Diagnosis and management of angina pectoris

Editorial B(,ard (clockwise from top): W. Proctor William C. Roberts, Robert A. O’Rourke, Frank de Leon

Harvey, James J. L.eona Ird, 1. Marcus and Ant onio C.

EDITOR’S PREFACE Coronary artery disease is, and will continue to be, one of the major problems of cardiovascular disease. Because of this fact, we probably need at least an annual updating overview of this problem, and Dr. Desmond Julian has ably given us just this. The title of his article is Diagnosis and Management of Angina Pectoris and Doctor Julian discusses a wide spectrum ranging from the clinical symptoms of angina pectoris to the laboratory diagnosis of coronary artery disease, including the facts concerning coronary bypass surgery. Doctor Julian has had long experience in dealing with problems of coronary artery disease. I well remember visiting his hospital in Edinburgh, Scotland, approximately 9 years ago and seeing his excellent Coronary Care Unit, where he was in the midst of doing active clinical research on the problems of coronary artery disease. Desmond Julian is highly qualified to discuss this current problem, and he writes about it in a lucid and practical style that is easy and enjoyable to read.

Our readers are referred to a preceding issue of CURRENT IN CARDIOLOGY-A Practical Approach Disease, with Special Reference to Coronary

PROBLEMS

Artery

to Coronary Bypass Sur-

gery, by Drs. R. Bruce Logue, Spencer B. King and John S. Douglas, Jr. (May 1976). This makes a good companion to the discussion by Doctor Julian.

DIAGNOSIS AND MANAGEMENT OF ANGINA PECJORIS DESMOND G. JULIAN

TABLE DIAGNOSIS

OF CONTENTS

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Symptoms . Physical Examination

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SUMMARY

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38 40 41 45

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. . Artery Surgery . . . .

12 15 18 18 19

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CORONARY ARTERY SURGERY

Graft Patency . Results of Coronary Unstable Angina.

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MANAGEMENT

General Management Drugs in the Treatment

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THE PROGNOSIS OF STABLE ANGINA MEDICAL

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DIAGNOSIS OF DISORDERS THA’I MAY BE RESPONSIBLE FOR . . . . . . . . ANGINA PECTORIS

The Electrocardiogram Echocardiography Nuclear Imaging. . Cardiac Catheterization

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is British Heart Foundation Professor of ~Cardiology, University of Newcastle upon Tyne. He graduated from Cambridge Uni“versity and trained in clinical medicine at ; the Middlesex Hospital, London. His postgraduate training was at the National Heart Hospital, London and the Royal Infirmary, Edinburgh, and at the Peter Bent Brigham Hospital in Boston. Dr. Julian has been cardiologist at Sydney Hospital and consultant physician to the Royal Infirmary, Edinburgh. His principal research interests are in the field of acute myocardial infarction and the arrhythmias associated with it, particularly in ventricular fibrillation.

ANGINA PECTORIS is a term used to describe a well-known syndrome in which the usual feature is central chest pain, provoked by exercise and relieved within a few minutes by rest; it usually has a crushing, vise-like or heavy character. It is agreed that the pain may radiate to many areas, including the neck, jaw and both arms, particularly the left, but sometimes it radiates to the back and to other adjacent areas. But is it angina if the discomfort is confined to the arm or jaw? Most physicians would agree that it is if they have good evidence that the origin of the pain is in the heart. Historically, angina is intrinsically related to .exercise, but does angina occur at rest? Most physicians would agree that it does, even in the absence of any alternative provoking factors such as anemia or anxiety. Classically, angina is relieved by rest or by glyceryl trinitrate. Many cases of “unstable angina” are not relieved in these ways. If a pain in the central chest of a tight or burning character were provoked by exertion and relieved by rest but found to be due to esophageal reflux, would that be angina? Surely not. What is the pain of angina due to? There appears to be no accepted answer to this question. It can occur in the absence of coronary arterial disease and even of demonstrable ischemia as, for example, in some cases of cardiomyopathy. It has not been possible to associate it in all cases with a rise in end-diastolic pressure in the left ventricle or to the presence of abnormal metabolites. Perhaps, at present, the closest we could get to a definition of angina pectoris is a discomfort in the chest or adja5

cent areas resulting from a transient and reversible inadequate oxygenation of myocardial tissue. The foregoing discussion may be regarded as pedantic, but it is important to realize the problems in defining angina so that one does not make automatic assumptions that, for example, a certain degree of ST depression or of coronary arterial stenosis proves the diagnosis. w ROBERT A. O’ROURKE: As pointed out above, physicians should remember that angina1 chest pain due to myocardial ischemia may occur

in the absence of angiographic evidence of coronary artery disease and that a 50% or greater narrowing of one or more of the major coronary arteries often is demonstrable in patients who have neither angina pecto& nor ischemic ST-T wave changes at rest or during exercise. Furthermore, electrocardiographic evidence of myocardial ischemia may be present at rest or exercise without coincident angina pectoris.

DIAGNOSIS Because angina is a symptom, the diagnosis depends essentially on a correct interpretation of the patient’s complaints. The full syndrome as described by Heberden can be denied only if investigations demonstrate that this clearly is due to some cause outside the myocardium. If the symptoms are somewhat atypical, it is desirable to establish the diagnosis by one of the tests that suggest or prove myocardial hypoxia at the time of the discomfort. SYMPTOMS

SITE. -The discomfort of angina pectoris most commonly is located at or behind the middle or upper third of the sternum. Even when the predominant sensation is elsewhere there usually is some involvement of the sternal region. The first or main site of the discomfort may, however, be in the lower sternal region, on either or both sides of the chest or in the arms, particularly the left, and in the neck or lower jaw. Much more rarely, the discomfort is predominantly or even exclusively in the interscapular or left scapular region. Early in the history of the disorder, and at the onset of individual attacks, the discomfort may be located in one of these areas but radiate to one or more of the others at a later stage. The most common pattern is for the discomfort to be initiated in the sternal region and radiate to the region of the left shoulder and upper arm. Frequently, too, the discomfort extends farther down one or both arms to the elbow, wrist or fingers. Not uncommonly, some of these areas are “skipped,” so that, for example, 6

there may be discomfort in the chest, left elbow and fingers but not in the shoulder region. In many patients, the discomfort may start peripherally- i.e., in the jaw or arm and spread subsequently to the chest. It has been emphasized by many cardiologists that pain in the left submammary region is unlikely to be anginal. However, the discomfort of true angina quite often radiates from the central chest to the left submammary region. Furthermore, there are many well-documented cases in which it is clear that angina is predominantly or even exclusively located in this area. Fortunately, most cases of left submammary pain are not of the character associated with true angina pectoris and are not related in the same way to exertion and rest. CHARACTER. -Although the pain can be severe, in the vast majority of cases it is mild to moderate and can be limited by restriction of activity. It is common for patients to specifically deny the existence of pain, sometimes forcefully, while emphasizing the presence of a discomfort that is described as an oppression, heaviness or tightness. Cultural and linguistic difficulties often lead to the choice of words that are unhelpful or even misleading. Thus, some patients describe the pain as “sharp” to indicate severity rather than “knife-like,” which might be interpreted from this word. In any case, the description of discomfort or pain inevitably is difficult and many individuals prefer to use gestures rather than words to convey their unease. Although it often is taught that one should not ask leading questions, I often have found it helpful in cases of suspected angina to provide patients with severe1 words from which they can choose, starting with those, such as “stabbing,” that are slightly misleading so as not to lead the patient too readily to use the words suggestive of angina itself. It is important to recognize that the nature of the sensation differs with its site. Whereas the discomfort in the chest often is described as a heaviness, or a tightness, or a strangling, or a vise-like sensation, it may also be likened to heartburn. One or both arms may be described as heavy or useless; not infrequently, the sensation in the fingers is described as a numbness or tingling. In the neck, a choking sensation often is reported whereas the sensation in the jaw more usually is an ache, sometimes being likened to toothache. RELATIONSHIP TO EXERCISE,EMOTION AND OTHER FACTORS.- By far the most common provoking factor of angina pectoris is walking. In its earlier stages, angina often is provoked only by walking uphill or in the cold or after a meal. As the symptom progresses in its severity, it is elicited by decreasing amounts of exercise, so that in the most advanced cases it may occur on the 7

slightest exertion. This degree of severity is rare, and the majority of patients can, by minor restriction of their activities, avoid exercise-induced angina. However, there is a considerable variability from time to time during the day and at different times of year. Many patients experience angina only on first going out in the morning and can work all day at jobs requiring a moderate amount of physical exertion without any stress. Usually, the -, patient has himself realized that he must slow down or stop. when he develops an attack, but some are able to walk the attack off and many others find that if they have stopped after the first attack, a similar amount of exercise will not produce the pain. The variability of the symptom is such that few patients are able to quantitate precisely the amount of exercise required to produm pain. Although reported much less commonly, angina1 pain can be provoked by arm movements and, indeed, for a given amount of work there is evidence that arm movements are more likely to produce angina than is walking. In the most severe cases of angina, relatively minor exercise such as rubbing oneself after a shower or shaving may provoke symptoms. Emotion is only slightly less important than exercise as a major provoker of angina. Anger, anxiety and, frequently, watching competitive sport provoke symptoms. It may also be induced by car driving and public speaking. Both exercise and emotion contribute to the development of angina during sexual intercourse. Angina experienced in bed is common, but the cause varies with the circumstances. A frequent complaint is of angina while getting into bed, either because of the physical exertion involved in getting ready for bed or because of cold sheets. Many patients are awakened from their sleep by angina, sometimes by dreams that may be exciting or involving imaginary physical exercise. A more sinister variety is that in which the patient experiences angina whenever he lies down. This-the so-called angina decubitus - usually signifies advanced disease and often is associated with gross limitation of activity. Tobacco is, perhaps surprisingly, a rather uncommon cause of angina, although it is well recognized. Spontaneous angina, that is, angina occurring without a clear precipitating factor, is relatively uncommon and calls for special consideration, as it may well have a different pathogenesis from other forms of angina. Many patients with this type of angina do not have exercise-induced discomfort and the angina1 attack may be accompanied by ST elevation rather than depression. This particular syndrome, which was described originally by Prinzmetal and his colleagues’ in 1960, recently has been summarized by Sherf and Cohen2 as follows: 8

1. The angina1 pain occurs at rest or during normal activity and is not provoked by exercise or emotion. 2. The pain often is more severe and of longer duration than the usual angina1 pain. 3. In some patients, the pain is cyclic in character and often recurs at the same time of day or night. This particular type of angina has been attributed by some to coronary atherosclerosis affecting a single major coronary artery, by others to severe coronary artery disease and by yet others to coronary artery spasm. Its investigation will be discussed in a subsequent section. RELIEF FROM ANGINA PECMRIS. -Almost as specific as the provocation of angina by exercise is its relief by rest. Indeed, if an exercise-provoked attack is not relieved in this way, one should suspect the possibility of infarction. Emotion-induced attacks are less readily voluntarily terminated. As a result of this, many patients with emotion-induced angina learn to avoid charged situations. Nitroglycerin usually can terminate an attack of angina pectoris in less than 3 minutes. However, if angina pectoris is severe, it may be ineffective or take longer to act. Carotid sinus pressure frequently is capable of terminating an attack.3 It is important not to use this test in a patient with suspected carotid artery stenosis and the test always should be carried out with the patient recumbent because of the danger of hypotensive syncope. b FRANK I. MARCUS:It is of interest to read the description of the effect of carotid sinus massageby the late Dr. Samuel Levine, a keen observer

and master clinician: “Quite recently an interesting relationship between carotid sinus stimulation and angina1 pain has been discovered. It has been found that frequently the pain can be made to disappear in several seconds by massaging one or the other carotid sinus. In an experience now comprising over 100 episodes I have observed that whenever satisfactory slowing is produced the pain either promptly disappears or is markedly lessened. Furthermore, whenever no significant slowing of the heart results the pain is unalfected. No such relief was obtained when the pain was due to a variety of other nonanginal causes, except in a rare case of functional pain. The response was so distinctive that I believe this test has diagnostic value. If well-marked slowing takes place from carotid stimulation while the patient has pain and it is not lessened, I believe that the pain is very unlikely angina1 in nature. In many instances the particular episode is completely relieved and the pain does not return. In others, as the heart rate speeds up again, the pain comes back” (Levine, S. A., Clinical Heart Disease [Philadelphia: W. B. Saunders Company, 19511, p. 98). DURATION OF THE ATTACK. -Most

attacks of exercise-induced 9

angina resolve in 3 minutes or less but few patients time their attacks and most think that their attacks last much longer than they actually do. However, in some individuals, particularly those with emotionally induced angina, the discomfort may go on for 10 or 15 minutes or even longer, particularly if the provoking cause persists. Even in those in whom the major discomfort disappears rapidly, a vague ache sometimes may persist. It is unusual for an attack to last less than a minute and virtually never for seconds. “NONVERBAL” DESCRIPTION OF ANGINA. -Many individuals who experience angina find it extremely difficult to describe one or more of its characteristic features. They usually can delineate the site of the discomfort, but its character and duration may elude their descriptive powers. Martin,4 in writing on what he called “the nonverbal diagnosis of the pain of coronary insufficiency,” noted several different types of gestures that might be made. Thus, the patient might lay his hand on the chest or sweep it from side to side, or he may place one hand on each side of the chest with the fingers touching over the sternum and then separate them or place them laterally in this way and bring them toward the midline. Frequently, the hand is held in the clutching position over the neck or sternum. It is very rare for a patient with true angina to point with a finger to the site of the pain, particularly if he points to the left submammary region. ACCOMPANYING SYMPTOMS. -Breathlessness is a common accompaniment to angina and some patients find it difficult to differentiate between the two symptoms. Thus, some will say that they have noted a curious difficulty with breathing when they walk but then deny breathlessness, but others will clearly describe both the distinctive chest discomfort and dyspnea. Very often, however, the patient will only volunteer the angina1 symptoms but admit to dyspnea when the direct question is put.

