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Seminar 3 Seminars from internal medicine for the 5th year Prof.

Ji Hork


Ischemia refers to a lack of oxygen due to inadequate perfusion. Ischemic heart disease is a condition of diverse etiologies, all having in common an imbalance between oxygen supply and demand. Etiology and pathophysiology. The most common cause is atherosclerotic disease of coronary arteries; also arterial thrombi, spasm, and rarely coronary emboli as well as by ostial narrowing due to luetic aortitis. Myocardial ischemia can also occur if myocardial oxygen demands are abnormally increased, as in severe ventricular hypertrophy due to hypertension or aortic stenosis. A reduction in the oxygen-carrying capacity of the blood, as in extremely severe anemia or in the presence of carboxyhemoglobin, is a rare cause of myocardial ischemia. Not infrequently, two or more causes of ischemia will coexist. The normal coronary circulation is dominated and controlled by the myocardial requirements for oxygen. This need is met by the heart's ability to vary coronary vascular resistance (and therefore blood flow) considerably while the myocardium extracts a high and relatively fixed percentage of oxygen. CORONARY ATHEROSCLEROSIS Major risk factors for atherosclerosis. high plasma LDL, low plasma HDL, cigarette smoking, diabetes mellitus, and hypertension dysfunction of vascular endothelium and an abnormal interaction with blood monocytes and platelets subintimal collections of abnormal fat, cells, and debris (i.e., atherosclerotic plaques) segmental reductions in cross-sectional area. When the luminal area is reduced by more than approximately 80 percent, blood flow at rest may be reduced, and further minor decreases in the stenotic orifice can reduce coronary flow dramatically and cause myocardial ischemia. Severe coronary narrowing and myocardial ischemia are frequently accompanied by the development of collateral vessels, especially when the narrowing develops gradually. When well developed, such vessels can provide sufficient blood flow to sustain the viability of the myocardium at rest but not during conditions of increased demand. Once severe stenosis of a proximal epicardial artery has reduced the cross-sectional area by more than approximately 70 percent, the distal resistance vessels (when they function normally) dilate to reduce vascular resistance and maintain coronary blood flow. A pressure gradient develops across the proximal stenosis, and poststenotic pressure falls. RECOGNITION OF ATHEROSCLEROSIS Angiographic visualization of deformity in the lumen of a vessel remains the best presumptive test of silent atherosclerosis. Coronary angiography now permits visualization and assessment of arteries as small as 0.5 mm in diameter. Functional tests based on pathophysiologic or metabolic effects of a narrowed arterial lumen often give indirect clues. Assessment of electrocardiographic changes induced after standardized exercise is a relatively simple noninvasive aid to the diagnosis of coronary atherosclerosis with significant narrowing. Myocardial perfusion defects demonstrable with imaging techniques using radionuclides are usually attributable to atherosclerosis.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork Ischemic heart disease (IHD), synonymous with coronary heart disease or arteriosclerotic heart disease, is the most reliable indicator of atherosclerosis available today. Practically all patients with myocardial infarction, as defined by electrocardiographic and enzymatic changes, have coronary atherosclerosis. Rare exceptions are due to congenital anomalies of the coronary vessels, emboli, or ostial occlusion due to the other types of cardiac or vascular disease. Cerebrovascular disease (stroke) is a less reliable criterion for the presence of atherosclerosis. It includes cerebral thrombosis and cerebral hemorrhage. Cerebral thrombosis, including infarction or softening without evidence of embolus, is usually due to atherosclerosis. On the other hand, cerebral hemorrhage is most often the result of congenital aneurysms or of vascular defects peculiar to hypertension and diabetes. Dissections of the aorta, peripheral vascular disease, thrombosis of other major vessels, and ischemic renal disease likewise are not used to determine the prevalence of atherosclerosis in a population or as an index of atherosclerosis elsewhere. Therefore, from an epidemiologic standpoint, consideration of atherosclerosis focuses on IHD. PATHOLOGY Data from necropsies of SCD victims parallel the clinical observations on the prevalence of coronary heart disease as the major structural etiologic factor. More than 80 percent of SCD victims have pathologic findings of coronary heart disease, and these commonly include ruptured atherosclerotic plaques and/or coronary thrombi. The most consistent coronary artery abnormality is extensive chronic coronary atherosclerosis. Seventy-five percent of the victims have two or more major vessels with >=75 percent stenosis. The pathology of the myocardium in SCD reflects the extensive coronary heart disease which usually precedes the fatal event. As many as 70 to 75 percent of males who die suddenly have prior myocardial infarctions (MIs), and 20 to 30 percent have recent acute MIs. A high incidence of left ventricular (LV) hypertrophy coexists with prior MIs. Clinical, epidemiologic, and experimental data suggest that LV hypertrophy itself predisposes to SCD, and it is likely that coexistence with prior MI adds additional risk. PATHOPHYSIOLOGY Discomfort due to myocardial ischemia occurs when the oxygen supply to the heart is deficient in relation to the oxygen need. Oxygen consumption is closely related to the physiologic effort made during contraction, and coronary venous blood is normally much more desaturated than that draining other areas of the body. As a consequence, the removal of more oxygen from each unit of blood, which is one of the adjustments commonly utilized by exercising skeletal muscle, is already employed in the heart in the basal state. Therefore, the heart must rely primarily on an increase in the coronary blood flow for obtaining additional oxygen. The blood flow through the coronary arteries is directly proportional to the pressure gradient between the aorta and the ventricular myocardium during systole and the ventricular cavity during diastole but is also proportional to the fourth power of the radius of the coronary arteries. A relatively slight alteration in coronary luminal diameter below a critical level can produce a large decrement in coronary flow, provided that other factors remain constant. Coronary blood flow occurs primarily during diastole, when it is unopposed by systolic myocardial compression of the coronary vessels. When the epicardial coronary arteries are narrowed critically (>70 percent stenosis of the luminal diameter), the intramyocardial coronary arterioles dilate in an effort to maintain total flow at a level that will avert myocardial ischemia at rest. Further dilatation, which normally 2/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork occurs during exercise, is therefore not possible. Hence any condition in which increased heart rate, arterial pressure, or myocardial contractility occurs in the presence of coronary obstruction tends to precipitate anginal attacks by increasing myocardial oxygen needs in the face of a fixed oxygen supply. By far the most frequent underlying cause of myocardial ischemia is organic narrowing of the coronary arteries secondary to coronary atherosclerosis. A dynamic component of increased coronary vascular resistance, secondary to spasm of the major epicardial vessels (often near an atherosclerotic plaque) or more frequently to constriction of smaller coronary arterioles, is present in many, perhaps the majority, of patients with chronic angina pectoris. There is no evidence that systemic arterial constriction or increased cardiac contractile activity (rise in heart rate or blood pressure or increase in contractility from liberation of catecholamines or adrenergic activity) due to emotion can precipitate angina unless there is also organic or dynamic narrowing of the coronary vessels. Acute thrombosis superimposed on an atherosclerotic plaque is frequently the cause of unstable angina and acute myocardial infarction. Aside from conditions that narrow the lumen of the coronary arteries, the only other frequent causes of myocardial ischemia are disorders such as valvular aortic stenosis or hypertrophic cardiomyopathy, which cause a marked disproportion between the coronary perfusion pressure and the heart's oxygen requirements. An increase in heart rate is especially harmful in patients with coronary atherosclerosis or with aortic stenosis, because it both increases myocardial oxygen needs and shortens diastole relatively more than systole, thereby decreasing the total available perfusion time per minute. Tachycardia, a decline in arterial pressure, thyrotoxicosis, and diminution in arterial oxygen content (such as occurs in anemia or arterial hypoxia) are precipitating and aggravating factors rather than underlying causes of angina. EFFECTS OF ISCHEMIA The inadequate oxygenation may cause transient disturbances of the mechanical, biochemical, and electrical functions of the myocardium. The abrupt development of ischemia usually affects a segment of left ventricular myocardium with almost instantaneous failure of normal muscle contraction and relaxation. The relatively poor perfusion of the subendocardium causes more intense ischemia of this portion of the wall. Ischemia of large segments of the ventricle will cause transient left ventricular failure, and if the papillary muscles are involved, mitral regurgitation can complicate this event. When ischemic events are transient, they may be associated with angina pectoris; if prolonged, they can lead to myocardial necrosis and scarring with or without the clinical picture of acute myocardial infarction. When oxygenated, the normal myocardium metabolizes fatty acids and glucose to carbon dioxide and water. With severe oxygen deprivation, fatty acids cannot be oxidized, and glucose is broken down to lactate; intracellular pH is reduced as are the myocardial stores of high-energy phosphates, adenosine triphosphate (ATP), and creatine phosphate. Impaired cell membrane function leads to potassium leakage and the uptake of sodium by myocytes. The severity and duration of the imbalance between myocardial oxygen supply and demand will determine whether the damage is reversible or whether it is permanent, with subsequent myocardial necrosis. Ischemia also causes characteristic electrocardiographic changes such as repolarization abnormalities. Another important consequence of myocardial ischemia is electrical instability, since this may lead to ventricular tachycardia or ventricular fibrillation. Most patients who die 3/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork suddenly from ischemic heart disease do so as a result of ischemia-induced malignant ventricular tachyarrhythmias. CLINICAL MANIFESTATIONS ASYMPTOMATIC VERSUS SYMPTOMATIC CORONARY ARTERY DISEASE Coronary atherosclerosis often begins to develop prior to age 20 and is widespread even among adults who were asymptomatic during life. Before the menopause women develop less coronary atherosclerosis and have a much lower incidence of the clinical manifestations of coronary artery disease. This protection is lost progressively after the menopause. When all age groups are considered, ischemic heart disease is the most common cause of death not only in men but also in women. Approximately 25 percent of patients who survive acute myocardial infarction may not reach medical attention, and these patients carry the same adverse prognosis as those who present with the classic clinical syndrome. Sudden death may be unheralded and is a common presenting manifestation of ischemic heart disease. Patients can also present with cardiomegaly and heart failure secondary to ischemic damage of the left ventricular myocardium that caused no symptoms prior to the development of heart failure; this condition is referred to as ischemic cardiomyopathy. In contrast to the asymptomatic phase of ischemic heart disease, the symptomatic phase is characterized by chest discomfort due to either angina pectoris or acute myocardial infarction. Having entered the symptomatic phase, the patient may exhibit a stable or progressive course, revert to the asymptomatic stage, or suddenly die. CHRONIC STABLE ANGINA PECTORIS This episodic clinical syndrome is due to transient myocardial ischemia. Males constitute approximately 70% of all patients with angina pectoris and an even greater fraction of those younger than 50 years of age. The typical patient with angina is a 50- to 60-year-old man or 65- to 75-year-old woman who seeks medical help for troublesome or frightening chest discomfort, usually described as heaviness, pressure, squeezing, smothering, or choking and only rarely as frank pain. When the patient is asked to localize the sensation, he or she will typically press on the sternum, sometimes with a clenched fist, to indicate a squeezing, central, substernal discomfort. This symptom is usually crescendo-decrescendo in nature and lasts 1 to 5 min. Angina can radiate to the left shoulder and to both arms, and especially to the ulnar surfaces of the forearm and hand. It can also arise in or radiate to the back, neck, jaw, teeth, and epigastrium. Although episodes of angina are typically caused by exertion (e.g., exercise, hurrying, or sexual activity) or emotion (e.g., stress, anger, fright, or frustration) and are relieved by rest, they may also occur at rest and at night while the patient is recumbent (angina decubitus). The patient may be awakened at night distressed by typical chest discomfort and dyspnea. The pathophysiology of nocturnal angina is analogous to that of paroxysmal nocturnal dyspnea, i.e., the expansion of the intrathoracic blood volume that occurs with recumbency causes an increase in cardiac size and myocardial oxygen demand that lead to ischemia and transient left ventricular failure. The threshold for the development of angina pectoris varies from person to person and may vary by time of day and emotional state. A patient may report symptoms upon minor exertion in the morning (a short walk or shaving) yet by midday may be capable of much greater effort without symptoms. Angina may be precipitated by unfamiliar tasks, a heavy meal, or exposure to cold. 4/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork A positive family history of ischemic heart disease, diabetes, hyperlipidemia, hypertension, cigarette smoking, and other risk factors for coronary atherosclerosis. In variant (Prinzmetal's) angina, the chest discomfort characteristically occurs at rest or awakens the patient from sleep. It may be accompanied by palpitations or severe shortness of breath, explosive in onset, severe, and frightening. It may also be brought on by effort, although the workload at which it is precipitated usually varies considerably. Variant angina is caused by focal spasm of proximal epicardial coronary arteries; in approximately threefourths of the patients atherosclerotic coronary artery obstruction is present, in which case the vasospasm occurs near the stenotic lesion. Physical examination is often normal. The patient's general appearance may reveal signs of risk factors associated with coronary atherosclerosis such as xanthelasma or diabetic skin lesions. There may also be signs of anemia, thyroid disease, and nicotine stains on the fingertips from cigarette smoking. Palpation can reveal thickened or absent peripheral arteries, signs of cardiac enlargement, and abnormal contraction of the cardiac impulse (left ventricular akinesia or dyskinesia). Examination of the fundi may reveal increased light reflexes and arteriovenous nicking as evidence of hypertension (an important risk factor for ischemic heart disease), while auscultation can uncover arterial bruits, a third and/or fourth heart sound, and, if acute ischemia or previous infarction has impaired papillary muscle function, a late apical systolic murmur due to mitral regurgitation. Laboratory examination. The urine should be examined for evidence of diabetes mellitus and renal disease. Examination of the blood should include measurements of lipids (cholesterol-total, low density, and high density), glucose, creatinine, hematocrit, and, if indicated based on the physical examination, thyroid function. A chest x-ray is important, since it may show the consequences of ischemic heart disease, i.e., cardiac enlargement, ventricular aneurysm, or signs of heart failure. Calcification of the coronary arteries can sometimes be identified on chest fluoroscopy. Electrocardiogram. A normal ECG does not exclude the diagnosis of ischemic heart disease. A 12-lead ECG recorded at rest is normal in about half the patients with typical angina pectoris, but there may be signs of an old myocardial infarction. Serial tracings are particulary useful to look for past or evolving myocardial infarction. Although repolarization abnormalities, i.e., T-wave and ST-segment changes and intraventricular conduction disturbances at rest, are suggestive of ischemic heart disease, they are nonspecific, since they can also occur in pericardial, myocardial, and valvular heart disease or with anxiety, changes in posture, drugs, or esophageal disease. Typical ST-segment and T-wave changes that accompany episodes of angina pectoris and disappear thereafter are more specific. The most characteristic changes include displacement of the ST segment. The ST segment is usually depressed during angina but may be elevated--sometimes strikingly so--as in the early stages of myocardial infarction and in Prinzmetal's angina. PROGNOSIS The principal prognostic indicators in patients with ischemic heart disease are the functional state of the left ventricle, the location and severity of coronary artery narrowing, and the severity or activity of myocardial ischemia.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork On cardiac catheterization, elevations in left ventricular end-diastolic pressure and ventricular volume and a reduced ejection fraction are the most important signs of left ventricular dysfunction and are associated with a poor prognosis. Patients with chest discomfort but normal left ventricular function and normal coronary arteries have an excellent prognosis. In patients with normal left ventricular function and mild angina but with critical stenoses (>=70 percent luminal diameter) of one, two, or three epicardial coronary arteries, the 5-year mortality rates are approximately 2, 8, and 11 percent, respectively. Obstructive lesions of the proximal left anterior descending coronary artery are associated with a greater risk than are lesions of the right or left circumflex coronary artery, since the former vessel usually perfuses a greater quantity of myocardium. Critical stenosis of the left main coronary artery is associated with a mortality of about 15 percent per year.

