease tends to be distal in location and diffuse in nature. It is probably partially attributable to chronic rejection of the organ and is not closely related to the presence of the standard risk factors for coronary disease.