) ANTONIO C. DE LEON, JR.: I have encountered one patient who complained only of breathlessness with mild effort, quickly relieved by sublingual nitroglycerin. without any associated discomfort or pain.

Other accompanying symptoms are not very common. Palpitation is rare and few patients complain of nausea and sweating. Not surprisingly, apprehension is common but the sense of impending dissolution - “angor animi” - is rare; nor is it as pathognomonic as Friedberg suggested. Actual syncope is extremely rare except in those cases in which bradycardia, secondary either to heart block or to sinus disease, is responsible for both the chest pain and loss of consciousness. 10

) ROBERT A. O’ROURKE: In this era of selective coronary arteriography and coronary artery vein bypass graft surgery, it has become even more important for the physician to carefully question his patients as to whether or not angina pectoris is truly present. We see a large number of patients who have undergone coronary bypass surgery for anatomic lesions in the coronary circulation who continue to have the same pain after surgery as before. In many cases, a careful history indicates that this pain has few, if any, of the characteristics of angina pectoris.

PHYSICAL

EXAMINATION

Physical examination plays an essential part in the assessment of the patient with angina pectoris, although it relatively seldom has an important role in its diagnosis. It is, of course, vital in those cases in which the syndrome is secondary to valvular heart disease, but most patients with angina pectoris exhibit no abnormal features between attacks. There may, however, be features associated with coexisting hypertension or following a previous myocardial infarction. Cardiomegaly, therefore, may be present and a fourth heart sound is common. Third heart sounds are much less frequent and indicate left ventricular failure. A systolic murmur may be present because of functional mitral regurgitation or as a consequence of papillary muscle malfunction. The paradoxic

pulsation

of a ventricular

aneurysm

may be

present. If the patient is seen during an attack of angina, it is usual for the pulse rate to be moderately increased and the blood pressure generally higher than prior to the attack.5 However, during spontaneous angina pectoris, the blood pressure may be normal or relatively low. A number of other physical signs have been noted during attacks, including pulsus alternans, a fourth heart sound and paradoxic splitting of the second heart sound. Occasionally, an apical systolic murmur due to mitral regurgitation may be heard. F ANTONIO C. DE LEON, JR.: In some patients, the apical systolic murmur of papillary dysfunction is present only just before and during the episode of angina. ) ROBERT A. O’ROURKE: We believe that the physical examination of a hospitalized patient with undefined chest pain during an attack can be extremely helpful in deciding whether or not the chest discomfort results from ischemic heart disease. In our experience, most of these patients develop an increase in blood pressure and heart rate (unless receiving propranolol) during the episode of ischemia. The presence of a new fourth heart sound, the existence of left ventricular dyssynergy on palpation, the appearance of an apical systolic murmur and/or the development of bibasilar rales all point to the diagnosis of ischemic heart disease. 11

DIAGNOSIS OF DISORDERS THAT MAY BE RESPONSIBLE FOR ANGINA PECT~RIS CORONARY ATHEROSCLEROSIS. - Coronary atherosclerosis is responsible for the vast majority of cases of angina pectoris in the m iddle-aged and elderly. There is no direct clinical way of proving atherosclerosis as the cause, although it may be suspected when several risk factors are present, when there is a family history of the disorder and when other causes can be excluded. CONGENITAL ANOMALIES OF THE CORONARY ARTERIES. -There are several congenital abnormalities of the coronary arteries that may lead to angina with or without complicating atherosclerosis. Thus, there may be an anomalous origin of a vessel from the pulmonary artery, or from the aorta, or there may be a coronary arteriocameral fistula. These may give rise to angina in childhood or adolescence. These disorders require coronary arteriography for their demonstration, although in the case of the fistula the presence of a continuous murmur may give rise to suspicion. AORTIC STENOSIS. -After coronary atherosclerosis, severe calcific aortic stenosis probably is the most common single cause of angina pectoris. Congenital aortic stenosis may be responsible for angina in childhood. The combination of angina with dyspnea and, particularly, exertional syncope suggests this diagnosis. Most patients have the characteristic slow, flat pulse, the aortic systolic murmur, often accompanied by a thrill, clinical electrocardiographic and radiologic evidence of left ventricular hypertrophy and calcification of the aortic valve on fluoroscopy. The mere presence of an aortic systolic murmur in the elderly should not be regarded as evidence of aortic stenosis in the absence of the other features. As aortic stenosis and coronary atherosclerosis frequently coincide, cardiac catheterization with coronary angiography is necessary for the assessment in such cases. (Generally speaking, if a relatively small gradient is found, e.g., 40-50 m m Hg, coronary atherosclerosis often is present. This is not so when the gradient is more severe. It is our standard practice to carry out coronary angiography in all patients under consideration for surgery for aortic stenosis. AORTIC REGURGITATION. -Angina pectoris is not a common symptom of isolated aortic regurgitation, but it occurs frequently when aortic stenosis and aortic regurgitation coexist. It often complicates syphilitic aortic regurgitation when the valve disorder may be accompanied by coronary ostial obstruction. The diagnosis of aortic regurgitation usually is easy from the presence of an aortic diastolic murmur, although its assessment may be difficult unless there is a collapsing pulse with a large 12

pulse pressure and left ventricular dilatation. of aortic regurgitation may be suspected from other clinical features of tertiary syphilis and of calcification in the ascending aorta as well rology.

Syphilitic origin the history, from from the presence as by positive se-

w FRANK I. MARCUS:One does not frequently have the opportunity to observe a large population of patients with aortic insufficiency to obtain the true incidence of angina pectoris in this population. In the classic study by Saga1 et al. @gal, J., Harvey, P., and Hufnagel, C.: A clinical study of 100 cases of severe aortic insufficiency, Am. J. Med. 21:200, 19561, of 83 patients with .seuererheumatic insufficiency 9 were asymptomatic. Of those who had symptoms, angina was present in almost half. It usually appeared after the onset of congestive heart failure, although in 6 cases angina was present without cardiac congestion for an average of 4 years. Nocturnal angina was fairly common and in several cases was the predominant form present. These authors emphasize the frequency of angina in underlying severe aortic regurgitation. It should be noted that the average age of these patients with angina was 34 years and in several patients with this symptom who came to necropsy, whom I have personally observed, the coronary arteries were widely patent. CARDIOMYOPATHY. -Angina

is a not uncommon

complication

of the cardiomyopathies but is particularly associated with idiopathic hypertrophic subaortic stenosis (hypertrophic obstructive cardiomyopathy). This latter condition should be suspected in the presence of features that suggest aortic stenosis but in which the pulse is more sharply rising than it is in valvular aortic stenosis. There often is associated mitral regurgitation. Additional clues are the absence of an ejection click and of calcification of the valve. Echocardiography usually provides reliable evidence of this disorder, asymmetric hypertrophy of the septum and systolic anterior movement of the mitral valve being notable fehtures. The diagnosis may be further confirmed by cardiac catheterization

and left ventriculography.

w FRANK I. MARCUS:The murmur in patients with hypertrophic obstructive cardiomyopathy frequently is maximal at the apex or lower left sternal border. As mentioned, the murmur frequently is due to the, associated mitral regurgitation. Nevertheless, the differential diagnosis frequently is that of mitral regurgitation rather than valvular aortic stenosis. Since angina is present infrequently in mitral regurgitation, the presence of an angina1 type of pain in a patient with an apical systolic murmur should make one suspect the possibility of hypertrophic obstructive cardiomyopathy. MITRAL STENOSIS.-Although

rarely

seen nowadays,

mitral

stenosis at one time was regarded as a relatively frequent cause of angina in younger women. Thus, Stuckep reported the symptom in 8.5% of 400 patients. The apparent rarity tom now may be partly due to the sharp reduction

of this sympin the preva13

lence of mitral valve disease but also because it is associated with pulmonary hypertension; because of the success of surgery, few patients today are allowed to proceed to pulmonary hypertension. Another mechanism of angina in mitral valve disease is coronary embolism. IMITRAL axGuaGrrArroN. -Angina pectoris is not a feature of isolated mitral regurgitation except where there is prolapse of! the mitral valve. It now is well recognized that chest pain is a common complaint with this disorder but, at least on echocardiographic grounds, this anomaly is so frequent in young women that it must not be regarded necessarily as the cause of any chest pains that are encountered. Many of the subjects have left submammary pain that otherwise would be regarded as due to an anxiety neurosis. In such patients, this may well be the case, because. the finding of abnormality on auscultation, particularly if buttressed by echocardiography, may induce the sense of anxiety. However, in some patients, more classic symptoms of angina pectoris are encountered. The diagnosis is suspected by the combination of a midsystolic click and late systolic murmur, although the click may be absent and the murmur variable both in its timing during systole and in its intensity. The diagnosis may be reinforced by echocardiography and left ventriculography. CORONARY ARTERY SPASM.-It is becoming increasingly recognized that, in some patients, coronary artery spasm is the mechanism for angina pectoris. This is not a new concept, for in 1910 Sir William Osler’ wrote “Spasm or narrowing of the coronary artery or even of one branch may so modify the action of a section of the heart that it works at disturbed tension and there are stretching and strain sufficient to arouse painful sensations.” Despite this, for many years the existence of coronary artery spasm was doubted because it was found that nearly all patients dying with a history of angina pectoris showed coronary atherosclerotic lesions unless some other well-defined pathology could be shown. With the development of coronary arteriography, spasm was noticed in segments of artery adjacent to the catheter tip in many cases. However, such instances are not usually associated with chest pain or significant ST changes and it has not been thought that this finding is relevant to the genesis of angina. F’rinzmetal et al.,’ in their report describing %ariant angina,” suggested the possibility of increased tone of a large coronary artery as a mechanism of the pain. In recent years there have been numerous reports of spasm being demonstrated by coronary arteriography, although in many cases it has been difficult to prove that this spasm has not been due to local irritation. However, Maseri et aLa have described patients who developed 14

ST segment elevation when no coronary artery catheter was in position; immediately subsequent selective injection into the artery supplying the myocardium corresponding to the area where the ST changes were seen demonstrated spasm in that vessel. Furthermore, in these cases, the hemodynamic features of angina (that is, a rise in enddiastolic pressure and impaired relaxation of the left ventricle1 were not preceded by hypertension or tachycardia, as usually is found in exercise-induced angina. It still is by no means clear why coronary artery spasm occurs and what the provoking factors are. However, certain drugs can be responsible, particularly ergot alkaloids, and it is possible that nitroglycerin withdrawal is another factor. w ROBERT A. O’ROURKE: The subject of variant angina recently has been reviewed in CURRENT PROBLEMS IN CARDIOLOGY (July 1977) by Dr. Bertron Groves. The interested reader is referred to Doctor Groves’excellent monograph on the subject.

THE ELECTROCARDIOGRAM

The electrocardiogram (ECG) plays an important diagnosis and assessment of angina pectoris.

role in the

THE RESTING ELECTROCARDIOGRAM.-The ECG at rest is ofrestricted value in the diagnosis, for it is normal in 50- 75% of patients with angina. In many of the remaining cases there is residual evidence of old myocardial infarction, particularly the presence of Q waves, and in some there is persistent ST segment elevation or T wave inversion. In others there are left ventricuv lar hypertrophic changes secondary to hypertension. In a substantial number of patients there are minor abnormalities that are not specific for myocardial ischemia. These may be minor ST segment depression, flattening or inversion of the T waves, flat ST segments without depression or arrhythmias. SPONTANEOUS ANGINA rEcToRIs. -Unfortunately, it is relatively unusual to see a patient during a spontaneous attack of angina pectoris except when the patient is under observation either in an intensive care unit or by Holter monitoring. It has been observed that ST segment depression usually precedes the onset of the pain, but this is not necessarily so, and commonly the ST segment does not return to normal for some time after the disappearance of pain. The most common change is that of horizontal or downwardsloping depression of the ST segment. In a few cases, it is possible to demonstrate that an arrhythmia has been the immediate triggering factor for the pain. ST segment elevation is the well-recognized characteristic of 15

so-called Prinzmetal’s variant angina and is seen most often with the patient at rest. It has been increasingly assumed that such changes are due to coronary artery spasm. In continuous monitoring studies, it has become apparent that, in susceptible patients, both ST depression and ST elevation occur frequently in the absence of pain and without changes in the blood pressure and heart rate. ) ROBERT A. O’ROURKE:We have studied more than 80 patients with chest pain suggestive of angina pectoris and a normal resting electrocardiogram by treadmill exercise testing, continuous ambulatory ECG rnonitoring and selective coronary arteriography. The results of our studies indicate that continuous ambulatory ECG monitoring is less sensitive than the ECG exercise test for detecting ST segment changes in patients with ischemic heart disease. Furthermore, a number of false positive > 1 mm ST segment depressions occur during continuous ambulatory ECG monitorings that are related to changes in position, hyperventilation, meals and medications. However, ambulatory ECG monitoring for quantitative ST segment changes is additive to ECG exercise testing in patients whose exercise ability is limited and in patients who have ST segment elevation during spontaneous chest pain, as occurs frequently with variant angina.