How the exercise tolerance test affects the probability of coronary artery disease. The beforetest probability of coronary artery disease (CAD) will be modified by the result of the exercise electrocardiogram to yield an after-test probability of CAD. Note that the finding of <1 mm of ST-segment depression will reduce the probability of CAD, whereas >=1 mm of ST-segment depression will increase the probability. For example, if a patient with a before-test probability of CAD of 90 percent (about that of a middle-aged man with typical anginal symptoms) had 2 to 2.49 mm on ST-segment depression on exercise testing, the after-test probability of CAD would be 99.5 percent. In contrast, the same exercise test result in a patient with 30 percent before-test probability of CAD (about that of a patient with atypical anginal symptoms) would yield an after-test probability of about 90 percent. In an asymptomatic patient, with a before-test probability of about 5 percent, the same exercise test result would yield an after-test probability of 53 percent. Thus the same test yields different after-test probabilities in patients with different before-test probabilities.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork

Approximate probability of coronary artery disease before and after noninvasive testing of a patient with typical (A) and atypical (B) angina pectoris. The percentages demonstrate how the sequential use of an exercise electrocardiogram and an exercise thallium test may affect the probability of coronary artery disease. MANAGEMENT Each patient must be evaluated individually with respect to life patterns, risk factors, control of symptoms, and prevention of damage to left ventricular myocardium. The management plan should consist of:


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork 1) explanation and reassurance, 2) reduction of risk factors (secondary prevention): The discontinuance of cigarette smoking is vital. The risk of coronary events is low when the total plasma cholesterol is less than 200 mg/100 mL, intermediate when it is 200 to 240 mg/100 mL, and abnormally increased when the plasma cholesterol is over 240 mg/100 mL. Ideal weight should be attained and maintained. Aggravating factors (e.g., endocrine disorders, hypertension, and drugs such as glucocorticoids) should be treated and eliminated when possible. Diabetes mellitus and hypertension, when present, should be treated. The administration of estrogen to postmenopausal women appears to provide significant protection with a reduction in coronary events. Nevertheless, there is a modest increase in the occurrence of some malignancies and therefore therapy should be individualized. 3) treatment of coexisting conditions capable of aggravating angina (hypertension, anemia and hyperthyroidism). 4) sensible adaptations of activities to minimize anginal attacks. Patients must appreciate the diurnal variation in their tolerance of certain activities and should reduce their energy requirements in the morning and immediately after meals. It may be necessary to recommend a change in employment to avoid physical stress. 5) a program of drug therapy: Nitrates act by causing systemic venodilation, thereby reducing myocardial wall tension and oxygen requirements, as well as by dilating the epicardial coronary vessels and increasing blood flow in collateral vessels. Nitroglycerin is administered sublingually in tablets of 0.4 or 0.6 mg. Patients with angina should be instructed to take the medication both to relieve an attack and also in anticipation of stress (exercise or emotional). Headache and a pulsating feeling in the head are the most common side effects of nitroglycerin. If relief is not achieved after the first dose of nitroglycerin, a second or third dose may be given at 5-min intervals. If discomfort continues despite treatment, the patient should consult a physician or report promptly to a hospital emergency room for evaluation of possible unstable angina or acute myocardial infarction. None of the long-acting nitrates is as effective as sublingual nitroglycerin for the acute relief of angina. These preparations can be swallowed, chewed, or administered as a patch or paste by the transdermal route. They can provide effective plasma levels for up to 24 h, but the therapeutic response is highly variable. Useful preparations include isosorbide dinitrate (10 to 40 mg PO tid), nitroglycerin ointment (0.5 to 2.0 inches qid), or sustained-release transdermal patches (5 to 25 mg/d). Longacting nitrates are relatively safe and can be used together with intermittent sublingual nitroglycerin to relieve discomfort and prevent attacks of angina. Beta-adrenoceptor blockers reduce myocardial oxygen demand by inhibiting the increases in heart rate and myocardial contractility caused by adrenergic activity. Beta blockage reduces these variables most strikingly during exercise while causing only small reductions in heart rate, cardiac output, and arterial pressure at rest. Propranolol is usually administered in an initial dose of 20 to 40 mg four times a day and is increased as tolerated to 320 mg per day in divided doses. Long-acting beta-blocking drugs (atenolol, 50 to 100 mg/d, and nadolol, 40 to 80 mg/d) offer the advantage of once-a-day dosage. The therapeutic aims include relief of angina and ischemia. These drugs can also reduce mortality and reinfarction when given to patients after myocardial infarction. Side effects: fatigue, impotence, cold extremities, intermittent claudication, and bradycardia. They can worsen disturbed cardiac conduction, left ventricular failure,


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork and bronchial asthma or intensify the hypoglycemia produced by oral hypoglycemic agents and insulin. Calcium antagonists: verapamil (80 to 120 mg tid), diltiazem (30 to 90 mg qid) and other calcium antagonists are all coronary vasodilators that produce variable and dosedependent reductions in myocardial oxygen demand, contractility, and arterial pressure. These combined pharmacologic effects are advantageous and make these agents quite effective in the treatment of angina pectoris. Verapamil and diltiazem may produce symptomatic disturbances in cardiac conduction and bradyarrhythmias, exert negative inotropic actions, and are more likely to worsen left ventricular failure, particularly when used in combination with beta blockers in patients with underlying left ventricular dysfunction. Careful individual titration of dose is essential with these potent combinations. Variant (Prinzmetal's) angina responds particularly well to calcium antagonists, supplemented when necessary by nitrates. The calcium antagonists are now formulated as long-acting preparations including nifedipine (30 to 90 mg once daily), diltiazem (60 to 120 mg twice daily), and verapamil (180 to 240 mg once daily). Verapamil should not be combined with beta-adrenoreceptor blocking drugs because of the combined effects on heart rate and contractility Aspirin is an irreversible inhibitor of platelet cyclooxygenase activity. Chronic administration of 100 to 325 mg orally per day has been shown to reduce coronary events in asymptomatic adult men, patients with asymptomatic ischemia after myocardial infarction, patients with chronic stable angina, and patients who have survived unstable angina and myocardial infarction. Administration of this drug should be considered in all patients with coronary artery disease in the absence of side effects such as gastrointestinal bleeding, allergy, or dyspepsia.

6) mechanical revascularization. UNSTABLE ANGINA PECTORIS 1. patients with new onset (<2 months) angina that is severe and/or frequent (>=3 episodes per day); 2. patients with accelerating angina, i.e., those with chronic stable angina who develop angina that is distinctly more frequent, severe, prolonged, or precipitated by less exertion than previously; 3. those with angina at rest. Unstable angina, particularly when it is characterized by rest pain or occurs in the postinfarction state, carries an adverse prognosis, with significant risk of acute myocardial infarction or the development of intractable chronic stable angina. When unstable angina is accompanied by objective electrocardiographic evidence of transient myocardial ischemia (ST-segment changes and/or T-wave inversions during episodes of chest pain), it is almost always associated with critical stenoses in one or more major epicardial coronary arteries. The atherosclerotic lesions may have a complicated morphology, with evidence of superimposed thrombosis in approximately 25 to 60 percent of cases. Segmental spasm in the vicinity of atherosclerotic plaques may also play a role in the development of unstable angina. MANAGEMENT The patient should be admitted promptly to the hospital for observation, further diagnosis, and treatment.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork Identify and treat concomitant conditions that can intensify ischemia, such as uncontrolled tachycardia, hypertension and diabetes mellitus, cardiomegaly, heart failure, arrhythmias, thyrotoxicosis, and any acute febrile illness. Acute myocardial infarction should be ruled out by means of serial ECGs and measurements of plasma cardiac enzyme activity. Continuous electrocardiographic monitoring should be carried out and the patients should receive reassurance and sedation. Thrombus formation frequently complicates this condition. Therefore, intravenous heparin should be given for 3 to 5 days to maintain the partial thromboplastin time at 2 to 2.5 times control, together with or followed by oral aspirin at a dose of 325 mg/d. Beta-adrenoceptor blocking drugs and calcium antagonists should be administered, but with caution and an awareness of the possible side effects discussed above. Dosages must be titrated to avoid bradycardia, heart failure, and hypotension. Nitroglycerin should be given by the sublingual route as needed for symptoms. In addition, intravenous nitroglycerin is quite effective, although it requires continuous monitoring of arterial pressure. It is begun at a dosage of 10 g/min and is raised in 5ug/min increments to a level at which chest pain is abolished but systolic arterial pressure is maintained or reduced only slightly and other side effects are avoided.

The majority of patients improve with such treatment. However, if angina and/or electrocardiographic evidence of ischemia do not diminish within 24 to 48 h of the comprehensive treatment described above in patients with no obvious contraindications for revascularization, then cardiac catheterization and coronary arteriography should be performed. If the anatomy is suitable, PTCA can be performed with surgical standby. PTCA in this condition, particularly in the presence of thrombus, is attended by increased risk of acute closure and ischemia. If angioplasty cannot be done, coronary artery bypass grafting should be considered to relieve symptoms and myocardial ischemia and as a means of preventing myocardial damage. If the patient's symptoms and signs are controlled on medical therapy, a diagnostic exercise ECG should be obtained near the time of hospital discharge. If there is evidence of severe myocardial ischemia, serious consideration should be given to catheterization and revascularization. It should be recognized that severe coronary artery disease is often present in patients with unstable angina who respond to medical therapy. Many patients in whom the unstable state is controlled are left with severe chronic stable angina and ultimately require mechanical revascularization.

ACUTE MYOCARDIAL INFARCTION In the United States, approximately 1.5 million myocardial infarctions occur each year. Mortality with acute infarction is approximately 30%, with more than half of the deaths occurring before the stricken individual reaches the hospital. An additional 5 to 10 percent of survivors die in the first year following myocardial infarction and the number of myocardial infarctions each year in the United States has remained largely unchanged since the early 1970s. Thrombotic occlusion of a coronary artery previously narrowed by atherosclerosis myocardial infarction. Factors such as cigarette smoking, hypertension, and lipid accumulation vascular injury. In the majority of cases, infarction occurs when an atherosclerotic plaque fissures, ruptures, or


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork ulcerates, and, with conditions favoring thrombogenesis (factors which may be local or systemic), a mural thrombus forms leading to coronary artery occlusion. The amount of myocardial damage caused by coronary occlusion depends upon the territory supplied by the affected vessel, whether or not the vessel becomes totally occluded, native factors which can produce early spontaneous lysis of the occlusive thrombus, the quantity of blood supplied by collateral vessels to the affected tissue, and the demand for oxygen of the myocardium whose blood supply has been suddenly limited. Patients at increased risk of developing acute myocardial infarction include those with unstable angina, multiple coronary risk factors and Prinzmetal's variant angina. Less common etiologic factors include hypercoagulability, coronary emboli, collagen vascular disease, and cocaine abuse. CLINICAL PRESENTATION In roughly one-half of cases no precipitating factor appears to be present. In other cases, triggers such as physical exercise, emotional stress, and medical or surgical illnesses can often be identified. A higher frequency of onset occurs in the morning within a few hours of awakening. Pain is the most common presenting complaint. The pain of myocardial infarction is deep and visceral; adjectives commonly used to describe it are heavy, squeezing, and crushing. It is similar in character to the discomfort of angina pectoris but is usually more severe and lasts longer. Typically the pain involves the central portion of the chest and/or epigastrium, and in about 30 percent of cases it radiates to the arms. Less common sites of radiation include the abdomen, back, lower jaw, and neck. The location of the pain beneath the xiphoid and patients' denial that they may be suffering a heart attack are chiefly responsible for the mistaken diagnosis of indigestion. The pain of myocardial infarction may radiate as high as the occipital area but not below the umbilicus. The pain is often accompanied by weakness, sweating, nausea, vomiting, giddiness, and anxiety. The discomfort usually commences with the patient at rest. When the pain begins during a period of exertion, in contrast to angina pectoris, it does not usually subside with cessation of activity. Approximately one-half of patients with myocardial infarction exhibit the prodrome of unstable angina. A minimum of 15 to 20 percent of myocardial infarcts are painless. The incidence of painless infarcts is greater in women and patients with diabetes mellitus, and it increases with age. In the elderly, myocardial infarction may present as sudden-onset breathlessness, which may progress to pulmonary edema. Other less common presentations, with or without pain, include sudden loss of consciousness, a confusional state, a sensation of profound weakness, the appearance of an arrhythmia, evidence of peripheral embolism, or merely an unexplained drop in arterial pressure. The pain of myocardial infarction can be similar to pain from acute pericarditis, pulmonary embolism, acute aortic dissection, or costochondritis. These conditions should be considered in the differential diagnosis. PHYSICAL FINDINGS Most patients are anxious and restless. Pallor is common and is often associated with perspiration and coolness of the extremities. The combination of substernal chest pain persistent for more than 30 min and diaphoresis strongly suggests acute myocardial infarction. Within the first hour of infarction about one-fourth of patients with anterior infarction have manifestations of sympathetic nervous system hyperactivity (tachycardia and/or hypertension), and up to one-half with inferior infarction show evidence of parasympathetic hyperactivity (bradycardia and/or hypotension).