EXERCISE TESTS.-Because the electrocardiogram often is normal at rest and because spontaneous attacks of angina seldom are observed, stress tests have proved to be an important way of demonstrating evidence of myocardial ischemia. In submaximal exercise tests, the level of exercise is progressively increased until either a target heart rate or a target work rate is achieved. In previous years, the most commonly used was the two-step test described by Master.g This involves the performance of 15-25 trips up and down two steps each 9” high in a period of lY2 minutes. According to Master’s protocol, the number of trips varied with the age, weight and sex of the patient. The test was stopped if the patient experienced pain and it was recommended that the test should be performed only if a 12-lead ECG was normal and there was no history suggesting recent or impending myocardial infarction. If this test was normal, a double two-step test was administered in which twice as many steps were performed as in the single test over a period of 3 minutes. The ECG, usually recorded from leads II, V,, V, and V,, was recorded as soon as possible after exercise had stopped and repeated at a-minute intervals until the ECG returned to normal, if abnormalities were observed. Quite often the test might become abnormal for the first time 4 minutes or more after the conclusion of the test. In the original test, ST segment depression of 0.5 mm or more was regarded as abnormal, but subsequent modifications required horizontal or downward-sloping ST segment changes lasting for at least 0.03 second. Master also believed that J depression of any depth but of relatively long duration 16

was significant. It has been found that this test yields a large number of false negatives and some false positives, largely because the amount of exercise involved in the test is relatively small and the target heart rates seldom achieved. Many patients complain of fatigue or dizziness long before angina occurs. However, more recent modifications of the Master test can provide quite heavy loads and are useful in institutions in which a treadmill or a bicycle ergometer is not available. Both bicycle ergometers and treadmills now are in widespread use; experts differ in their preferences. The bicycle has the advantage that the patient can control his work rate more directly and the simplest ergometers are cheap. On the other hand, the treadmill probably permits more severe exercise testing and, unlike the bicycle, the technique can be mastered by virtually every patient. Most of those using submaximal tests utilize a target heart rate that is related to the maximal anticipated heart rate for an individual of a given age and sex.‘O Increasingly, symptom-limited maximal exercise tests are being used because it is common for patients with heart disease to reach symptom-limited work capacity before they reach the expected target heart rate.” We conduct exercise tests using a bicycle ergometer. We record from V,, V, and V, during exercise and from these leads and from leads I, II and III immediately after exercise and repeatedly over the next 10 minutes. We progressively increase the workload on the bicycle at 3-minute intervals until fatigue, chest pain, dyspnea or other symptoms limit the test. Blood pressure is recorded every 3 minutes. The test is regarded as positive if there is a l-mm depression of the ST segment persisting until 0.08 second after the J point. The inability to increase blood pressure and heart rate in response to maximal exercise provides an important clue to the severity of the underlying coronary heart disease. The justifiability of regarding ST depression as diagnostic of ischemic heart disease has been discussed in detail in an interesting article by Redwood et ~2.~~These authors point to the high incidence of ST segment changes in populations who have been shown by coronary angiography to have normal coronary arteries. They stress the importance of taking the electrocardiographic findings in the context of the clinical situation and discuss how this should affect the interpretation of the changes. Thus, in a normal population, ST depression is unlikely to indicate ischemic heart disease, but in patients in whom chest pain is a symptom, ST depression is more sensitive and more specific. Their conclusions have been severely criticized by Sheffield et aLi3 and McHenry,i4 who emphasized the importance of correct technique and of identifying correctly the abnormalities due to vasoregulatory dysfunction and hyperventilation. 17

ECHOCARDIOGRAPHY

Echocardiography has, at present, a limited place in the assessment of patients with suspected coronary heart disease. It can play a useful role in the diagnosis of angina due to such entities as idiopathic hypertrophic subaortic stenosis, calcific aortic stenosis and a prolapsed mitral cusp. It has also been used to demonstrate left main coronary artery disease,lSbut it is unlikely that even with technical advances it will prove possible to delineate other coronary artery lesions. We have found echocardiography valuable in providing evidence of left ventricular malfunction. Unfortunately, with current techniques, only limited assessment of regional abnormalities can be obtained, but we have used it to detect over-all poor left ventricular function, thus preventing one from proceeding with an unnecessary invasive investigation. By contrast, we have, unexpectedly, found good movement of the inferior wall or septum in some patients, which has encouraged us to a more aggressive approach than we had originally planned.

NUCLEAR IMAGING It is apparent that nuclear imaging will play an increasingly important part in the diagnosis and assessment of coronary artery disease. The injection of ‘%hallium during exercise reveals a “cold spot” in a poorly perfused region of myocardium. This technique has proved to be a valuable screening test for suspected disease; for example, in those with ST abnormalities on the electrocardiogram but without symptoms. A negative scan would discourage us from undertaking arteriography. Gated pool scanning permits a good estimate of left ventricular performance, including regional function. It is being used increasingly as a screening technique prior to coronary angiography and may render left ventriculography unnecessary in some cases. ) FRANK I. MARCUS: A word of caution is in order regarding a negative scan obtained after the injection of 201thallium during exercise. We have studied 49 patients with this technique who were evaluated for chest pain. Six of these patients had false negative scans. In other words, they had greater than ‘70% occlusion of at least one coronary artery and the thallium scan was interpreted as normal. Among these patients were 2 with significant triple vessel disease, 1 who had a complete occlusion of the left anterior descending artery and another who had a complete right coronary artery occlusion and 50- 75% occlusion of the left anterior descending artery (Okada, R. D., et aZ.,unpublished observations).

18

CARDIAC

CATHETERIZATION

Although noninvasive methods provide valuable information about myocardial function that may allow one to deduce the extent and distribution of coronary artery disease in a crude way, coronary arteriography and left ventriculography are essential techniques in the full evaluation of a patient with angina. Coronary arteriography gives quite precise information about the pathologic anatomy of the major coronary arteries, which allows the physician to give a more accurate prognosis than can be achieved in any other way and the surgeon to assess the potentialities of the bypass procedure. Left ventriculography not only provides information about over-all ventricular function, which usually can be obtained in other less-invasive ways, but provides the only accurate information about disturbances in regional performance. In skilled hands, these investigations can be carried out with a low mortality and morbidity, but these risks cannot be totally abolished, and in weighing the desirability of this type of cardiac investigation one has to consider the discomfort and hazard to the patient and the limitations of the information obtained. b FRANK I. MARCUS:This statement should not be interpreted to mean that every patient with angina should have coronary arteriography and left ventriculography. Doctor Julian clarifies this point later in his discussion. In many laboratories, particularly those in which a small number of cases are undertaken, coronary arteriography may not be an accurate tool. Thus, if the apparatus is not entirely satisfactory or the operator thoroughly skilled, good visualization of the vessels may not be obtained. Comparison between coronary arteriography and postmortem arteriography has shown that the in vivo technique may seriously underestimate the amount of coronary artery disease but it usually is not of practical significance. The coronary arteriogram is likely to be most misleading in diffuse circumferential narrowing of the artery and also when, because of proximal narrowing, the distal vessels are poorly seen. Other technical problems include the overlapping of vessels, the lack of an appropriate view of a vessel and the estimation of the size of vessels that are being perfused by collaterals. A major factor that must not be neglected is the importance of intra- and inter-observer error. It has been shown that even with great experience there can be very great differences in interpretation. Thus, in one study, four internationally famous coronary arteriographers could not agree as to whether or not there was significant left main stenosis in one patient. Left ventriculography and the hemodynamic evaluation of left 19

ventricular function may be misleading in a number of ways. In order to ensure adequate visualization of the left ventricle, at least two views should be obtained. If this is not done, important areas of myocardial wall and septum cannot be adequately seen. Even then, this may be difficult, particularly in the presence of an aneurysm. For example, the aneurysm may be so large that residual and possibly well-functioning myocardium cannot be L adequately seen. Another factor is the variability in left ventricular function from time to time. Thus, if the patient is investigated during an episode of angina, regional dysfunction will be observed and there will be a high left ventricular end-diastolic pressure. Ventricular ectopic beats during injection may prevent accurate evaluation of left ventricular performance. Although it is important to bear these limitations in mind, these investigations usually provide quite sensitive evidence of coronary artery anatomy and ventricular function. INDXCATIONS FOR CARDIAC CATHETEBIZATION. -There now are clear-cut situations in which coronary arteriography and left ventriculography are indicated. The most important of these is in the evaluation of the patient with angina pectoris that is stable but incapacitating. We believe that coronary arteriography should be carried out in any patient whose angina limits him to such an extent that he cannot perform his job or that other major aspects of his life are seriously affected. The presence of cardiac failure is not a contraindication unless other studies have shown a largely akinetic ventricle. This investigation should not be carried out when the age of the patient or the presence of concurrent disease precludes coronary artery surgery. Coronary arteriography probably carries a somewhat higher risk in unstable angina, both because the patient may have had a recent undetected myocardial infarction and because there is a relatively high incidence of left main coronary artery stenosis in this condition. In our view, this investigation should not be undertaken in the acute stage and one should wait at least until attempts have been made to ‘(cool off the situation. In the vast majority of cases, the pain rapidly comes under control and the patient subsequently may remain symptom free or with minimal complaints. However, if symptoms continue for more than a few days on full medical treatment, we consider that coronary arteriography should be undertaken with a view to early surgery. In these circumstances, it is advisable either to use counterpulsation during the procedure or to have the apparatus immediately available. In suspected coronary artery spasm, coronary arteriography is indicated if the symptoms are continuing to be troublesome despite medical treatment. Spasm may be suggested by ST segment elevation occurring spontaneously at rest, but it has also been reported as a cause of ST depression. It may be particularly 20

suspected if arrhythmias accompany the ST changes. This is an episodic condition and it seldom is possible to ensure that the investigation is carried out at the time of spontaneous pain. It is wise first to carry out a conventional coronary arteriogram. If this shows no abnormality, one then may use ergonovine maleate in an attempt to provoke coronary artery spasm. One must start very cautiously with a small dose such as 0.01 mg and gradually increase the amount. Reports to date suggest that it is specific for coronary artery spasm but is not very sensitive. If a patient is investigated during this quiescent phase, there may be no response to the ergonovine whereas at another time they may be exquisitely sensitive. Those patients who have a combination of coronary artery disease and spasm must be treated with the greatest caution, particularly with regard to the administration of ergonovine. Coronary arteriography now forms an essential part of the full assessment of a patient with cardiac valve disease prior to surgery. It is particularly important in the evaluation of angina occurring in the presence of aortic stenosis, although one may suspect the coexistence of coronary disease when the gradient across the aortic valve is relatively small. In most patients who have coronary artery disease complicating valve lesions, angina is a prominent symptom but this is not always so. Furthermore, delineation of the coronary arteries, particularly in patients with aortic disease, helps the surgeon decide on the technique of perfusing the coronary arteries, should this prove necessary. Coronary arteriography plays a small but important role in the diagnosis of coronary heart disease. It often is misused, however. The important fact here is that it is not yet established what the prevalence of coronary artery stenosis is in individuals without coronary heart disease. Undoubtedly, many patients whose chest pain is not due to coronary heart disease show “significant” lesions on the coronary arteriogram. Furthermore, in some 5 - loo/o of patients with true coronary artery disease the lesions cannot be well demonstrated on coronary arteriography. The results of arteriography, therefore, always should be reviewed in the light of the history and of the other investigations that may be of value in this context, such as stress testing and radionuelide scanning. As a diagnostic tool, coronary arteriography finds its chief place in the evaluation of individuals whose job carries a high risk. Thus, patients who are airline pilots, drivers of heavy vehicles or have similar occupations on which other peoples’lives depend are appropriate candidates. An increasingly important indication is the need to assess the significance of electrocardiographic changes on stress testing. There are many patients being inappropriately labeled as having coronary artery disease on the basis of ST depression on exercise, and apart, perhaps, for radionuclide scanning, the only way in which the diagnosis can be denied is by coronary arteriography. 21