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork The precordium is usually quiet, and the apical impulse may be difficult to palpate. In about one-fourth of patients with anterior wall infarction, an abnormal systolic pulsation caused by dyskinetic bulging of infarcted myocardium develops in the periapical area within the first days of the illness. Other physical signs: fourth (S4) and third (S3) heart sounds, decreased intensity of heart sounds, and, rarely, paradoxical splitting of the second heart sound. A transient apical systolic murmur, presumably due to mitral regurgitation secondary to papillary muscle dysfunction during acute infarction, may be midsystolic or late systolic in timing. A pericardial friction rub is heard in many patients with transmural myocardial infarction at some time in their course if they are examined frequently. Jugular venous distention occurs commonly in patients with right ventricular infarction. The carotid pulse is often decreased in volume, reflecting reduced stroke volume. Temperature elevations up to 38 degC may be observed during the first week following acute myocardial infarction; however, a temperature exceeding 38 degC should prompt a search for other causes. The arterial pressure is variable; in most patients with transmural infarction systolic pressure declines approximately 10 to 15 mmHg from the preinfarction state. LABORATORY FINDINGS The nonspecific reaction to myocardial injury is associated with polymorphonuclear leukocytosis, which appears within a few hours after the onset of pain, persists for 3 to 7 days, and often reaches levels of 12,000 to 15,000 leukocytes per microliter. The erythrocyte sedimentation rate rises more slowly than the white blood cell count, peaking during the first week, and sometimes remaining elevated for 1 or 2 weeks. The electrocardiographic manifestations: transmural infarction is often present if the electrocardiogram demonstrates Q waves or loss of R waves; nontransmural infarction may be present if the electrocardiogram shows only transient ST-segment and sustained T-wave changes. Serum enzymes are released in large quantities into the blood from necrotic heart muscle following myocardial infarction. The rate of liberation of specific enzymes differs following infarction, and the temporal pattern of enzyme release is of diagnostic importance. Creatine phosphokinase (CK) rises within 8 to 24 h and generally returns to normal by 48 to 72 h, except in the case of large infarctions, when CK clearance is delayed. Lactic dehydrogenase (LDH) rises later (24 to 48 h) and remains elevated for as long as 7 to 14 days. The serum aminotransferase enzymes AST and ALT (previously designated SGOT and SGPT) were utilized in the diagnosis of myocardial infarction for many years but have fallen out of favor. The MB isoenzyme of CK has the advantage over CK and LDH in that it is not present in significant concentrations in extracardiac tissue and therefore is more specific. CK-MB isoenzymes are particularly useful when skeletal muscle and/or brain damage are suspected since both of these tissues contain large quantities of the CK enzyme but none of the MB isoenzyme. Cardiac surgery, myocarditis, and electrical cardioversion often result in elevation of serum levels of MB isoenzyme. Cardiac-specific troponin T and cardiac-specific troponin I are now the preferred biochemical markers of AMI. The ECG is a cornerstone in the diagnosis of acute and chronic ischemic heart disease. The findings depend on several key factors: the nature of the process [reversible (i.e., ischemia) versus irreversible (i.e., infarction)], the duration (acute versus chronic), extent (transmural versus subendocardial), and localization (anterior versus inferoposterior), as well as the presence of other underlying abnormalities (ventricular hypertrophy, conduction defects). 12/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork Ischemia exerts complex time-dependent effects on the electrical properties of myocardial cells. Severe, acute ischemia lowers the resting membrane potential and shortens the duration of the action potential. Such changes cause a voltage gradient between normal and ischemic zones. As a consequence, current flows between these regions. These so-called currents of injury are represented on the surface ECG by deviation of the ST segment. When the acute ischemia is transmural, the ST vector is usually shifted in the direction of the outer (epicardial) layers, producing ST elevations and sometimes, in the earliest stages of ischemia, tall, positive so-called hyperacute T waves over the ischemic zone. With ischemia confined primarily to the subendocardium, the ST vector typically shifts toward the subendocardium and ventricular cavity so that overlying (e.g., anterior precordial) leads show ST-segment depression (with ST elevation in lead aVR). Multiple factors affect the amplitude of acute ischemic ST deviations. Profound ST elevation or depression in multiple leads usually indicates very severe ischemia. Complete resolution of ST elevation promptly following thrombolytic therapy is a relatively specific, though not sensitive, marker of successful reperfusion. The ECG leads are more helpful in localizing regions of Q wave than non-Q wave ischemia. For example, acute anterior wall ischemia leading to Q wave infarction is reflected by ST elevations or increased T-wave positivity in one or more of the precordial leads (V1 to V6) and leads I and aVL. Anteroseptal ischemia produces these changes in leads V1 to V3, apical or lateral ischemia in leads V4 to V6. Inferior wall ischemia produces changes in leads II, III, and aVF. Posterior wall ischemia may be indirectly recognized by reciprocal ST depressions in leads V1 to V3. Prominent reciprocal ST depressions in these leads also occur with certain inferior wall infarcts, particularly those with posterior or lateral wall extension. Right ventricular ischemia usually produces ST elevations in right-sided chest leads. When ischemic ST elevations occur as the earliest sign of acute infarction, they are typically followed within a period ranging from hours to days by evolving T-wave inversions and often by Q waves occurring in the same lead distribution. (T-wave inversions due to evolving or chronic ischemia correlate with prolongation of repolarization and are often associated with QT lengthening.) Reversible transmural ischemia, e.g., due to coronary vasospasm (Prinzmetal's variant angina), may cause transient ST-segment elevations without development of Q waves. Depending on the severity and duration of such ischemia, the ST elevations may either resolve completely within minutes or be followed by T-wave inversions that persist for hours or even days. Patients with ischemic chest pain who present with deep T-wave inversions in multiple precordial leads (e.g., V1 to V4) with or without cardiac enzyme elevations typically have severe obstruction in the left anterior descending coronary artery system. In contrast, patients whose baseline ECG already shows abnormal T-wave inversions may develop Twave normalization (pseudonormalization) during episodes of acute transmural ischemia. With infarction, depolarization (QRS) changes often accompany repolarization (ST-T) abnormalities. Necrosis of sufficient myocardial tissue may lead to decreased R-wave amplitude or frank abnormal Q waves in the anterior or inferior leads. Previously, abnormal Q waves were considered to be markers of transmural myocardial infarction, while subendocardial infarcts were thought not to produce Q waves. Infarcts are more appropriately classified as "Q-wave" or "non-Q-wave". Loss of depolarization forces due to posterior or lateral infarction may cause reciprocal increases in R-wave amplitude in leads V1 and V2 without diagnostic Q waves in any of the conventional leads. Atrial infarction may be


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork associated with PR-segment deviations due to an atrial current of injury, changes in P-wave morphology, or atrial arrhythmias. In the weeks and months following infarction, these ECG changes may persist or begin to resolve. Complete normalization of the ECG following Qwave infarction is uncommon but may occur, particularly with smaller infarcts. In contrast, persistent ST-segment elevations several weeks or more after a Q-wave infarct usually correlate with a severe underlying wall motion disorder (akinetic or dyskinetic zone), although not necessarily a frank ventricular aneurysm. ECG changes due to ischemia may occur spontaneously or may be provoked by various exercise protocols (stress electrocardiography). In patients with severe ischemic heart disease, exercise testing is most likely to elicit signs of subendocardial ischemia (horizontal or downsloping ST depression in multiple leads). ST-segment elevation during exercise is most often observed after a Q-wave infarct. This repolarization change does not necessarily indicate active ischemia but correlates strongly with the presence of an underlying ventricular wall motion abnormality. However, in patients without prior infarction, transient ST-segment elevation with exercise is a reliable sign of transmural ischemia. The ECG has important limitations in both sensitivity and specificity in the diagnosis of ischemic heart disease. Cardiac imaging. Acute infarct scintigraphy ("hot-spot" imaging) is carried out with an infarct-avid imaging agent such as [99mTc]stannous pyrophosphate. Scans are usually positive 2 to 5 days after infarction, particularly in patients with transmural infarcts; although they aid in localizing infarcts and provide a measure of infarct size, these scans are less sensitive than CK determination for making the diagnosis of myocardial infarction. Myocardial perfusion imaging with thallium 201 or technetium 99m Sesta-Mibi, which are distributed in proportion to myocardial blood flow and concentrated by viable myocardium, reveals a defect ("cold spot") in most patients during the first few hours after development of a transmural infarct. However, since it is not possible to distinguish acute infarcts from chronic scars, perfusion scanning, although extremely sensitive, is not specific for the diagnosis of acute myocardial infarction. Through sequential [99mTc]Sesta-Mibi imaging (e.g., before and after thrombolysis) the area of myocardium at risk may be estimated; likewise, sequential scanning may permit assessment of the area of successful reperfusion and comparison of infarct size (late) with the area at risk (early). Two-dimensional echocardiography can also be of value in patients with acute myocardial infarction. Abnormalities of wall motion are almost universally present. In the emergency room setting, the early use of echocardiography can aid in management decisions such as whether or not thrombolytic agents should be administered. Echocardiographic estimation of left ventricular function is relatively accurate and can be useful prognostically. MANAGEMENT The prognosis in acute myocardial infarction is largely related to the occurrence of two general classes of complications: (1) electrical (arrhythmias) and (2) mechanical ("pump failure"). Ventricular fibrillation is the most common form of arrhythmic death in acute myocardial infarction. The vast majority of deaths due to ventricular fibrillation occur within the first 24 h of the onset of symptoms, and of these deaths, over half occur in the first hour. Most out-of-hospital deaths from myocardial infarction are due to ventricular fibrillation. It may occur without warning symptoms or arrhythmias. Over the last 30 years, with careful monitoring and prompt attention to arrhythmias, the in-hospital mortality for acute myocardial


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork infarction has been reduced from about 30 to between 10 and 15 percent, and death from inhospital ventricular arrhythmia is now unusual. Pump failure is now the primary cause of in-hospital death from acute myocardial infarction. The extent of ischemic necrosis correlates well with the degree of pump failure and with mortality, both early, i.e., within 10 days of infarction, and later as well. The principal objectives of management of the patient with myocardial infarction are to prevent death from arrhythmia and to minimize the mass of infarcted tissue. CORONARY CARE UNITS These have resulted in improved care of patients with myocardial infarction, reduction in mortality rates, and major increases in knowledge about myocardial infarction. Patients should be admitted to these units early in their illness when they may expect to derive maximum benefit from the care provided. REPERFUSION Thrombolysis. Early reperfusion of ischemic myocardium can potentially salvage tissue before it becomes irreversibly injured. Since most infarctions are caused by a relatively sudden thrombotic occlusion overlying an atherosclerotic plaque in a major epicardial coronary vessel, recent attention has been appropriately directed at techniques to pharmacologically or mechanically recanalize the "culprit" vessel. The thrombolytic agents streptokinase, anisoylated plasminogen streptokinase activator complex (APSAC), and tissue plasminogen activator (tPA) have been approved by the Federal Drug Administration for intravenous use in the setting of acute myocardial infarction. Institution of therapy remains of benefit in many patients seen 3 to 6 h after the onset of infarction, and some benefit appears possible up to 12 h. tPA is more effective than streptokinase or APSAC at restoring coronary artery flow, and has a small edge in improving survival as well. The current recommended total dose of tPA is 100 mg, beginning with a 5 to 10 mg bolus followed by 60 mg intravenously over the first hour, followed by 20 mg each in the second and third hours. Streptokinase is administered as 1.5 million units intravenously over 1 h. APSAC has the benefit of being administered as a single dose of 30 mg over 2 to 5 min, making it an ideal agent when given out of the hospital. Anticoagulant and platelet regimens appear to aid in establishing and maintaining vessel patency, and aspirin has been shown to lower mortality when given with thrombolytic therapy. Recent studies suggest that 160 to 325 mg of aspirin and 5000 units of I.V. heparin should be given with the institution of thrombolytic therapy. This should be followed by 325 mg of aspirin daily and a continuous infusion of heparin for 2 to 5 days. Clear contraindications to the use of thrombolytic agents include a history of cerebrovascular accident, a recent (within 2 weeks) invasive or surgical procedure (or prolonged cardiopulmonary resuscitation), marked hypertension (systolic arterial pressure greater than 180 mmHg and/or diastolic pressure greater than 100 mmHg) at any time during the acute presentation, and active peptic ulcer disease. Allergic reactions to streptokinase or APSAC occur in approximately 2 percent of cases. Hemorrhage is the most frequent and potentially the most serious complication. Hemorrhagic stroke is the most serious complication and occurs in approximately 0.4 percent of cases. This rate increases with advancing age, with patients greater than 70 years of age experiencing roughly twice the rate of intracranial hemorrhage as those less than 65 years of age.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork Primary percutaneous transluminal coronary angioplasty. Primary PTCA without preceding thrombolysis is also effective in restoring perfusion in acute myocardial infarction. It has the advantages of being applicable to patients with contraindications to thrombolytic therapy; it appears to be more effective than thrombolysis in opening occluded coronary arteries and may be associated with a somewhat better clinical outcome. The early administration of nitrates and beta blockers, with or without thrombolytic therapy, appears to be of benefit. ROUTINE TREATMENT OF THE PATIENT WITH MYOCARDIAL INFARCTION ANALGESIA. One of the important initial therapeutic objectives is the relief of pain. Morphine is an extremely effective analgesic for the pain associated with myocardial infarction. However, it may reduce sympathetically mediated arteriolar and venous constriction. The resultant venous pooling may produce a reduction in cardiac output and arterial pressure. Morphine also has a vagotonic effect and may cause bradycardia or advanced degrees of heart block, particularly in patients with posteroinferior infarction. These side effects of morphine usually respond to atropine (0.5 mg intravenously). Morphine is routinely administered by repetitive (every 5 min) intravenous injection of small doses of drug (2 to 4 mg) rather than by administration of a larger quantity by the subcutaneous route, by which absorption may be unpredictable. Meperidine hydrochloride or hydromorphone hydrochloride may be effectively employed in place of morphine. Prior to administering morphine, sublingual nitroglycerin can be given safely to most patients with myocardial infarction. As long as hypotension does not occur, up to three 0.4-mg doses should be administered at about 5-min intervals. In addition to diminishing or abolishing chest discomfort, this form of therapy, may be capable of both decreasing myocardial oxygen demand (by lowering preload) and increasing myocardial oxygen supply (by dilating infarctrelated coronary vessels or collateral vessels). However, therapy with nitrates should be avoided in patients who present with a low systolic arterial pressure (<100 mmHg). Intravenous beta blockers are also useful in the control of the pain of acute myocardial infarction. These drugs have been shown to control pain effectively in some patients, presumably by diminishing ischemia consequent to lowering myocardial oxygen demand. More importantly, there is some evidence that intravenous beta blockers reduce in-hospital mortality. OXYGEN. The routine use of oxygen is supported by the observation that the arterial PO2 is reduced in many patients with myocardial infarction and that oxygen inhalation reduces the area of ischemic injury in experimental animals. Oxygen should be administered by face mask or nasal prongs for the first day or two after infarction. ACTIVITY. Factors which increase the work of the heart during the initial hours of infarction may increase the size of the infarct. Circumstances in which heart size, cardiac output, or myocardial contractility are increased should be avoided. 6 to 8 weeks are required for complete healing, i.e., replacement of the infarcted myocardium by scar tissue. The purpose of a graded increase in physical activity is to provide the most favorable possible circumstances for this healing. Most patients with myocardial infarction should be admitted to a coronary care unit and remain there until clinical stability has been demonstrated (usually 1 to 3 days). A catheter should be introduced into a peripheral vein. The patient should be in bed most of the day, with 16/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork one or two periods of 15 to 30 min in a bedside chair. The patient should be bathed but may eat unassisted. By the third or fourth day the patient with an uncomplicated course should be spending at least 30 to 60 min in a chair twice a day. Standing and gradual ambulation are usually begun between the second and fourth days post infarction in patients with uncomplicated myocardial infarction. Ambulation is progressively increased, eventually including walks about the hospital floor. The total duration of hospitalization in uncomplicated cases is usually 6 to 11 days. If ischemia occurs at rest, or if ischemia and/or hypotension occur during limited exercise, coronary arteriography should be carried out, except in the very elderly or in those for whom contraindications to invasive procedures exist. If a large quantity of viable myocardium, perfused by critically narrowed vessel(s), is found at angiography, then revascularization (either by angioplasty or by operation) may be required. The remainder of the convalescent phase of myocardial infarction may be accomplished at home. From 2 to 6 weeks, the patient should be encouraged to increase activity by walking about the house and outdoors in good weather. Patients should still spend 8 to 10 h in bed each night. Additional rest periods in the morning and afternoon may be advisable for selected patients. Normal sexual activity may be resumed during this period. From 6 to 8 weeks onward, the physician must regulate the patient's activity on the basis of his or her exercise tolerance. It is during this period of increasing activity that the patient may become aware of profound fatigue. Postural hypotension may still be a problem. Most patients will be able to return to work after 12 weeks, and many patients much earlier. If not performed earlier, a maximal exercise test is frequently performed after 6 to 8 weeks or prior to returning to work. A trend toward earlier ambulation, hospital discharge, and resumption of full activity for patients recuperating from acute myocardial infarction has developed in recent years. DIET. During the first 4 or 5 days, a low-calorie diet divided into multiple small feedings is preferred. If heart failure is present, sodium intake should be restricted. BOWELS. Bed rest of 3 to 5 days and the effect of the narcotics utilized for the relief of pain often lead to constipation. A bedside commode, rather than a bed pan, a diet rich in bulk, and the routine use of a stool softener are recommended. If the patient remains constipated despite these measures, a laxative can be safely used. SEDATION. Most patients require sedation during hospitalization in order to withstand the period of enforced inactivity with tranquility. Diazepam, 5 mg, oxazepam, 15 to 30 mg, or lorazepam, 0.5 to 2 mg, given three or four times daily, is usually effective. An additional dose of any of the above medications may be given at night to ensure adequate sleep. ANTICOAGULANTS AND ANTIPLATELET AGENTS. At the time of thrombolytic therapy, unless contraindications exist, most patients with possible or probable myocardial infarction should be started on aspirin, 160 or 325 mg daily. Patients with acute myocardial infarction not undergoing thrombolytic therapy should also generally receive aspirin. Additionally, in order to prevent venous thrombosis in patients not treated with thrombolytic therapy, either intravenous heparin or small subcutaneous doses of heparin (5000 units every 8 to 12 h) should be employed as well. Controversy persists about the use of oral anticoagulants once the patient is out of the intensive care area. Warfarin should be used for patients with congestive heart failure which persists for more than 3 to 4 days or for those with large anterior infarctions in whom the risk 17/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork of developing a left ventricular thrombus is greater. The indication for anticoagulation as prophylaxis against arterial embolism increases with the extent of infarction. The appropriate duration of therapy is unknown, but probably should be carried out for 3 to 6 months. Evidence suggests that warfarin lowers late mortality and the incidence of reinfarction after an acute myocardial infarction. BETA-ADRENOCEPTOR BLOCKERS. The chronic routine use of oral beta-adrenoceptor blockers for at least 2 years following acute myocardial infarction is supported by wellconducted placebo-controlled trials which have convincingly demonstrated reductions in total mortality, sudden death, and in some instances, reinfarction rate. For patients presenting with the clear picture of a hyperdynamic state, in the absence of contraindications such as congestive heart failure, hypotension, bradycardia, atrioventricular block, or a history of asthma, an intravenous dose of a beta blocker such as metoprolol may be given (5 mg every 5 to 10 min for a total dose of 15 mg, stopping between doses if any complications arise). This is usually followed by an oral dose regimen of metoprolol (50 to 100 mg bid). Later in the hospital course, a long-acting beta blocker, such as atenolol (50 to 100 mg qd) can be prescribed. Beta blocker therapy is probably indicated for most patients after myocardial infarction, except those for whom its use is specifically contraindicated. ANGIOTENSIN CONVERTING ENZYME INHIBITORS. The administration of angiotensin-converting enzyme (ACE) inhibitors can now be recommended for improvement in mortality as well as for prevention of heart failure and recurrent myocardial infarction. ACE inhibitors should be prescribed within 24 h to all patients with AMI and overt congestive heart failure. Magnesium appears to have favorable effects on cardiac arrhythmias, coronary blood flow, platelet aggregation, as well as myocardial metabolism. The early use of intravenous magnesium (8 mmol MgSO4 over 15 min, followed by 65 mmol over the next 24 h) significantly reduces serious arrhythmias and total mortality after myocardial infarction. As noted earlier, nitrates (intravenous or oral) may be useful in the relief of pain associated with acute myocardial infarction. Favorable effects on the ischemic process and ventricular remodeling (see below) has led many physicians to routinely use intravenous nitroglycerin (5 to 10 ug/min initial dose and up to 200 ug/min as long as hemodynamic stability is maintained) for the first 24 to 48 h after the onset of infarction. Complications Ventricular premature systoles. Pharmacologic therapy is now reserved for patients with sustained or symptomatic ventricular arrhythmias. Prophylactic antiarrhythmic therapy (either intravenous lidocaine early or oral agents later), in the absence of clinically important ventricular tachyarrhythmias, is contraindicated as such therapy may actually increase late mortality. Beta-adrenoceptor blocking agents are effective in abolishing ventricular ectopic activity in infarction patients and in the prevention of ventricular fibrillation. They should be used routinely in patients without contraindications. In addition, hypokalemia is a risk factor for ventricular fibrillation in patients with acute myocardial infarction, and the serum potassium concentration should be adjusted to approximately 4.5 mmol/L. Ventricular tachycardia and ventricular fibrillation. Sustained ventricular tachycardia is treated first with lidocaine, and if it cannot be terminated by one or two 50- to 100-mg doses, electroconversion should be employed. Electroshock is used immediately in patients with ventricular fibrillation, or when ventricular tachycardia causes hemodynamic deterioration. If fibrillation has persisted for more than a few seconds, the first shock may be unsuccessful, 18/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork and in this situation it is advisable to administer closed-chest massage and mouth-to-mouth respiration before attempting electroconversion again. Improvement of oxygenation and perfusion increase the likelihood of successful defibrillation. Long-term survival is good (generally better than 90 percent at 1 year) in patients with primary ventricular fibrillation, i.e., ventricular fibrillation resulting as a primary response to acute ischemia and not associated with predisposing factors such as congestive heart failure, shock, bundle branch block, or ventricular aneurysm. This prognosis is in sharp contrast to that for patients who develop ventricular fibrillation secondary to severe pump failure. In patients who develop ventricular tachycardia or ventricular fibrillation late in their hospital course, the mortality in 1 year may be as high as 85 percent. Supraventricular arrhythmias. Sinus tachycardia is the most common arrhythmia of this type. If it occurs secondary to other causes (such as anemia, fever, heart failure, or a metabolic derangement), the primary problem should be treated first. However, if sinus tachycardia appears to be due to sympathetic overstimulation, such as is seen as part of a hyperdynamic state, then treatment with a relatively short acting beta blocker such as propranolol should be considered. Other common arrhythmias in this group are junctional rhythm and tachycardia, atrial tachycardia, atrial flutter, and atrial fibrillation. These rhythm disturbances are often secondary to left ventricular failure. The administration of digoxin is usually the treatment of choice for supraventricular arrhythmias if heart failure is present. If heart failure is absent, verapamil is an ideal alternative, as this agent may also help control ischemia. If the abnormal rhythm persists for more than 2 h with a ventricular rate in excess of 120 beats per minute, or at any time when tachycardia induces heart failure, shock, or ischemia (as manifested by recurrent pain or ECG changes), electroshock should be utilized. Sinus bradycardia. Treatment of sinus bradycardia is indicated if hemodynamic compromise results from the slow heart rate. Elevation of the legs and/or the foot of the bed is frequently helpful in the treatment of sinus bradycardia. Atropine is the most useful drug for increasing heart rate and should be given intravenously in doses of 0.5 mg initially. If the rate remains below 60 beats per minute, additional doses of 0.2 mg, up to a total of 2.0 mg, may be given in divided doses. Persistent bradycardia (<40 beats per minute) despite atropine may be treated with electrical pacing. Atrioventricular and intraventricular conduction disturbances. The in-hospital mortality rate of patients with complete AV block in association with anterior infarction is markedly higher (60 to 75%) than that of patients who develop AV block with inferior infarction (25 to 40%), and the risk of subsequent death in those who survive to leave the hospital is also increased in the former group. This difference is related to the fact that heart block in inferior infarction is usually caused by AV nodal ischemia. The AV node is a small discrete structure, and thus a small amount of ischemia or necrosis can result in AV nodal dysfunction. In anterior wall infarction, heart block is usually related to ischemic malfunction of all three fascicles of the conduction system and thus commonly results only from extensive myocardial necrosis. Electrical pacing provides an effective means of increasing the heart rate of patients with bradycardia due to AV block. HEART FAILURE Some degree of transient impairment of left ventricular function occurs in over half of patients with myocardial infarction. The most common clinical signs are pulmonary rales and