This investigation can also be of value in the diagnosis of obscure cardiomyopathies. Many of these cases do not justify full investigation because even if coronary artery disease is discovered, they usually are not suitable candidates for coronary artery surgery in view of the very poor left ventricular function. Coronary arteriography may also be useful when life-threatening ventricular arrhythmias are occurring despite full medi- . cal treatment. However, it is extremely rare for such arrhythmias to be due to a surgically remediable lesion. Some physicians believe that coronary arteriography should be undertaken as a routine in young patients who recently have suffered a myocardial infarction in order to establish whether they have such abnormalities as an anomalous coronary artery or a coronary AV fistula and to exclude the presence of “normal” arteries. We believe that this seldom is justifiable in this context, but there are occasional circumstances in which it may be worthwhile. Thus, we recently have seen some patients under the age of 30 in whom we suspected that the combination of “infarct-like” ST and T wave changes on the ECG with enzyme abnormalities might be due to a viral infection rather than to coronary artery disease, having had suggestive evidence from viral antibody studies. The demonstration of normal coronary arteries has proved to be valuable in returning these individuals to work and reassuring them of the good prognosis. w ROBERT A. O'ROURKE: There is considerable disagreement concerning the current indications for coronary angiography. A relevant recent report concerning the indications for coronary arteriography was prepared by a subcommittee of the Council on Clinical Cardiology of the American Heart Association (Circulation 55969.1977). CATHETERIZATIONTECHNIQUE. -Although it is not the purpose of this review to consider in detail the technical aspects of coronary arteriography, it is necessary to discuss the scope and limitations of this procedure. The catheter laboratory must be equipped with high-quality cineangiographic equipment to permit the visualization of flow through the arteries. Better resolution may be obtained by using rapid serial roentgenograms at 6-12 frames per second, the combination of both forms of apparatus probably is ideal. It is essential to have continuous electrocardiographic and arterial pressure monitoring during the studies and the nurses and technicians in the laboratory must be fully trained to recognize the complications that may ensue. In particular, it is essential to have a cardiopulmonary resuscitation team approach to the patient and the appropriate equipment, including a defibrillator, immediately available. One famous American laboratory recently experienced the embarrassment of a patient developing ventricular fibrillation when the defibrillator had been borrowed 22

by another department; it took several minutes before defibrillation could be undertaken. It now is generally recommended that coronary arteriography should not be carried out except when surgical facilities, including intra-aortic balloon counterpulsation, are immediately at hand. Although this certainly is the ideal to be aimed at, the dispersion of facilities in many centers makes this impracticable. However, this ideal should be achieved within the next 2 or 3 years in every center. It is important to recognize the toxic and hemodynamic effects of the study. Because coronary arteriography may lead to temporary impairment of left ventricular function, left ventriculography should be performed first. This itself, however, results in an increased vascular volume because of the dye injected and there usually is also vasodilatation and both inotropic and chronotropic effects on the heart. This produces an increased cardiac output and increased ventricular filling pressures. Some investigators consider the rise in end-diastolic pressure after dye injection as an index of left ventricular function, but this is of dubious validity. An important complication of catheterization, and particularly of coronary arteriography, is the development of bradycardia and hypotension. This sometimes occurs simply from the presence of a catheter in the aortic arch, but direct injection of dye may lead to depression of pacemaker tissue and there may also be vagal suppression of the sinus node. Routine premedication with atropine usually will prevent this complication but does not always do so. Cardiac catheterization can be performed by either the brachial or femoral route. Using the brachial route, pioneered by Sones, it is usual to do a brachial arteriotomy with a catheter specially designed for this purpose. The alternative approach is the percutaneous femoral route initiated by Judkins. In past years there appears to have been greater safety in using the brachial approach, as early experience with the Judkins technique in a number of centers resulted in quite high mortalities. The probable reasons for this are because the percutaneous femoral approach is technically much easier for the relatively unskilled operator, because the catheters are end-hole only and because plugging of the right coronary artery can easily occur. Furthermore, it is probable that thrombogenesis occurs more easily with the woven dacron percutaneous femoral catheters than it does with the brachial artery catheters. With increasing experience, and with appropriate care and with a swift technique, there now is evidence that there is little to choose in terms of complications between the brachial and femoral approaches.i6 The only detectable difference is the higher incidence of arterial thrombosis with the brachial approach. Nonetheless, 23

the Sones method certainly is necessary in those patients who have severe atherosclerotic changes in the femoral or iliac arteries, or who are extremely obese. In some cases of aortic valve disease it is easier to enter the left ventricle and coronary arteries with the brachial approach. As coronary arteriography is a potentially hazardous procedure with significant complications and with defined limita-, tions, it should be undertaken only after the patient has been, carefully appraised clinically and as much information as possible has been obtained from other approaches, including noninvasive investigations, There is no excuse for the common practice of scheduling patients for coronary arteriography on the first diagnosis of angina without first trying thoroughly to assess its severity symptomatically and on other grounds and trying to predict the location of the lesions that are likely to be found, while recognizing that this may be impossible. Cardiac catheterization can be carried out much more intelligently if one is looking for a specific anatomic area of abnormality and if the additional tests that one wishes to carry out during catheterization can be thought out in advance. Thus, if it is thought likely that the patient may have coronary artery spasm, it is inadvisable to give nitroglycerin before the coronary angiogram has been performed. On the other hand, if the patient is likely to have severe atherosclerotic narrowing and develops angina early during the procedure, it is only humane to give nitroglycerin at this stage. Such a flexible approach to investigation is absolutely essential. In some patients, again, where one is concerned about the length of the procedure or its risk, it may be advisable to carry out coronary angiography first. This sometimes is worthwhile in patients with suspected left main coronary artery disease in whom the whole investigation may be prejudiced by an untoward reaction to a left ventriculogram, which then might preclude the possibility of doing a coronary arteriogram. It should be unnecessary to say that the investigator should take his own history and examine the patient prior to investigation, but one sometimes finds that the angiographer first meets the patient in the catheter room. It is particularly important to know whether the patient has had any symptoms suggestive of recent myocardial infarction or nocturnal dyspnea. These may not have been present at an outpatient interview not long before, so a fresh history-taking is obligatory. Other features that must be determined in advance include whether the patient might have evidence of valvular dysfunction or whether there may be evidence of peripheral vascular disease, which would determine the catheterization approach. At the same time, the angiographer should discuss with the patient exactly what is involved in terms of the nature of the procedure, the discomforts encoun24

tered, the kind of information that might be obtainable and the ways in which this investigation could help in diagnosis and the approach to surgery. Routine electrocardiographic and radiologic investigation normally will have been undertaken, but checks on the hemoglobin and biochemical abnormalities should not be omitted. An exercise electrocardiogram should be a routine before coronary angiography, except in those cases in which it is contraindicated because the patient has been having recent rest pain or rapidly progressive angina. The location of the ECG changes shown on the exercise test often will be of value in determining the site at which coronary artery lesions may be found and regional dyskinesia detected. We undertake echocardiography routinely to assess left ventricular function, and have found it useful in excluding from catheterization some patients with very poor ventricular function. THE PROCEDURE.-A major problem is posed by the risk of beta-blockade withdrawal prior to coronary arteriography. The disadvantage of continuing with propranolol is that it impairs left ventricular function and may accentuate the bradycardiac response to dye injection. It is our practice to continue proprano101in patients with unstable angina or who have had very severe angina before receiving this drug. In other patients, we progressively withdraw the drug over a period of a few days prior to the investigation. We have not encountered untoward reactions with this policy and believe that propranolol withdrawal has been a rather exagsrated phenomenon. It is important that cardiac failure should have been brought under optimal control before the investigation is undertaken, and digitalis and diuretics are used as required for this purpose. Warfarin is discontinued 2- 3 days before the procedure, but our normal practice has been to continue heparin if this is being used. Infection is a rarity as a complication of coronary arteriography and prophylactic antibiotics are not used. It is our usual practice to premeditate the patient with Valium 5- 10 mg orally before coming to the catheterization room. In some patients, we use diphenhydramine (50 mg) to prevent an allergic reaction to contrast material or local anesthetics. In some institutions, atropine is given prior to the whole catheterization procedure. It is our practice to use this only after the left ventriculogram has been performed, but it is given routinely in a dosage of 0.6 mg intramuscularly at this time. Nitroglycerin is not given routinely but administered only if the patient is suffering from angina and spasm is not suspected. If 25

spasm is suspected, nitroglycerin is given following the coronary arteriograms. If the patient has had a negative exercise test and the diagnosis remains in doubt, we will carry out an atria1 pacing test as the initial procedure. For this purpose, a pacing electrode is introduced into the right basilic vein with its tip positioned in the atrium. The heart rate then is accelerated by pacing up to a rate of ldO/min, atropine being used if the development of atrioventricular block prevents a rapid rate being achieved. After the test, the electrode is removed unless it is believed desirable to retain it in the right atrium because bradycardia during the procedure is feared. We then carry out percutaneous femoral catheterization using a pigtail catheter, which is passed to the ascending aorta for pressure recording and then advanced into the left ventricle. Pressure recordings are obtained and a left ventriculogram then undertaken in the right anterior oblique view. This sometimes is the only ventriculographic view obtained, but if dyskinesia of the inferior wall or septum is suspected, especially if aneurysm formation is thought likely, a left ventriculogram in the left anterior oblique view is also obtained. The pigtail catheter then is withdrawn and a left Judkins catheter is introduced and positioned in the ascending aorta close to the origin of the left main coronary artery. An injection then is made to ensure that there is not occlusion of the left main artery. Following this, the left main artery is entered and three or four injections are made in different projections to outline the branches of this artery. Subsequently, the Judkins right coronary catheter is substituted and right coronary arteriography undertaken in at least three projections. Further views may be necessary in some cases. If normal coronary arteries are encountered, ergonovine maleate or ergometrine is administered to see if coronary artery spasm can be provoked. The procedure usually is quite uncomplicated, but various problems may develop. The most common of these is bradycardia, despite premeditation with atropine; further doses of atropine may have to be given. Ventricular fibrillation, which occurs in about 1% of cases, usually can be corrected without difficulty. If this is achieved, there is no reason for the procedure not to be continued. Severe hypotension is a muchdreaded complication, as is myocardial infarction, but if these complications ensue, it may be necessary to institute intra-aortic balloon counterpulsation. Appropriate modifications must be introduced if the patient is considered to have coexistent valvular heart disease. In such cases, the investigation for the valvular disease should precede coronary arteriography so as to obtain an accurate record of the 26

hemodynamic situation prior to the instillation rial.

of contrast mate-

INTERPRETATION 0F THE CORONARY ARTERIOGRAM AND LEFT VENTRICULOGRAM. -Very careful scrutiny of the films is neces-

sary. It is advisable, if possible, to have two independent observers assessing the lesions, as observer error is so common and important. Differences of opinion exist as to the severity of the stenosis, which may be regarded as significant. In the views of some, angina always is associated with a stenosis of at least 70%.‘* Undoubtedly, angina can be seen with lesser degrees of obstruction than this, particularly if they are multiple stenoses, as they frequently are. THE PROGNOSIS OF STABLE ANGINA It has been well demonstrated in recent years that the pathologic anatomy of the coronary arteries and the functional state of the myocardium are the most powerful predictors of prognosis.lBdoHowever, there is much useful information to be obtained from features of the history, physical examination and other investigations short of subjecting the patient to angiography. Useful estimates of left ventricular malfunction can be obtained by detecting cardiomegaly clinically or radiologically and by demonstrating a poor ejection fraction by noninvasive techniques, including echocardiography and nuclear imaging. Studies of natural history that do not include coronary angiography in the assessment inevitably include patients who did not have angina pectoris due to coronary atherosclerosis; the material, therefore, will be diluted by patients with incorrect diagnoses. However, in our experience, the misdiagnosis rate. is no more than 10%. Our impression is that those clinics that have reported a high incidence of normal coronary arkriograms in angina1 patients have had referred to them many patients with dubious histories of the syndrome. Most studies have suggested that symptoms are not a guide to prognosis, although it might be supposed that those with disabling angina had a much worse prognosis than those without. However, two recent reports may indicate otherwise. Webster et aL21 noted that functional disability was related to mortality rates for each of the groups with single, double and triple vessel disease; a possibly related observation was that a better prognosis was found in those with collateral vessels. MargoliP has suggested that the level of exercise that can be achieved is a useful predictor of survival, independent of the severity of coronary artery disease and left ventricular malfunction. It is rather difficult to reconcile these different viewpoints, but it is of inter27

est that it has been noted that the incidence of the sinister left main coronary artery disease is high in those with severe stable angina or unstable angina and relatively low in those with few symptoms. Likewise, it has been noted that those with single vessel disease often have transient symptoms whereas those with three vessel disease usually have persistent angina, which may be more resistant to drug therapy.23 The discrepancy be-: tween various reports might be explained if the duration as well as the severity of the angina were taken into account. Patients with single vessel disease may go through a period of severe or unstable angina that may resolve or diminish spontaneously. Those with three vessel disease may have persistent but milder symptoms. Thus, there may seem to be no difference between patients with one and three vessel disease if only the most severe attacks of angina are considered, but one will become apparent if a more detailed longitudinal history is taken. A history of previous myocardial infarction certainly is of importance in assessing prognosis. Block et aLz4 reported a 5 year mortality rate of 54% in patients with a history of acute myocardial infarction whereas those without had a mortality rate of 33%. Weinblatt et a1.,25in the Hospital Insurance Plan (HIP) study from New York, found that resting ECG changes were associated with a poor prognosis; even when postinfarction appearances were excluded, the incidence of death at 40 months was 4 times as high in those with such ECG changes as in those without. Similar observations were made by Seim.26 Not unexpectedly, cardiac failure is associated with a substantially increased death rate. Thus, in the HIP study, the death rate within 30 months was twice as great in patients with heart failure as it was in those without. In the study by Block et aZ.F4 the &year survival rate over-all was 58% and the lo-year survival rate 33%. In those with congestive heart failure, the &year survival rate was 20% and the lo-year survival rate 8%. Humphries et al. l7 have reported on 224 patients who were investigated by coronary arteriography and electrocardiography. The death rate during the observation period of 5- 12 years was 26% in those with abnormal ST and T waves compared with 6.5% in those without. Mortality in the patients with angiographically moderate or severe disease with abnormal ST and T waves was nearly double that of patients with similar degrees of severity and normal ST and T waves. ST depression during an exercise test has also been found to be of prognostic va1ueF7,2* although it is likely that this relationship depends very much on the types of patients who are studied. Thus, ST segment depression may be found in many asymptomatic individuals who, on coronary angiography, are found to have no coronary artery disease.2g,3o Follow-up studies on such patients show an excellent over-all prognosis. On the 28

other hand, when patients with angina1 symptoms are being followed, the amount of ST segment depression appears to be of significance. Hypertension is another prognostic feature of importance in patients with angina pectoris. Thus, in the study by Block et uZ.,~~ the 5 and lo-year survival rates were 63% and 40%, respectively, in those without hypertension, compared with 22% and only 1% in those who had grade III retinal changes. In the HIP study,25 h ypertensive patients had 3 times as great a mortality as had the nonhypertensives. Individuals who had both a raised blood pressure and resting ECG abnormalities had 9 times as great a mortality at 2.5 years than did those with neither of these unfavorable features. Cigarette smoking was found in the HIP study25 to be associated with a death rate at 30 months twice that of those who were not cigarette smokers. In the same study, diabetic patients had a death rate 4 times that of nondiabetics and those physically least active had a death rate 1.5 times that of those who were the most active. These workers did not find serum cholesterol levels or weight of any prognostic significance. Many reports1&20 have confirmed the excellent correlation between the number of vessels that are severely &nosed and prognosis. A classic study by Friesinger et ~1.‘~ involved followup of 224 patients subjected to coronary angiography at the Johns Hopkins Hospital between 1961 and 1967. Grading the severity of the disease in each of the three major arteries from 0 to 5, they found that the mortality at 5 years was 10 times as great in those with scores of lo-15 as it was in those with scores of 4- 9. Not one of 22 patients with single vessel involvement died a known coronary death in a mean follow-up period of 4.5 years. It is notable that the patients in this group were exceptionally young, the mean age of those with single vessel disease being only 39 years. Other authors have confirmed the benign course of single vessel disease, several studies reporting an annual mortality of 2-3%. I’m20It has been noted that disease of the left anterior descending artery has a mortality approximately twice that of disease affecting the right coronary artery. It has also been noted by several observers that obstruction proximal to the first septal perforating branch of the left anterior descending artery carries a considerably higher mortality than obstruction distal to this vessel. However, some authors have not found this difference.31 When disease affects two of the main vessels there is a mortality of 6- 8% per annum.17-20When three vessels are involved, the annual mortality has been reported to be lo- 12%.‘7-29 Stenosis of the left main coronary artery has been found to be associated with a particularly bad outlook, mortality rates varying from 8% to 50% per annum. Lim et aZ.,32reporting on 141 29

patients from the Cleveland Clinic followed for 5- 10 years, found a 22% mortality in 1 year but a diminishing mortality rate in survivors over the succeeding years, SO that at 5 years 45% of the patients had died, giving an average annual mortality of 9%. Most of the data described above were reported from the centers carrying out coronary arteriography before the era of coronary artery surgery. These figures have been used to compare 1 with those obtained from patients who have been subjected to coronary artery surgery. There are considerable dangers in this comparison, because there have been many changes in the investigation and management of angina in the intervening years. For example, coronary arteriography now is being undertaken sooner after the onset of symptoms that it used to be. Inevitably, therefore, today there will be a longer interval between coronary arteriography and death than formerly, irrespective of any medical and surgical treatment given. In addition, some changes in therapy, such as the introduction of beta-adrenergic blockade and coronary care, must have affected prognosis in the past decade. The prognostic significance of coronary artery anatomy has tended to obscure the equally important matter of left ventricular malfunction. The importance of this was clearly brought out in the papers from Bruschke et &X9 who showed that the prognosis of one, two and three vessel disease was in each case significantly worsened if there was diffuse scarring or aneurysm formation. THE EFFECT OF MEDICAL TREATMENT ON PROG.VOSIS- It has been widely assumed that medical treatment for angina has no effect on prognosis. It is true that, as yet, no study has firmly established the value of any particular drug, but there are good reasons to suppose that certain forms of therapy are beneficial. Dewar and OliveP4 found that angina1 patients who had taken clofibrate in a double-blind controlled study had a lower mortality than those who did not. The study was not designed with this group of patients particularly in mind and further observations are required to substantiate these findings. Furthermore, the Coronary Drug Project Research Group35 showed that antihyperlipidemic agents failed to improve prognosis after myocardial infarction; this does not necessarily invalidate their use in patients with angina pectoris only. The effects of smoking on prognosis of angina pectoris already have been referred to and it is known that the cessation of smoking is associated with a lower risk of death from coronary artery disease. Furthermore, it has been demonstrated that the cessation of smoking after a myocardial infarction is associated with a relatively improved prognosis.36 Thus, although it has not yet been proved that stopping smoking in those with angina improves prognosis, it seems likely that it does so.

30

Treatment of coexistent hypertension may well improve the prognosis of angina. Although in the Veterans Administration Co-operative Study Group on Antihypertensive Agents3’ there was no reduction in coronary death rate, there was a reduction in mortality rate from congestive heart failure, an important cause of death in angina1 patients. Furthermore, it may well be that a longer study would have shown a reduction in coronary death rate and it may also be that if other drugs had been used a more favorable effect would have been shown. The reports by Lambert and 53te~ar-t~~both suggest that the treatment of hypertension with beta-adrenergic blocking drugs reduces the mortality from coronary disease compared with other forms of antihypertensive therapy. The study by Lambert also suggests the possibility of a reduction in death rate by the use of beta-adrenergic blocking drugs in patients with angina even if they do not have hypertension. Indeed, this is likely to be so, as it has been shown in the case of two beta-adrenergic blocking drugs -alprenolo140 and practolo141-that mortality is reduced following their use after myocardial infarction, particularly in relation to the occurrence of sudden death. There is general disenchantment, except in some European countries, with the use of anticoagulants in the treatment of coronary heart disease. The possible benefits of treatment, however, should not be neglected, since, as Lovelr2 has pointed out, the long-term anticoagulant studies in patients following myocardial infarction suggested that anticoagulants are of particular value in those patients who have suffered from angina pectoris some time prior to their heart attacks. A randomized controlled study by Borchgrevink43 also strongly suggested the value of intensive anticoagulant therapy. MEDICAL MANAGEMENT Notwithstanding the immense benefits that coronary artery surgery bestows, medical management does and will contribute essentially to the well-being of the patient. It has several purposes, which include education of the patient so that he understands the purposes of medical and surgical treatment, adjusts his life style as appropriate and learns to live happily within whatever restrictions are necessary. The control of risk factors, although not yet proved to be of value, should be undertaken in the younger patient. Finally, prevention and treatment of pain are important. GENERAL MANAGEMENT The first essential in general management is to have a full discussion with the patient to determine exactly how he lives, 31

what makes life worthwhile for him and the extent to which his symptoms are limiting his enjoyment of life and his ability to undertake his occupation. The physician then must carefully explain, depending on the individual patient’s intelligence, the nature of the disorder from which he suffers or is suspected to suffer. This is particularly important if the term “angina” is used, SOthat there is no misunderstanding as to its meaning. Many patients regard the word as a sentence of death, and, of course, many often know of relatives dying of “angina.” It can be brought home to the patient that, either spontaneously or as a result of treatment, it is almost certain that his symptoms can be controlled, if not abolished, and that life expectancy is very much greater than the lay public and, indeed, many members of the medical profession believe. On the other hand, it is important not to give the patient the impression that he will neonssarily be able to undertake all the activities he would wish. This is particularly important for the heavy-smoking, heavy-drinking, overeating, high-powered executive who is reluctant to take any form of advice. It is also important at this stage to point out to the patient ways in which his life might be modified. Ways should be found to minimize the necessity for unexpected extremes of physical or mental stress. For example, if he travels by public transportation, he can be advised to try to avoid the rush hour and tight schedules. In some cases it may be necessary to recommend a change in occupation. This is particularly applicable to drivers of public service or heavy vehicles and to airline pilots. Physical work should not necessarily be avoided and, indeed, it is amazing how many patients who are unable to walk uphill or watch a football match without angina can undertake apparently strenuous jobs such as gardening if they have long experience in this. Undoubtedly some patients with angina are unduly anxious and, for these, sedation may be necessary. Diazepam usually is the most helpful drug in this regard. CONTROL OF RISK FACTORS.-The risk factors associated with coronary artery disease and with angina generally are well known. Those of particular relevance are hyperlipidemia, hypertension, cigarette smoking, obesity and lack of physical exercise. Evidence thus far has not shown that the control of hyperlipidemia reduces the symptoms of angina and it is doubtful that it diminishes the risk of infarction and death. Nonetheless, as it is known that atherosclerosis is a progressive disorder, it seems reasonable to control the lipids. Furthermore, although hyperlipidemia clearly is an important risk factor in the younger coronary patient, it seems to play little part in the atherosclerosis of the elderly. In our view, therefore, there is no point in diagnosing or treating lipid disorders in those over 55 years of age, and 32

it is our practice to undertake lipid studies only in individuals under 50. We give patients of all ages general dietetic advice that would, in any case, tend to reduce lipid levels. Thus, all patients should be instructed to get their weight down to the-ideal for their age and height and should avoid excessive consumption of animal fat and carbohydrate. Those who indulge excessively in alcohol should be advised to reduce this considerably. When lipid studies are undertaken, it is important that the triglycerides are measured when the patient is fasting. Furthermore, these studies should not be undertaken within 3 months of an acute myocardial infarction because of the disturbances in lipid metabolism at that time. The lipid profile should be characterized and appropriate treatment instituted. Depending on their type of hyperlipidemia, appropriate dietetic advice should be given. It is our practice to confine drug treatment to those who have not responded to the dietetic regimen. Although, in principle, it usually seems best to give cloflbrate first to patients with Type IV hyperlipidemia and cholestyramine to those with Type II hyperlipidemia, these rules are not always helpful and a &rapeutic trial should be instituted for each case. It is important to be aware of the toxic effects of these drugs, which include nausea and constipation in the case of cholestyramine and leg pains and the symptoms of cholecystitis with clofibrate. ) FRANK I. MARCUS:It should be emphasized that the serum cholesterol does not have to be drawn when the patient is fasting in order to obtain a representative serum cholesterol level. It has been demonstrated that the serum cholesterol obtained within 36 hours after the onset of symptoms of myocardial infarction is not different from that obtained 3 months after an infarction (Fyfe, T., et al.: Plasma-lipid changes after myocardial infarction, Lancet 2:997, 1971). Therefore, it has been my practice to request a serum cholesterol level in patients on admission with a suspected acute myocardial infarction.