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork S3 and S4 gallop rhythms. Pulmonary congestion is also frequently seen on the chest roentgenogram. The management of heart failure in association with myocardial infarction: Diuretic agents are extremely effective since they diminish pulmonary congestion in the presence of systolic and/or diastolic heart failure. A fall in left ventricular filling pressure and an improvement in orthopnea and dyspnea follow the intravenous administration of furosemide. Nitrates in various forms may be used to decrease preload and congestive symptoms. Oral isosorbide dinitrate, topical nitroglycerin ointment, or intravenous nitroglycerin, all have the advantage over a diuretic of lowering preload through venodilatation without decreasing the total plasma volume. Additionally, nitrates may improve ventricular compliance if concurrent ischemia is present, since ischemia causes an elevation of left ventricular filling pressure. ACE inhibitors are ideal, esp. in the long-term use. Ventricular remodeling. Soon after myocardial infarction, the left ventricle begins to dilate. Acutely, this occurs as the result of expansion of the infarct. Later, lengthening of the noninfarcted segments occurs as well. Overall chamber enlargement is related to the size of the infarction, with greater degrees of dilatation causing more marked hemodynamic impairment, more frequent heart failure, and a poorer prognosis as well. Progressive dilatation and its clinical consequences may be attenuated by afterload-reducing therapy such as vasodilatation induced by an ACE inhibitor. Cardiogenic shock. It is useful to consider cardiogenic shock as a form of severe left ventricular failure. This syndrome is characterized by marked hypotension with systolic arterial pressure <80 mmHg and a marked reduction of cardiac index [<1.8 (L/min)m2] in the face of elevated left ventricular filling (pulmonary capillary wedge) pressure >18 mmHg. Hypotension alone is not a basis for the diagnosis of cardiogenic shock, because many patients who make an uneventful recovery will have serious hypotension (systolic pressure <80 mmHg) for several hours. Cardiogenic shock is generally associated with a mortality rate of >70 percent. Pathophysiology of pump failure Marked reduction in the quantity of contracting myocardium cardiogenic shock. The initial insult results in a decrease in arterial pressure and hence in coronary blood flow. The reduction in coronary perfusion pressure and myocardial blood flow further impairs myocardial function and may increase the size of the myocardial infarction. Arrhythmias and metabolic acidosis also contribute to this deterioration because they are the result of inadequate perfusion. It is this positive feedback loop which accounts for the high mortality rate associated with the shock syndrome. Treatment of pump failure All patients with shock should have continuous monitoring of arterial pressure and of left ventricular filling pressure (as reflected in the pulmonary capillary wedge pressure measured with a pulmonary artery balloon catheter) as well as frequent determinations of cardiac output. When pulmonary edema coexists, endotracheal intubation may be necessary to ensure oxygenation. The relief of pain is important, as some vasodepressor reflex activity may be a response to severe pain. However, narcotics should be used cautiously in view of their propensity to lower arterial pressure.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork Attempt to maintain coronary perfusion by raising the arterial blood pressure with vasopressors, intraaortic balloon counterpulsation, and manipulation of blood volume to a level that ensures an optimum left ventricular filling pressure (approximately 20 mmHg). The latter may require either infusion of crystalloid or diuresis. In patients seen within the first 4 to 8 h of the onset of infarction, reperfusion by thrombolytic therapy and/or PTCA may improve left ventricular function dramatically, thereby interrupting the cycle of hemodynamic deterioration. Hypovolemia Hypovolemia may be secondary to previous diuretic use, to reduced fluid intake during the early stages of the illness, and/or to vomiting associated with pain or medications. Consequently, hypovolemia should be identified and corrected in patients with acute myocardial infarction and hypotension. The optimal left ventricular filling or pulmonary artery wedge pressure may vary considerably among different patients (generally at approximately 20 mmHg). Central venous pressure reflects right rather than left ventricular filling pressure and is an inadequate guide for adjustment of blood volume, since left ventricular function is almost always affected much more adversely than right ventricular function in acute myocardial infarction. Vasopressors Isoproterenol is a sympathomimetic amine which is now rarely used in the treatment of shock due to myocardial infarction. Although this agent increases contractility, it also produces peripheral vasodilatation and increases heart rate. The resultant increase in myocardial oxygen consumption and reduction of coronary perfusion pressure may extend the area of ischemic injury. Norepinephrine is a potent alpha-adrenergic agent with powerful vasoconstrictive properties which also possesses beta-adrenergic activity and therefore enhances contractility. Because the increase in afterload and contractility associated with its use causes a marked increase in myocardial oxygen consumption, it should be reserved for desperate situations or for patients with cardiogenic shock and lowered systemic vascular resistance. It should be started at 2 to 4 ug/min. If pressure cannot be maintained with a dosage of 15 ug/min, it is unlikely that a further increase will be beneficial. Dopamine is useful in many patients with power failure. At low doses [2 to 10 (ug/kg)/min] the drug has positive chronotropic and inotropic effects as a consequence of beta receptor stimulation. At higher doses, a vasoconstrictive effect results from alpha receptor stimulation. At lower doses dopamine [<=2 (ug/kg)/min] also has the unique effect of dilating the renal and splanchnic vascular beds and apparently has little effect on myocardial oxygen consumption. Intravenous dopamine is started at an infusion rate of 2 to 5 (ug/kg)/min with increments in dosage every 2 to 5 min up to a maximum of 20 to 50 (ug/kg)/min. Systolic arterial blood pressure should be maintained at approximately 90 mmHg. Dobutamine is a synthetic sympathomimetic amine with positive inotropic action and minimal positive chronotropic or peripheral vasoconstrictive activity in the usual dosage range of 2.5 to 10 (ug/kg)/min. It should not be employed when a vasoconstrictor effect is required. However, in patients with less profound degrees of hypotension, dobutamine may be an extremely useful agent, particularly if positive chronotropy is to be avoided. Amrinone is a positive inotropic agent without catecholamine structure or activity. It resembles dobutamine in its pharmacologic activity, although it has a more potent vasodilating action. Initially a loading dose of 0.75 mg/kg is given over 2 to 3 min. If effective, this is followed by an infusion of 5 to 10 (ug/kg)/min, followed if necessary 30 min


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork later by an additional bolus of 0.75 mg/kg. If necessary, the dose may then be increased up to 15 (ug/kg)/min for short periods. Cardiac glycosides Controlled studies have failed to demonstrate significant beneficial effects of cardiac glycoside therapy in the early phases (0 to 48 h) of acute myocardial infarction. Aortic counterpulsation In cardiogenic shock mechanical assistance with an intraaortic balloon pumping system capable of augmenting both diastolic pressure and cardiac output can provide circulatory support. A sausage-shaped balloon at the end of a catheter is introduced percutaneously into the aorta via the femoral artery, and the balloon is automatically inflated during early diastole, thereby enhancing both coronary blood flow and peripheral perfusion. The balloon collapses in early systole, thereby reducing the afterload against which left ventricular ejection takes place. Improvement in hemodynamic status has been observed with balloon pumping in a large number of patients, but, in the absence of early revascularization, long-term survival following this mode of therapy in patients with cardiogenic shock is still disappointing. The balloon counterpulsation system may best be reserved for patients whose condition merits mechanical (surgery or angioplasty) intervention (e.g., patients with continuing ischemia, ventricular septal rupture, or mitral regurgitation) and in whom a successful result is likely to result in the reversal of cardiogenic shock. Intraaortic balloon pumping is contraindicated if aortic regurgitation is present or if aortic dissection is possible or suspected. MITRAL REGURGITATION. The reported incidence of apical systolic murmurs of mitral regurgitation during the first few days after the onset of a myocardial infarction varies widely (10 to 50 percent of patients) depending on the population studied and the acumen of the observers. In the first hours of infarction, mitral regurgitation can be demonstrated angiographically in approximately 15 percent of patients but is audible in only about onetenth of those with positive angiograms. Whether audible or angiographically demonstrated, mitral regurgitation is of hemodynamic importance in only a minority of these patients. The most common cause of mitral regurgitation following myocardial infarction is dysfunction of the papillary muscles of the left ventricle due to ischemia or infarction. CARDIAC RUPTURE Myocardial rupture is a dramatic complication of myocardial infarction most likely to occur during the first week after the onset of symptoms; its frequency increases with the age of the patient. The clinical presentation may often be that of a sudden disappearance of the pulse, blood pressure, and consciousness while the electrocardiogram continues to show sinus rhythm (apparent electromechanical dissociation). The myocardium continues to contract, but forward flow is not maintained as blood escapes into the pericardium. Cardiac tamponade ensues, and closed-chest massage is ineffective. This condition is almost universally fatal. SEPTAL PERFORATION The pathogenesis of perforation of the ventricular septum is similar to that of external rupture of the myocardium, but the therapeutic potential is greater. Patients with ventricular septal rupture present with severe heart failure in association with the sudden appearance of a pansystolic murmur, often accompanied by a parasternal thrill. It is often impossible to differentiate this condition from rupture of a papillary muscle with resultant mitral regurgitation, and a tall v wave in the pulmonary capillary wedge pressure in both conditions further complicates the differentiation. The diagnosis can be established by the demonstration 22/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork of a left-to-right shunt (i.e., an oxygen step-up at the level of the right ventricle) by limited cardiac catheterization performed at the bedside using a flow-directed balloon catheter. Color flow Doppler echocardiography can be extremely useful for making this diagnosis at the bedside. Rupture of the ventricular septum is amenable to immediate surgical treatment, albeit at a significant risk, but this form of therapy is ordinarily indicated on an urgent basis in patients whose condition cannot be stabilized rapidly. A prolonged period of hemodynamic compromise may produce end-organ damage and other complications that can be avoided by early intervention including nitroprusside infusion and intraaortic balloon counterpulsation. Ventricular aneurysm The term ventricular aneurysm is usually used to describe dyskinesis or local expansile paradoxical wall motion. Normally functioning myocardial fibers must shorten more if stroke volume and cardiac output are to be maintained in patients with ventricular aneurysm, and if they are unable to do so, overall ventricular function is impaired. Aneurysms are composed of scar tissue and neither predispose to nor are associated with cardiac rupture. The complications of left ventricular aneurysm do not usually occur for weeks to months following myocardial infarction; they include congestive heart failure, arterial embolism, and ventricular arrhythmias. Apical aneurysms are the most common and the most easily detected by clinical examination. The physical finding of greatest value is a double, diffuse, or displaced apical impulse. The electrocardiographic finding of ST-segment elevation at rest is present in precordial leads in 25 percent of patients with either apical or anterior aneurysms. Ventricular aneurysms are readily detectable by two-dimensional echocardiography, which may also reveal a mural thrombus within an aneurysm. Rarely, myocardial rupture may be contained by a local area of pericardium, along with organizing thrombus and hematoma. Over time this pseudoaneurysm enlarges, maintaining communication with the left ventricular cavity via a narrow neck. Because spontaneous rupture of a pseudoaneurysm often occurs, if recognized, it should be surgically repaired. Right ventricular infarction Approximately one-third of patients with inferoposterior infarction demonstrate at least a minor degree of right ventricular necrosis. An occasional patient with inferoposterior left ventricular infarction also has extensive right ventricular myocardial infarction, and rarely patients present with infarction limited to the right ventricle. These patients often present with signs of severe right ventricular failure (jugular venous distention, hepatomegaly) with or without hypotension. ST-segment elevations of the right-sided precordial electrocardiographic leads, particularly lead V4R, are present in the majority of patients with right ventricular infarction. Radionuclide ventriculography and two-dimensional echocardiography are also sensitive in the detection of right ventricular dysfunction associated with acute myocardial infarction. Catheterization of the right side of the heart often reveals a distinctive hemodynamic pattern resembling cardiac tamponade or constrictive pericarditis. Volume expansion is often successful in treating low cardiac output and hypotension associated with extensive right ventricular infarction. Postinfarction ischemia and extension Recurrent angina develops in approximately 25 percent of patients hospitalized for acute myocardial infarction. This percentage is even higher in patients undergoing successful thrombolysis. Since recurrent or persistent ischemia often heralds extension of the original infarct and is associated with a doubling of risk following acute myocardial infarction,