The control of high blood pressure is an essential feature of the management of angina in affected patients, not only because hypertension is an important risk factor in itself but also because it is a contributory factor in cardiac failure. The effective treatment of hypertension may abolish angina without any other therapy being necessary. It is difficult to give a precise figure at which hypertension should be treated, but, in the presence of angina, we certainly would treat all patients whose diastolic pressure was 100 mm Hg or above. In hypertensive patients with angina it is our practice, unless there are contraindications, to institute therapy initially with beta-adrenergic blocking drugs, as these have the virtue of controlling both conditions. In the majority of cases, this is quite sufficient, but in others it may be necessary to add a diuretic. In a relatively small proportion, other drugs may be required, including meth33

or adrenergic blocking agents. Our experience with the combination of vasodilators and beta-blockers in this circumstance is limited, but some unfavorable reports on the effects on angina have been issued concerning the combined alpha- and beta-blocking drug labetalol because of excessive falls in pressure. The discontinuance of smoking is of paramount importance in, the management of angina. It is true that tobacco-induced angina is a relatively rare complaint, but there is good evidence that cessation of smoking improves prognosis and may increase exercise ability. y&pa

DRUGS IN THE TREATMENT

OF ANGINA

NITRATES. -Since their introduction more than 100 years ago, the nitrates have continued to be the first line of treatment in angina pectoris. Their mode of action still is not clear and it is possible that more than one mechanism is responsible for their effectiveness. Most attention in recent years has been devoted to their vasodilating action on peripheral arteries and veins. Peripheral arteriolar dilatation leads to a reduction in afterload, by a fall in blood pressure, which diminishes myocardial oxygen demand. Myocardial oxygen demand is also reduced by a reduction in preload as a consequence of diminution in venous return. Reduction in both preload and afterload leads not only to a reduction in oxygen demand but to a fall in left ventricular enddiastolic pressure, which can permit a relative increase in endocardial blood flow. It has been shown that direct intracoronary injection of glyceryl trinitrate failed to relieve angina in patients with atherosclerotic heart disease when sublingual administration was effective. However, there can be little doubt that glyceryl trinitrate is a potent coronary vasodilator, and this action probably is important when coronary artery spasm is the cause of angina. Glyceryl trinitrate is effective in most patients’with angina pectoris and usually produces relief within 3 minutes. Its action usually lasts for about 45 minutes. Patients must be informed to chew the tablets rather than to swallow them and may spit out the residue if relief has been obtained. Details of storage and administration are important. The tablets should not be allowed to lie unused for long periods. The packing materials in which they are contained may be relevant; cotton wool may absorb the drug. The tablets should be kept in a dark bottle, free from packing materials. Headache is a common complaint at the beginning of treatment but with repeated use this usually diminishes to an acceptable level or disappears altogether. However, some patients find it permanently intolerable. Flushing can also be troublesome. 34

The drug is particularly helpful as a prophylactic, but patients (and physicians) often are reluctant to use it in this way. There is no evidence that it does any harm and patients should be advised to take the tablets whenever they are about to undertake exercise that they know will produce angina and also when they have to face emotional situations that they know will be stressful. Little restriction on repeated dosing is required, but it usually is advisable to tell patients not to take more than 2 tablets at one time. They should also be told that if 2 tablets have failed to relieve an individual attack when previous attacks have been readily relieved by glyceryl trinitrate, they may have sustained a myocardial infarction and should obtain medical aid. Nitrol paste has achieved some popularity in recent years, particularly in the relief from prolonged attacks of unstable angina. Although this undoubtedly is effective, the preparation of the paste is troublesome and it is doubtful whether the benefits are sufficiently great to justify its widespread use. After many years of neglect, long-acting nitrates seem once again to be a popular form of medication. The reason for the lack of* enthusiasm in the past certainly was to some extent due to giving inadequate doses. Isosorbide dinitrate probably is the most popular of the compounds available and is usable in both a “chewable” tablet and an orally administered preparation. F FLOBERT A. O'ROURKE: There is new evidence from a number of carefully planned double-blind randomized crossover studies that several oral nitrates improve exercise tolerance, decrease angina1 attack rate, reduce left ventricular size and improve segmental wall motion in many patients with ischemic heart disease. In larger doses than usually prescribed, oral nitrates appear to overcome the “denitrating” enzyme in the liver and are able to produce arterial and venous dilatation similar to that occurring with the sublingual route. We usually recommend an oral dose of isosorbide dinitrate that produces at least a lo-mm drop in the systolic blood pressure and/or a 10% increase in the heart rate 30 minutes after the drug has been administered. In most patients, a dose of 15 - 40 mg of oral isosorbide dinitrate produces a hemodynamic effect. OTHER NON-BETA-BLOCKING ANGINAL AGENTS. -A number of new antianginal agents are available in Europe but not as yet in the United States. Some of these are moderately effective and have been shown in double-blind controlled trials to produce a significant reduction in the number of attacks of angina. Perhexiline maleate has proved to be effective in some individuals who have failed to respond to other forms of antianginal

treatment, including Surgery. Treatment is started with 100 mg twice a day and increased, if necessary, to 200 mg twice a day.

Drowsiness and a muzzy feeling in the head are common in the first few days and occasionally persist. Transient -and sometimes prolonged-changes in liver function tests have been observed, but they always seem reversible on discontinuing the 35

drug and no serious effects of toxicity have been reported. HOWever, cases of severe peripheral neuritis have been encountered. prenylamine appears to be rather less effective, though less likely to produce toxic effects. In a dose of 60 mg 4 times a day, a modest reduction in the number of angina1 attacks has been reported. Both verapamil and dipyridamole have been reported to have antianginal e%cts, but these are not well substantiated.: Ni&dipine, a calcium blocking drug like verapamil, recently has been shown to be antianginal and seems to be particularly effective in cases of coronary artery spasm. BETA-ADRENERGIC BLOCKADE. -The value of beta-adrenergic blocking drugs is well substantiated in the management of angina. Numerous double-blind control studies have been carried out amfirming their value and there are relatively few patients, except for those with contraindications, who cannot be helped by the use of these drugs given in adequate doses. Most of the studies have been carried out with propranolol, the only beta-adrenergic blocking drug available in the United States at present. It has been shown that the beta-adrenergic blocking drugs work by a reduction in oxygen demand by the myocardium. Beta-receptor blockade results in slowing of heart rate, a reduction in the rise of blood pressure on exercise and in the velocity of cardiac contraction. Propranolol has a slight direct negative inotropic effect, which probably is not important. Its ability to counteract sympathetic activity when the heart is dependent on this may be. Propranolol can lead to a rise in end-diastolic pressure in patients on the verge of cardiac failure, but, paradoxically, in subjects with angina, the end-diastolic pressure may fall. There now are considered to be two main types of beta-receptors. The 61 type is located in the heart and the 62 type in bronchial smooth muscle and in the peripheral arterioles. F’roprano101is a “nonselective” in that it blocks both types of receptors. There now are several alternative preparations that are selective in blocking only the cardiac receptors. There are other differences between the available beta-adrenergic blocking drugs, such as differences in membrane-stablizing activity and in intrinsic sympathomimetic activity. The importance of these is questionable. More important are the different pharmacokinetic characteristics. Thus, propranolol is rapidly metabolized in the liver on its first passage and is largely bound to plasma protein. Several other preparations are not metabolized in the liver and are not protein bound. One of the consequences of the characteristics of propranolol is the very variable dosage required in different patients. Over-all, propranolol can be considered beneficial in that it decreases both the resting and the exercise heart rate and the 36

systolic pressure; it also decreases the rate of left ventricular pressure increase and the velocity of myocardial fiber contraction. Its effectiveness in reducing blood pressure in hypertensive patients is an added benefit. On the other hand, it prolongs systolic ejection period, increases, in some patients, the left ventricular end-diastolic pressure and increases cardiac volume and wall tension. Probably some three-quarters of the patients receiving betaadrenergic blocking drugs can be benefited by them. Our practice is to start with an initial dose of propranolol, 10 mg 4 times a day. If this fails to produce any untoward effects, such as excessive bradycardia or bronchospasm, the dose then is rapidly increased to 160,320 and 480 mg a day if necessary. Further increases in dose sometimes are required, particularly if concomitant hypertension has to be kept under control. It often is thought that the ability to get the resting pulse rate below 60 is sufficient. However, it has been shown by Jackson et ~1.~ that some patients can have bradycardia at rest but substantial tachycardia on exercise. Additional doses of the betaadrenergic blocking drug may control the exercise heart rate and angina. The complications of airways obstruction and congestive failure are well recognized but they are rare in patients treated for angina by physicians who are aware of the danger and they seldom arise in patients in whom this possibility has not been considered. Other side-effects are rare, the most important being vivid dreams, lethargy and cold extremities. If the precipitation of cardiac failure is thought likely, propranolol may be combined most effectively with a digitalis preparation. In avoiding obstructive airways disease, alternative beta-adrenergic blocking preparations should be used, if available. Considerable alarm has been occasioned by reports of the worsening of angina or the development of myocardial infarction on the abrupt withdrawal of propranolol.45 Although these complications undoubtedly occur in a few patients, this is rare in our experience. It seems to be even rarer with the other beta-adrenergic blocking drugs. When it does occur, it usually develops in patients who have previously had very severe angina that has been well controlled by propranolol and have led an active life. Because of this risk, it is our practice always to discontinue beta-adrenergic blocking drugs slowly. This can be a problem in patients who are about to undergo coronary arteriography, and, unless there is a good reason to do otherwise, we tend to reduce the drug rather than stop it completely. However, if one is to carry out satisfactory exercise tests in cases in which the diagnosis is in doubt, the discontinuance of beta-blocking therapy is 37

mandatory. We usually withdraw the drug over a period of 2 weeks before the test. Opinions are divided as to the importance of stopping betablocking therapy prior to cardiac or other surgery. Increasingly, the practice is to continue using the drug until the time of the operation and beyond, if necessary. Quite apart from their ability to control angina and hypertent sion, beta-adrenergic blocking drugs seem to have a genuine role in the prevention of sudden death. In Sweden, it has been shown that alprenolol reduces the risk of death in patients who have recovered from a myocardial infarction,@ and in the Multicentre International Study with practolol,4l it was shown that there was a substantially lower sudden death rate in patients taking practolol rather than a placebo. Unfortunately, the development of blindness and plastic peritonitis in a small number of patients has resulted in the withdrawal of this drug. Whether the findings with alprenolol and practolol can be applied to propranolol and the other beta-adrenergic blocking drugs remains to be determined. w FRANK I. MARCUS: The studies cited certainly are suggestive that beta-blocking agents will, indeed, be shown to be valuable in the prevention of sudden death. Nevertheless, there are certain questions that are as yet unanswered. For example, in the practolol trial it was found that there was a statistical decrease in sudden death in patients who had anterior myocardial infarction before practolol was initiated but not in patients who suffered an inferior myocardial infarction and then were entered into the study. In addition, there was a high dropout rate in the practolol study. To clarify these questions, and to determine whether propranolol will be effective in decreasing sudden death after an infarction, the National Institutes of Health are initiating a multicenter trial, the results of which will be awaited with considerable interest.

CORONARY ARTERY SURGERY Several centers now have reported mortalities of less than 2% ris. The efficacy and safety of the procedure mean that every patient presenting with the syndrome should be considered a potential surgical candidate. However, because it still is not clear what the long-term effects of surgery are on either symptoms or prognosis, the decision as to whether it should be undertaken and, if so, when is far from easy. It is not the function of this review to consider technical aspects of coronary artery surgery, but it is important to recognize the benefits, limitations and complications of the procedure, which may determine its final role. 38

THE MORBIDITY AND MORTALITY OF CORONARY ARTERY SURGERY

Over the years there has been a progressive decline in the morbidity and mortality of coronary artery saphenous vein bypass. Typical mortality figures published between 1972 and 1974 were around 6%.469 47 Such figures then were regarded as satisfactory but now would be regarded as excessively high. Several centers now have reported mortalities of less than 2% and some as low as 0.5%. To a large extent, these falls in death rate can be attributed to the improvements in surgical techniques and the availability of better means of supporting the myocardium during the procedure. The facility of intra-aortic balloon pulsation has saved a substantial number of patients who otherwise would have died in the postoperative period. However, another factor in lowering mortality has been the improved selection of eases and the avoidance of those at highest risk. Thus, it has become recognized that surgery during the first days after infarction or in the most acute phase of acute coronary insufficiency carries an unwarranted risk. A further factor that is difficult to evaluate is the increasing awareness of poor left ventricular function as a determinant of the outcome after surgery. Although many physicians no longer refer to surgeons patients whose left ventriculogram shows extremely poor function, it is also true that surgeons have been more aggressive in the past 3 or 4 years in accepting patients who have poor left ventricular function but still are disabled by angina. One of the factors in the higher mortality in earlier years was the development of pulmonary embolism.48 The routine use of anticoagulants has virtually abolished this complication. Another complication that probably is also diminishing in frequency is intraoperative or postoperative myocardial infarction. Estimates for this have varied widely from 5% to49%.4s~5oCaves and StinsonsO reported an incidence of infarction in patients with stable angina of 7-8% when diagnosed stringently on the basis of new postoperative Q waves supported by characteristic serial enzyme changes. In contrast, the same authors have reported an infarction rate of approximately 16% in those v+ith unstable angina. They consider that profound local myocardial hypothermia is effective in protecting the myocardium and leads to a lower incidence of myocardial infarction. However, they comment that “it seems unlikely that myocardial infarction during direct coronary artery revascularization can be avoided altogether” and that “this feature must continue to be weighed as a variable in the evaluation of the therapeutic efficacy of coronary bypass grafting.” ä ROBERT A. O’ROURKE:Several recent studies utilizing preoperative and postoperative technetium pyrophosphate scans, serial electrocar39

diagrams and vectorcardiograms and serial measurements of serum creatine phosphokinase isoenzymes indicate that the incidence of myocardial necrosis in patients undergoing coronary artery vein bypass graft surgery is approximately 30%. Infarction at the time of revascularization is associated with a low perioperative mortality and most patients do well, with only a few developing a deterioration in left ventricular performance.

Other complications include hemorrhage requiring reoperation and arrhythmias, including atria1 fibrillation and ventricular fibrillation, which usually are readily correctable. Caves and StinsonS” have pointed to risk factors for coronary bypass grafting. Factors that increase operative risk include congestive heart failure, severe electrocardiographic abnormalities and acute myocardial infarction. Angiographic findings include severe left ventricular dysfunction, severe mitral regurgitation of ischemic etiology, an ejection fraction of less than 25%, a cardiac output of less than 2.2 l/min/sq m and diffuse distal coronary artery disease. Factors that did not seem to correlate importantly with operative risk included age, sex, severity of angina, “controlled” unstable angina, remote myocardial infarction and such clinical risk factors as diabetes mellitus, hypertension, smoking history, lipid abnormality or family history. Angiographically, the number of diseased vessels or the presence of a localized asynergic segment of left ventricle also seemed unimportant. Although others have disagreed, they did not believe that the number of grafts placed or the duration of cardiopulmonary bypass was of importance. Another factor to be taken into account, although seldom mentioned in surgical papers, is the discomfort as the result of the sternal wound and of the leg scar, as well as swelling of the leg due to venous insufficiency. Although these seldom are disabling, they can be annoying complicating features during the convalescence and delay return to work in those with occupations involving vigorous use of the limbs. GRAFT PATENCY

Clearly, the patency of the grafts inserted is a major factor in the long-term effectiveness of coronary artery bypass grafting. It still is not known

what percentage

of grafts may be expected to

stay patent for 3 years or more, as most centers with substantial experience are finding graft patency rates improving as experience increases. Alderman et CZZ.*~ have demonstrated that graft patency rose significantly with the introduction of improved methods for the construction of anastomosis. In most centers, the average patency rate for the vein bypass grafts is approximately 80% at 1 year. Many surgeons have found that patency 40

rates in grafts to the left anterior descending coronary artery and right coronary artery are excellent, with a substantially lower rate with grafts into the circumflex distribution. It has been claimed that direct mammary artery to coronary artery bypass is associated with a higher patency rate than saphenous vein bypass, but more recent studies have suggested that there is little difference in similarly selected cases. An important factor in determining the long-term patency of grafts is the level of graft flow, which, in turn, reflects the distal runoff. Thus, Lesperance et al. 51thought that the critical factors with regard to patency were the coronary artery diameter at the point of grafting, the size of the distal vascular bed and, to a lesser degree, the presence or absence of distal atherosclerosis. They noted that if the artery concerned had only a small vascular bed, such as was found in a nondominant posterior descending artery or a short anterior descending coronary artery, the chances of graft occlusion were great. Furthermore, when moderate to severe distal coronary atherosclerosis was present, only 43% of vein grafts were patent after 1 year. Late vein graft closure of stenosis, which is relatively uncommon, seems to be mainly due to fibrous intimal hyperplasia and does not appear to be predictable either on the basis of venous anatomy or the characteristics of the arterial bed into which the vein is inserted. However, as pointed out by Vlodaver and Edwards52 and others, it probably is related to the hydraulic stresses produced by the introduction of the venous segment into an arterial circuit. Atherosclerosis of the vein graft is extremely rare. RESULTS OF CORONARY ARTERY SURGERY

There is widespread agreement as to the beneficial effect of coronary artery bypass surgery on the relief from angina pectoris. There is some diminution in symptoms in 80- 90% of survivors. In most series, 60-70% of patients are totally symptom free and require no drug therapy; a further lo- 20% still require antianginal therapy but are greatly improved. It is recognized that subjective improvement is a poor test of the value of an operation, as many ineffective or sham -procedures used in the past have produced a substantial relief from symptoms. The “placebo” effect is so common in the therapy of angina pectoris that the success of any method of treatment must be evaluated by objective means. The benefits of bypass surgery for myocardial ischemia have been demonstrated in two ways. First, in general, there is a close correlation between the relief from symptoms and the patency of grafts. It must be admitted, however, that, in some cases, a loss of symptoms has been associated with infarction of 41

a previously ischemic segment. Another confirmation of the benefits of surgery has been the demonstration by graded stress testing-by either exercise or atria1 pacing- that angina pectoris and the ECG changes of ischemia become less easily provoked or disappear following surgery. There has been some confusion in the literature as to the effects of coronary bypass surgery on left ventricular functiod Many studies have failed to demonstrate any beneficial effect of this form of surgery on left ventricular function. Others have claimed substantial improvement in such aspects as left ventricular end-diastolic pressure and in the movement of previously dyskinetic segments. These differences of opinion probably are largely related to the circumstances under which left ventricular malfunction has been measured. Clearly, angina pectoris itself reflects left ventricular malfunction and it is known that, during an episode, the left ventricular end-diastolic pressure rises and movement of the affected myocardial area is impaired. Thus, if the preoperative studies are carried out when the patient is experiencing spontaneous angina (as in “unstable angina”) or if angina has been induced by exercise or atria1 pacing, these indices of left ventricular malfunction will be abnormal. Effective coronary artery bypass surgery will restore this type of left ventricular malfunction toward normal, as may, of course, rest, glyceryl trinitrate or beta-adrenergic blocking drugs. Surgery will not improve left ventricular function where this has been affected by extensive fibrotic change nor will it improve the function of a “normal” left ventricle. Over-all, it would seem that coronary artery bypass surgery can, in a few cases, improve resting left ventricular function whereas, in others, the development of myocardial infarction may impair it. Successful coronary artery bypass surgery produces an improvement in left ventricular motion in segments of the myocardium that become ischemic during stress. EXERCISE CAPACITY. -It has been clearly shown in a number of studies that coronary artery bypass surgery can improve exercise tolerance and result in the conversion of positive into negative electrocardiographic stress tests. Bruce and Hornsten showed that in patients whose angina was completely or markedly relieved by surgery, both the duration of exercise and the heart rate achieved at the end point of exercise were significantly improved over preoperative values. Furthermore, this improvement correlated with graft patency. The effect of successful surgery on return to work must depend very substantially on the selection of patients and their motivation. In the report by Wallwork et ~1.~~only 22% of a group of 115 patients were able to work prior to surgery; at a mean follow-up period of 14 months, 65% of the patients were back at 42

work full time without symptoms and only 10% were not working because of angina. In other studies, the return to work rate has been much lower, but this may reflect lack of motivation or local unemployment. EFFECTS OF SURGERY ON PROGNOSIS. -A key question yet to be answered is whether surgery improves the prognosis of patients with angina pectoris. Theoretically, the only certain way in which the relative merits of medical and surgical treatment could be evaluated would be by a double-blind controlled trial. This obviously is impossible, but some randomized non-blind controlled trials now are under way. Although these undoubtedly will prove to be of value in certain categories of patients, there are inevitable shortcomings of such trials that will limit extrapolation from them to the general population of patients in whom coronary artery surgery might be advised on prognostic grounds. Inevitably in such studies, certain rigid criteria must be laid down and the patients entered into them must be willing to participate. One must necessarily exclude patients whose symptoms are so severe that it would be ethically wrong to deny them surgery. On the other hand, the inclusion of patients with virtually asymptomatic coronary heart disease may well be objected to. A more cogent objection to such trials is that, because of the necessity for standardizing management, one cannot ensure optimal medical or surgical treatment for each individual. Indeed, “optimal” treatment has not yet been defined and is likely to vary from patient to patient. Preliminary results have been reported from two randomized trials. The most far advanced one is the Veterans Administration Co-operative Study Group. The number of cases is small and the duration of this study still is quite short, but it is evident from the report by Takaro et al. 55that there is a significant improvement in prognosis in patients with left main coronary artery disease submitted to surgery. Thus, 17 (38%) of 44 medically treated patients and 10 (17%) of 57 surgical patients died during a mean follow-up period of 22 months. Mathur and Guinn56 and Kloster et aL5’ have reported on early mortality in smaller groups of patients without any statistically significant result. Further randomized trials both in the United States and in Europe are under progress and it would be wise to wait for the results of these before making categoric statements about the effects of surgery on prognosis. Furthermore, it is important that conclusions should not be drawn on the basis simply of a l- or 2year follow-up and that a period of at least 3- 5 years is necessary before one could conclude that surgery was or was not justifiable for prognostic reasons alone. In view of the inadequate information available from random43

ized studies, it is necessary to review the experience of nonrandomized studies. The best known material from this point of view has been produced from the Cleveland Clinic. Sheldon et aL5* have compared the mortality of 741 patients subjected to “pure” vein graft techniques at the Cleveland Clinic with that of 469 patients who would have been potential surgi; cal candidates but were studied at an earlier period but not op erated on. The mortality rate in the nonsurgical group was 8.8% per annum and that in the surgically treated group was 3.3% per annum. These authors found that there was little effect on the prognosis of patients with single vessel disease. In double vessel disease, the annual mortality in the surgical group was 4.6% and in the nonsurgical group 9.8%. In triple vessel disease, the mortality was 4.6% and 19.3% respectively. There are several objections to the deductions that have been made from these results. In the first place, the medically treated group were followed up for a longer period but less thoroughly than the surgically treated group. The medically treated patients were a group recruited in the years before coronary care, the availability of beta-adrenergic blocking drugs and the appreciation of the dangers of smoking. Furthermore, with the current enthusiasm for treatment of coronary artery disease and for its investigation at an early stage, patients are being detected earlier during the natural history of angina pectoris. Obviously, if the diagnosis is made and treatment is instituted at an earlier phase of the illness, there will be an apparent prolongation of life’between the onset of investigation and death. A further question is whether the medically treated patients were indeed similar in character to the surgically treated ones. The report by Platia et ~1.~3 is of interest in this context. These workers reviewed the coronary angiograms and left ventriculograms of patients studied at the Johns Hopkins Hospital between 1961 and 1967 and found a group of 78 patients who would, by current criteria, be acceptable for coronary artery saphenous vein bypass surgery. Eight years after coronary arteriography there had been no deaths in 10 patients with single vessel disease. An annual mortality of approximately 3% was encountered in double vessel disease and 5% in triple vessel disease. It is apparent that these patients had a considerably better prognosis than had been reported by Bruschke et uZ.‘~ from the Cleveland Clinic. As Griffith and AchufFs have suggested, “It may be that a higher percentage of patients with better left ventricular function and less diffuse coronary artery disease were selected for implant surgery while the medical treatment series includes more patients with impaired left ventricular contractility.” Various reports have concerned themselves with the effect of prognosis in particular types of lesions. McNeer et aZ.,6Ousing material from the data bank of patients maintained at Duke, 44

could find no difference in over-all survival at 2 years between 402 patients treated medically and 379 patients treated surgically. However, they defined a specific subgroup with three vessel disease, an ,abnormal left ventriculogram and a normal arteriovenous difference in whom the survival was 90% with surgery and 75% with medical treatment. This study, as a whole, can be criticized on the grounds that the statistical approach was unsatisfactory and that the mortality in the surgical patients was, by current standards, excessively high. Reports by Talano et ~1.~~and Oberman et ~1.~~further support the evidence in favor of surgery improving the prognosis in patients with left main coronary artery disease. Considered over-all, it would be reasonable now to assume that coronary artery saphenous vein bypass has a favorable effect on prognosis in patients with left main coronary disease. However, the issue may not be as simple as this and the prognosis in patients in whom the disease is confined to the left main artery is much better than in those in whom it involves several vessels and the outlook in those in whom left ventricular function is good is much better than in those in whom it is poor. Furthermore, although this has not been established, it seems probable that the prognosis is better in those in whom the symptoms are mild (perhaps because they have collateral vessels) than it is in those whose symptoms are severe. With three vessel disease, the situation is more difficult. Certainly, the outlook is poor in these patients, and there is suggestive evidence that it may be better after surgery. However, much more information is required about the subgroup who benefit, if any do, before surgery can be recommended simply to improve prognosis. There is rather less evidence of the beneficial effect of surgery in two vessel disease and virtually none in the case of single vessel disease, notwithstanding some reports that disease of the left anterior descending artery is helped. UNSTABLE