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork patients with these symptoms should be considered for prompt coronary arteriography and mechanical revascularization. Thromboembolism Clinically apparent thromboembolism complicates acute myocardial infarction in approximately 10 percent of cases, but embolic lesions are found in 45 percent of patients in necropsy series, suggesting that thromboembolism is often clinically silent. Thromboembolism is considered to be at least an important contributing cause of death in 25 percent of infarct patients who die following admission to the hospital. Arterial emboli originate from left ventricular mural thrombi, while most pulmonary emboli arise in the leg veins. Thromboembolism most commonly occurs in association with large infarcts in the presence of heart failure. Thromboembolism occurs extremely commonly in patients with echocardiographic evidence of a left ventricular thrombus, but only rarely if a thrombus is not present on the echocardiogram. Although well-controlled trials do not exist, the incidence of embolization appears to be decreased by anticoagulation. Pericarditis Pericardial friction rubs and/or pericardial pain are frequently encountered in patients with acute transmural myocardial infarction. This complication can usually be managed with aspirin (650 mg qid). It is important to diagnose the chest pain of pericarditis accurately, since failure to appreciate it may lead to the erroneous diagnosis of recurrent ischemic pain and/or infarct extension with resultant inappropriate use of anticoagulants, nitrates, beta blockers, or coronary arteriography. The possibility exists that anticoagulants can cause tamponade in the presence of acute pericarditis, thus their use is contraindicated in patients with pericarditis Post-myocardial infarction syndrome--Dressler's syndrome This syndrome, characterized by fever and pleuropericardial chest pain, is thought to be due to an autoimmune pericarditis, pleuritis, and/or pneumonitis. It may begin from a few days to 6 weeks after myocardial infarction. The occurrence of Dressler's syndrome may be etiologically related to the early use of anticoagulants and appears to have decreased markedly in the last decade as long-term anticoagulants are used less frequently in acute myocardial infarction. The syndrome usually responds promptly to therapy with salicylates. On occasion, glucocorticoids may be required to relieve discomfort of an unusual, refractory nature. Effusions associated with Dressler's syndrome may become hemorrhagic if anticoagulants are administered. ASYMPTOMATIC (SILENT) ISCHEMIA Obstructive coronary artery disease, acute myocardial infarction, and transient myocardial ischemia are frequently asymptomatic. During continuous ambulatory electrocardiographic monitoring, the majority of ambulatory patients with typical chronic stable angina are found to have objective evidence of myocardial ischemia (ST-segment depression) during episodes of chest discomfort while they are active outside the hospital, but many of these patients also appear to have more frequent episodes of asymptomatic ischemia. Longitudinal studies have demonstrated an increased incidence of coronary events (sudden death, myocardial infarction, and angina) in asymptomatic patients with positive exercise tests. In addition, patients with asymptomatic ischemia after suffering a myocardial infarction are at far greater risk for a second coronary event. MANAGEMENT of patients with asymptomatic ischemia must be individualized. Consider the following: (1) the degree of positivity of the exercise test, particularly the stage of exercise 24/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork at which electrocardiographic signs of ischemia appear, the magnitude and number of the perfusion defect(s) on thallium scintigraphy, and the change in left ventricular ejection fraction which occurs during ischemia and/or during exercise on radionuclide ventriculography; (2) the electrocardiographic leads showing a positive response, with changes in the anterior precordial leads indicating a less favorable prognosis than changes in the inferior leads; and (3) the patient's age, occupation, and general medical condition. Patients with evidence of severe ischemia on noninvasive testing should undergo coronary arteriography. Asymptomatic patients with silent ischemia, three-vessel coronary artery disease, and impaired left ventricular function may be considered appropriate candidates for coronary artery bypass surgery. The chronic administration of aspirin to patients with asymptomatic ischemia after myocardial infarction has been shown to reduce adverse coronary events. While the incidence of asymptomatic ischemia can be reduced by treatment with beta blockers, calcium channel antagonists, and long-acting nitrates, it is not clear whether this is necessary or desirable in patients who have not suffered a myocardial infarction. Beta-adrenoceptor blockade begun 7 to 35 days after acute myocardial infarction improves survival Coronary arteriography This invasive diagnostic method outlines the coronary anatomy and can be used to detect important evidence of coronary atherosclerosis or to exclude this condition. By this means, one can assess the severity of obstructive lesions and when combined with left ventricular angiocardiography can evaluate both global and regional function of the left ventricle. Coronary arteriography is indicated in 1) patients with chronic stable or unstable angina pectoris who are severely symptomatic despite medical therapy and who are being considered for revascularization, i.e., percutaneous transluminal coronary angioplasty or coronary artery bypass graft surgery; 2) patients with troublesome symptoms that present diagnostic difficulties in whom there is need to confirm or rule out the diagnosis of coronary artery disease; and 3) patients suspected of having left main stem or three-vessel coronary artery disease based on signs of severe ischemia on noninvasive testing, regardless of the presence or severity of symptoms. SUDDEN CARDIAC DEATH ETIOLOGY, INITIATING EVENTS, AND CLINICAL EPIDEMIOLOGY Extensive epidemiologic studies have identified populations at high risk for SCD. In addition, a large body of pathologic data provides information on the underlying structural abnormalities in victims of SCD, and clinical/physiologic studies have begun to identify a group of transient functional factors which may convert a long-standing underlying structural abnormality from a stable to an unstable state. This information is developing into an understanding of the causes and mechanisms of SCD. Cardiac disorders constitute the most common causes of sudden natural death. After an initial peak incidence of sudden death between birth and 6 months of age (the sudden infant death syndrome), the incidence of sudden death falls abruptly and then increases to a second peak in the age range of 45 to 75 years. Moreover, increasing age is a powerful risk factor for sudden cardiac death. It follows that the proportion of cardiac causes among all sudden natural deaths increases dramatically with advancing years. From 1 to 13 years of age, only one of five sudden natural deaths is due to cardiac causes. Between 14 and 21 years of age, the proportion increases to 30 percent, and then to 88 percent in the middle-aged and elderly.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork Men and women have very different susceptibilities to SCD, and the gender differences decrease with advancing age. The overall male/female ratio is approximately 4:1, but in the 45- to 64-year-old age group, the male SCD excess is nearly 7:1. It falls to approximately 2:1 in the 65- to 74-year-old age group. The difference in risk for SCD parallels the risks for other manifestations of coronary heart disease in men and women. As the gap for other manifestations of coronary heart disease closes in the seventh and eighth decades of life, the excess risk of SCD narrows. Despite the lower incidence in women, the classic coronary risk factors still operate in the proportionately smaller subgroup of women--cigarette smoking, diabetes, hyperlipidemia, hypertension. Hereditary factors contribute to the risk of SCD, but largely in a nonspecific manner: They represent expressions of the hereditary predisposition to coronary heart disease. Coronary atherosclerotic heart disease is the most common structural abnormality associated with SCD. Up to 80 percent of all SCDs in the United States are due to the consequences of coronary atherosclerosis. The cardiomyopathies (dilated and hypertrophic) account for another 10 to 15 percent of SCDs, and all the remaining diverse etiologies cause only 5 to 10 percent of these events. The relative role of various factors contributing to the initiation of cardiac arrest has not been quantitated as well as the structural basis. Transient ischemia in the previously scarred or hypertrophied heart, hemodynamic and fluid and electrolyte disturbances, fluctuations in autonomic nervous system activity, and transient electrophysiologic changes caused by drugs or other chemicals (e.g., proarrhythmia) have all been implicated as mechanisms responsible for transition from electrophysiologic stability to instability. In addition, spontaneous reperfusion of ischemic myocardium, caused by vasomotor changes in the coronary vasculature and/or spontaneous thrombolysis, may cause transient electrophysiologic instability and arrhythmias. MYOCARDIAL PERFUSION IMAGING The potassium analogue thallium 201, cyclotron-produced with a half-life of 72 h, is the most commonly used agent to assess myocardial perfusion. Its active uptake by normal myocardial cells is proportional to regional blood flow. Areas of myocardial necrosis, fibrosis, and ischemia show reduced thallium accumulation ("cold spots") on images obtained soon after injection. Following its initial accumulation within cells, however, thallium 201 continues to exchange with the systemic pool. After several hours, equilibration occurs; viable myocardial cells having intact membrane function contain nearly equal concentrations. Thallium 201 scintigraphy is used most commonly to detect exercise-induced ischemia. Thallium is injected intravenously at peak exercise, and images are obtained 5 to 10 minutes later in several projections using either planar imaging or single photon emission computed tomography (SPECT). The images may be analyzed qualitatively or quantitatively using computer algorithms. Normal scans show relatively homogeneous distribution of activity, while those of patients with infarction or ischemia typically demonstrate one or more "cold spots." Because of continued exchange of thallium between viable cells and the systemic pool, however, most initial defects due to ischemia "fill in" on repeat imaging several hours later. Some, however, require up to 24 h for redistribution or are best identified following reinjection of thallium 4 h after exercise, but areas of infarction demonstrate persistent reduction of uptake. Compared with routine exercise electrocardiography, exercise thallium scintigraphy increases the sensitivity for detection of coronary disease from approximately 60 to 80 percent and increases specificity slightly from about 80 to 90 percent. It is most useful in patients with 26/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork atypical chest pain in whom the exercise ECG is nondiagnostic or uninterpretable due to baseline ST abnormalities, left bundle branch block, ventricular hypertrophy, or drug and electrolyte effects; in patients who fail to achieve 85 percent of predicted maximal heart rate; and in patients with a high likelihood of a false-positive exercise ECG study. Thallium scanning improves localization of ischemia and provides prognostic information, since the presence and number of redistributing defects correlate with the incidence of future cardiac events. Thallium scintigraphy also has been used to detect ischemia during spontaneous pain, pacing, and adenosine- and dipyridamole-induced coronary vasodilation. Dipyridamole thallium imaging appears to be as sensitive and specific as exercise thallium scintigraphy for detection of ischemic heart disease. It should be considered for patients unable to exercise, including those with peripheral vascular disease who have an increased risk of cardiac morbidity and mortality with vascular surgery.

Serial thallium 201 scintigrams obtained in the 45 degree(s) LAO projection in a patient undergoing exercise testing for evaluation of chest pain. The immediate postexercise image (left) demonstrates decreased perfusion of the septum. The 1- and 2-h delayed images (middle and right) demonstrate "filling in" of the defect, reflecting redistribution. The computerderived time-activity curves (bottom) confirm the significant reduction in initial counts in the septum, relative to the posterolateral wall, and demonstrate near equalization of activity by 2 h. S = septum; PL = posterolateral wall.

PERCUTANEOUS TRANSLUMINAL CORONARY ANGIOPLASTY PTCA is a widely used method to achieve revascularization of the myocardium in patients with symptomatic ischemic heart disease and suitable stenoses of epicardial coronary arteries. Whereas patients with stenosis of the left main coronary artery and those with three-vessel coronary artery disease who require revascularization are best treated with coronary artery bypass surgery, PTCA is widely employed in patients with symptoms and evidence of ischemia due to stenoses of one or two vessels, and even selected patients with three-vessel disease, and may offer many advantages over surgery. 27/30

Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork After a flexible guidewire is advanced into a coronary artery and across the stenosis to be dilated, a miniature balloon catheter is advanced over the guidewire and into the stenosis followed by repeated inflations until the stenosis is decreased or relieved.

Indications angina pectoris, stable or unstable, which should be accompanied by evidence of ischemia in an exercise test. This symptom should be sufficiently severe to warrant the consideration of bypass graft surgery. PTCA is more effective than medical therapy for the relief of angina in patients with single-vessel coronary artery disease. The value of this procedure in improving outcome has not been established, and therefore it is not generally indicted in asymptomatic or mildly symptomatic patients. to dilate stenoses in native coronary arteries and in bypass grafts in patients who have recurrent angina following coronary artery surgery. This is an important indication when the technical difficulties and the increased mortality that accompanies reoperation are considered. in patients with recent total occlusion (within 3 months) of a coronary artery and severe angina; in this group the primary success rate is decreased to approximately 50 percent. Efficacy Primary success, i.e., adequate dilation with relief of angina, is achieved in 85 to 90 percent of cases. Recurrent stenosis of the dilated vessels occurs in 20 to 40 percent of cases within 6 months of the procedure, and angina will recur within 6 to 12 months in 25 percent of cases. This recurrence of symptoms and restenosis is more common in patients with diabetes mellitus, unstable angina, incomplete dilation of the stenosis, dilation of the left anterior descending coronary artery, and stenoses containing thrombi. Dilation of arteries which are totally occluded and of stenotic or occluded vein grafts also exhibit a high incidence of restenosis. It is usual clinical practice to administer aspirin and a calcium channel antagonist for months after the procedure. Although aspirin may help prevent acute coronary thrombosis during and immediately following PTCA, there are no controlled clinical trials that have demonstrated that these medications or any other can clearly reduce the incidence of restenosis. If patients do not develop restenosis or angina within the first year after angioplasty, the prognosis for maintaining improvement over the subsequent 4 years is excellent. If restenosis occurs, PTCA can be repeated with the same success and risk, but the likelihood of restenosis increases with the third or subsequent attempt. Between 30 and 50 percent of patients with symptomatic coronary artery disease who require revascularization can be treated by PTCA and need not undergo coronary artery bypass surgery. Successful angioplasty is less invasive and expensive than coronary artery surgery, usually requires only two days in the hospital, and permits considerable savings in the cost of care. Successful PTCA also allows earlier return to work and the resumption of an active life. CORONARY ARTERY BYPASS GRAFTING In this procedure, a section of a vein (usually the saphenous) is used to form a connection between the aorta and the coronary artery distal to the obstructive lesion. Alternatively,


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork anastomosis of one or both of the internal mammary arteries to the coronary artery distal to the obstructive lesion may be employed. 1 The operation is relatively safe, with mortality rates less than 1 percent when the procedure is performed by an experienced surgical team in patients without serious comorbid disease and normal left ventricular function. 2 Intraoperative and postoperative mortality increases with the degree of ventricular dysfunction, comorbidities, and surgical inexperience. The effectiveness and risk of coronary artery bypass grafting vary widely depending on case selection and the skill and experience of the surgical team, so that the latter must be taken into account when a patient is being considered as a candidate for this procedure. 3 Occlusion of vein grafts is observed in 10 to 20 percent during the first postoperative year, and the incidence is approximately 2 percent per year during 5- to 7-year follow-up and 5 percent per year thereafter. Long-term patency rates are considerably higher for internal mammary artery implantations; in patients with left anterior descending coronary artery obstruction, survival is better when coronary bypass involves the internal mammary artery rather than a saphenous vein. 4 Angina is abolished or greatly reduced in approximately 85 percent of patients following complete revascularization. Although this is usually associated with graft patency and restoration of blood flow, the pain may also have been alleviated as a result of infarction of the ischemic segment or a placebo effect. 5 Coronary artery bypass grafting does not appear to reduce the incidence of myocardial infarction in patients with chronic ischemic heart disease; perioperative myocardial infarction occurs in 5 to 10 percent of cases, but in most instances these infarcts are small. 6 Mortality is reduced by operation in patients with stenosis of the left main coronary artery as well as in patients with three-vessel coronary artery disease and impaired left ventricular function. However, there is no evidence that coronary artery bypass surgery improves survival in patients with one- or two-vessel disease who have chronic stable angina and normal left ventricular function or in patients with one-vessel disease and impaired left ventricular function. DIFFERENTIAL DIAGNOSIS OF CHEST DISCOMFORT The key issue in the evaluation of the patient with is to distinguish potentially life-threatening conditions such as coronary artery disease, aortic dissection, and pulmonary embolism from other causes of chest discomfort. Even patients who have brief episodes of pain and are otherwise in apparently excellent health may have intermittent myocardial ischemia or even recurrent pulmonary emboli. The chest discomfort of myocardial ischemia is angina pectoris. Myocardial ischemia from coronary atherosclerosis is more common in patients who have hypercholesterolemia, diabetes mellitus, hypertension, obesity, or who smoke. Toxins, including cocaine ingestion or withdrawal of chronic exposure to nitroglycerin, can cause sufficient coronary vasoconstriction to result in myocardial ischemia, and cocaine also can cause myocardial infarction. Myocardial infarction The chest discomfort from myocardial ischemia that is caused by aortic stenosis, hypertrophic cardiomyopathy, and nonatherosclerotic causes of coronary artery disease is generally similar to that of angina pectoris from coronary atherosclerosis. Pericarditis can cause pain in several locations.


Seminar 3 Seminars from internal medicine for the 5th year Prof. Ji Hork Patients with marked right ventricular hypertension may have exertional pain which is quite similar to that of angina. This discomfort probably results from relative ischemia of the right ventricle brought about by the increased oxygen needs and by the elevated intramural resistance, with reduction of the normally large systolic pressure gradient which perfuses this chamber. The pain due to acute dissection of the aorta or to an expanding aortic aneurysm results from stimulation of nerve endings in the adventitia. The pain usually begins abruptly, reaches an extremely severe peak rapidly, is felt in the center of the chest and/or in the back depending on the site of the dissection, lasts for hours, and requires unusually large amounts of analgesics for relief. The pain resulting from pulmonary embolism may resemble that of acute myocardial infarction, and in massive embolism it is located substernally. In patients with smaller emboli, the pain is located more laterally, is pleuritic in nature, and may be associated with hemoptysis. Pleural pain from fibrinous pleurisy or any pneumonic process is very common. Substernal discomfort also frequently occurs in the presence of tracheobronchitis; it is commonly described as a burning sensation accentuated by coughing. The pain of mediastinal emphysema may be intense and sharp and may radiate from the substernal region to the shoulders; often a distinct crepitus is heard. The pain associated with mediastinitis and mediastinal tumors usually resembles that of pleuritis but is more likely to be maximal in the substernal region. The several abdominal disorders which may at times mimic anginal pain may usually be suspected from the history.

PROGNOSIS The principal prognostic indicators in patients with ischemic heart disease are the functional state of the left ventricle, the location and severity of coronary artery narrowing, and the severity or activity of myocardial ischemia. Angina pectoris of recent onset, unstable angina, angina which is unresponsive or poorly responsive to medical therapy or is accompanied by symptoms of congestive heart failure all indicate an increased risk for adverse coronary events. The same is true for the physical signs of heart failure, episodes of pulmonary edema, or roentgenographic evidence of cardiac enlargement. An abnormal resting ECG or positive evidence of myocardial ischemia during a stress test also indicate increased risk. Most importantly, the following signs during noninvasive testing indicate a high risk for coronary events: a strongly positive exercise test showing onset of myocardial ischemia at low workloads, large or multiple perfusion defects or increased lung uptake during stress thallium scanning, a decrease in left ventricular ejection fraction during exercise on radionuclide ventriculography, and hypotension with ischemia during stress testing. Obstructive lesions of the proximal left anterior descending coronary artery are associated with a greater risk than are lesions of the right or left circumflex coronary artery, since the former vessel usually perfuses a greater quantity of myocardium. Critical stenosis of the left main coronary artery is associated with a mortality of about 15 percent per year.