ANGINA

It has been recognized for many years that individuals’ in whom angina recently has started abruptly and unexpectedly or suddenly has deteriorated are at particular risk of myocardial infarction and sudden death. The subject has been confused by the plethora of names that have been used to describe it, including “impending acute coronary artery occlusion,” “impending infarction,” ”preinfarction angina,” “the premonitory phase of coronary occlusion,” ”acute coronary insufficiency,” “coronary failure,” “intermediate coronary syndrome,” “slight coronary attack! ” “the prodromal syndrome” and “acute and subacute coronary insufficiency.” In many cases, these terms have been used very loosely, the spectrum of syndromes ranging from the onset 45

of angina in one who is symptom free to unrelenting attacks of prolonged chest pain, unrelieved by glyceryl trinitrate and accompanied by ECG changes. In an attempt to overcome the confusion that has arisen, the term “unstable angina” has been adopted widely and has gained acceptance because this term does not imply a foreknowledge of the development of myocardial infarction, which is by no mean$ an invariable or predictable complication, and therefore to use such terms as preinfarction angina is quite misleading. However, the use of this term has been somewhat self-defeating, as it is being used to describe a wide variety of cases of varying symptoms and pathology. Although, retrospectively, one frequently has a history of new or worsening angina prior to myocardial infarction, the problem that confronts the practicing physician in therapy is that of the patient who ha8 developed severe new or progressive old angina that is occurring under less exertion or at rest and is difficult to relieve by glyceryl trinitrate. The pathology of this situation is not well established, although a report by Guthrie et aLs3 comparing the pathologic appearance8 in 12 patients with this syndrome who died during or shortly after coronary angiography or coronary artery bypass and 25 patients who died under similar circumstances with stable angina stated that they could find no difference between the two forms of angina in regard to age, sex, presence of hypertension, lipid abnormality, diabetes, smoking, family history of myocardial infarction or history of previous infarction. However, 4 of the 12 patients with unstable angina had pathologic evidence of recent but preoperative myocardial infarction whereas this was not found in 25 patients with stable angina. There has been increasing evidence from studies with creatine kinase isoenzymes and from nuclear imaging that, indeed, about 25% of patients who normally would be classified as “unstable angina” had in fact sustained a small myocardial infarction. In other patients, there may be factors that precipitate or worsen angina that are not immediately apparent. These may include the development of anemia, hypotension, asphyxia, arrhythmia, pulmonary embolism and hypotensive and hypothyroid crises. Coronary artery spasm may also be involved.8 In other patients, although this is difficult to demonstrate, physical or mental stress with associated catecholamine drive may have been a factor. Probably in the majority, however, the unstable form of angina is caused by the natural advance of coronary artery disease with the development of a critical degree of narrowing either because of the progression of atherosclerosis or by a superimposition of coronary thrombosis or subintimal hemorrhage. The most common ECG abnormality associated with unstable 46

angina is ST segment depression, but isolated T wave changes and ST elevation can occur also. The special interest in unstable angina lies not only in the difficulty of relieving the symptoms but in the reported bad prognosis in these patients. Thus, Levy4 reported a 32% mortality rate and a 23% myocardial infarction rate in 158 patients at an average of 6 weeks following presentation. Nichol et ~1.~~reported a mortality of 5% and a myocardial infarction rate of 12% at 2 months in 318 patients with impending myocardial infarction. However, the prognosis was found to be much better than this in a report by Duncan et aLss on 251 patients with ?iew and worsening angina” followed for 6 months. Only 13% developed definite or probable myocardial infarction and 3% had a cardiac arrest. In the preliminary reports from the Co-operative Study of the Myocardial Infarction Research Units, it would appear that the mortality rate is of a comparable order.67 It is well established that most patients with new or worsening angina will respond satisfactorily to a period of rest; if necessary, strictly in bed. In many cases, this is sufficient to control the symptoms, even without medicatiorP but glyceryl trinitrate and possibly concomitant use of long-acting nitrates usually are needed. Most physicians believe that, unless there is a contraindication, patients with this syndrome should receive a beta-adrenergic blocking drug. This may be required in quite large doses but it probably is as well to start off with propranololl0 mg 4 times a day for the first day then increase this daily to 160 mg, to 320 mg and to 480 mg. Few patients will not respond to this treatment. Other drugs (some of which are not available in the United States) have also been found valuable in this context, including perhexiline maleate and nifedipine. If, despite this medication, the patient does not respond and continuing rest pain occurs, consideration should be given to treatment by coronary artery saphenous vein bypass. This should not be undertaken unless the facilities for investigation and surgery are of the highest order. It may well be advisable to undertake coronary arteriography following the institution of intra-aortic balloon counterpulsation, but in any case apparatus for this should be immediately available. Because there is a high incidence of left main disease lesion in these patients, particular care must be exercised in coronary arteriography, which is associated with a relatively high mortality. The first injection should be into the aorta, preferably close to the origin of the left coronary artery. Hemodynamic studies undertaken during a period of angina may give a misleading impression of left ventricular function; a poor ejection fraction, marked dyskinesia and a high left ventricular end47

diastolic pressure at this time should not be regarded as a contraindication to surgery. Coronary artery saphenous vein bypass surgery is also relatively hazardous in this situation, as the patient may have sustained an unrecognized myocardial infarction. Most surgeons have reported a higher mortality and a considerably higher infarction rate than they experience in treating stable angina. The preliminary reports of the Myocardial Infarction Research Units’ Co-operative Study’ on unstable angina suggests that, over-all, the prognosis is not benefited by surgery. Not surprisingly, this study has shown that angina is significantly less severe at 6 months in those treated surgically. However, a substantial number of patients who present with unstable angina are symptom free on no medical treatment at all 6 months later.@ Furthermore, the long-term prognosis of those who survive unstable angina is little different from those who have stable angina. There seems to be little justification for an aggressive approach either during the acute or subsequent phase, and the views expressed by Seldon et al.@ seem appropriate: “It is possible to stabilize patients in the high-risk subgroup of acute coroPROBABLE or DEFINITE STABLE ANGINA ---pLry Physical

ECG X-ray

Hb

Severe

Mild to

NTG Beta-blockade Beta-blockade

CONTROLLED

? ANGINA ON HISTORY

Physical,

I ECG, X-ray if-w

Treat as

? Radionuclear

+ ARTERIOGRAM

UNSTABLE

ANGINA

Rest, Nitrates,.Beta-blockers \

Symptom/ Continue

Symptoms subside

Exercise Test

4

MEDICAL

TREAT

nary insufficiency by means of intensive medical therapy, and urgent bypass operation does not appear to offer any clear advantage in prevention of early myocardial infarction and death. Furthermore, after stabilization by medical treatment, a substantial number of patients maintain a satisfactory symptomatic state. With medical treatment initially, bypass could be performed subsequently as an elective procedure on patients whose eventual clinical course is unsatisfactory from the standpoint of residual incapacitating angina pectoris.” SUMMARY The diagnostic and therapeutic approach to the patient with (1) definite, (2) doubtful and (3) unstable angina is summarized in Figures 1- 3. REFERENCES 1. Prinzmetal, M., Ekmekci, A., and Kennamer, R.: Variant form of angina pectoris, previously undelineated syndrome, JAMA 174:1794, 1960. 2. Sherf, D., and Cohen, J.: “Variant” angina pectoris, Circulation 49787, 1974. 3. Lown, B., and Levine, S. A.: The carotid sinus: Clinical value of its stimulation, Circulation 23:766,1961. 4. Martin, W. B.: Patients’ use of gestures in the diagnosis of coronary insufficiency disease, Minn. Med. 40:691,1957. 5. Roughgarden, J. W., and Newman, E. V.: Circulatory changes during the pain of angina pectoris, 1772-1965-a critical review, Am. J. Med. 41:935, 1966. 6. Stuckey, D.: Cardiac pain in association with mitral stenosis and congenital heart disease, Br. Heart J. 17:397,1955. 7. Osler, W.: The Lumleian lectures on angina pectoris, Lancet, p. 839,191O. 8. Maseri, A., L’Abbate, A., Pesola, A., Ballestra, A. M., Marzilli, M., Maltinti, G., Severi, S., De Nes, D. M., Parodi, O., and Biagini, A.: Coronary vasospasm in angina pectoris, Lancet 1:713, 1977. 9. Master, A. M., and Rosenfeld, I.: Two-step exercise test: Current status after twenty-four years, Mod. Concepts Cardiovasc. Dis. 36:19, 1967. 10. Sheffield, L. T., Halt, J. H., and Reeves, T. J.: Exercise graded by heart rate in electrocardiographic testing in angina pectoris, Circulation 32:622, 1965. 11. Bruce, R. A.: Progress in Exercise Cardiology, in Yu, P. N., and Goodwin, J. F. (eds.), Progress in Cardiology 3 (Philadelphia: Lea & Febiger, 1974). 12. Redwood, D. R., Borer, J. S., and Epstein, S. E.: Whither the ST segment during exercise?, Circulation 54:703,1977. 13. Sheffield, L. T., Reeves, T. J., Blackburn, M., Ellestad, M. H., Froelicher, V. F., Roitman, D., and Kansal, S.: The exercise test in perspective, Circulation 55:681,1977. 14. McHenry, P. L.: The actual prevalence of false positive ST-segment responses to exercise in clinically normal subjects remains undefined, Circulation 55683, 1977. 15. Weyman, A. E., Feigenbaum, H., Dillon, J. C., Johnston, K. W., and Eggleton, R. C.: Non-invasive visualization of the left main coronary artery by cross-sectional echocardiography, Circulation 54:169,1976. 16. Abrams. H. L.. and Adams. D. F.: Personal Communication to Griffith. L. S. C., and Achuff, S. C., Coronary Arteriography and Left Ventriculography, 50

17. 18. 19. 20. 21.

22. 23. 24. 25. . 26. 27. 28. 29. 30. 31. 32. 33.

34. 35. 36. 37. 38.

in Julian, D. G. ted.), Angina Pectoris (Edinburgh: Churchill Livingstone, 1977). Humphries, J. O., Kuller, L., Ross, R. S., Friesinger, G. C., and Page, E. E.: Natural history of ischemic heart disease in relation to arteriographic findings, Circulation 49489,1974. Friesinger, G. C., Page, E. E., and Ross, R. S.: Prognostic significance of coronary arteriography, Trans. Assoc. Am. Physicians 83:78,1970. Bruschke, A. V. G., Proudfit, W. L., and Sones, F. M.: Progress study of 590 consecutive nonsurgical cases of coronary disease followed 5-9 years, Circulation 47:1147,1973. Reeves, T. J., Oberman, A., Jones, W. B., and Sheffield, L. T.: Natural history of angina pectoris, Am. J. Cardiol. 33:423, 1974. Webster, J. S., Moberg, C., and Rincon, G.: Natural history of severe proximal coronary disease as documented by coronary cineangiography, Am. J. Cardiol. 33~195, 1974. Margolis, J. R.: Treadmill stage as a predictor of medical and surgical survival in coronary disease, Circulation 52 (Supp. II):109, 1975. Basta, L. L., Kioschos, J. M., and Abboud, F. M.: Results of consecutive treatment of angina pectoris in candidates for aorta-coronary vein bypass, Br. Heart J. 35:531,1973. Block, W. J., Crumpacker, E. L., Dry, T. J., and Gage, R. P.: Prognosis. of angina pectoris, JAMA 150:259,1952. Weinblatt, E., Frank, C. W., Shapiro, S., and Sager, R. V.: Prognostic factors in angina pectoris, J. Chronic Dis. 21:231, 1968. Seim, S.: Angina pectoris-a prognostic study, Acta Med. Stand. 166255, 5960. Mattingly, T. W.: The postexercise electrocardiogram. Its value in the diagnosis and prognosis of coronary arterial disease, Am. J. Cardiol. 9395, 1962. Robb, G. P., and Marks, H. H.: Postexercise electrocardiogram in atherosclerotic heart disease, JAMA 200:918, 1967. Froelicher, V. F., Thomas, M. M., Pillow, C., and Lancaster, M. C.: Epidemiologic study of asymptomatic men screened by maximal treadmill testing for latent coronary artery disease, Am. J. Cardiol. 34:770,1974. 0.: False positive Erikssen, J., Enge, I., Forfang, K., and Storstein, diagnostic tests and coronary angiographic findings in 105 presumably healthy males, Circulation 54371, 1976. Kouchoukos, N. T., Oberman, A., Russell, R. O., and Jones, W. B.: Surgical vs medical treatment of occlusive disease confined to the left anterior descending artery, Am. J. Cardiol. 35:836,1975. Lim, J. S., Proudfit, W. L., and Sones, F. M.: Left main coronary arterial obstruction: Long-term follow-up of 141 nonsurgical cases, Am. J. Cardiol. 36:131,1975. Platia, E. V., Griffith, L. S. C., and Humphries, J. 0.: Location and severity of coronary artery narrowings as predictors of survival, Circulation 52(Supp. 11):91, 1975. Dewar, H. A., and Oliver, M. F.: Secondary prevention trials using clofibrate, Br. Med. J. 4:784,1971. Coronary Drug Project Research Group: Clofibrate and niacin in coronary heart disease, JAMA 231:360,1975. Wilhelmsson, C., Vedin, J. A., Ehnfeldt, E., Tibblin, G., and Wilhelmsen, L.: Smoking and myocardial infarction, Lancet 1:415,1975. Veterans Administration Co-operative Study Group on Antihypertensive Agents: Effects of treatment on morbidity in hypertension, JAMA 213:1143, 1970. Lambert, D. M. D.: Effeot of propranolol on mortality in patients with angina, Postgrad. Med. J. 52(Supp. 4):57, 1976. 51

39. Stewart, I. McD. G.: Compared incidence of first myocardial infarction in hypertensives under treatment containing propranolol or excluding betablockade, Clin. Sci. Mol. Med. Bl(Supp. 31509, 1976. 40. Wilhebnsson, C., Vedin, J. A., Wilhelmsen, L., Tibblin, G., and Werko, L.: Reduction of sudden deaths after myocardial infarction by treatment with alprenolol, Lancet 1:1257, 1976. 41. Multicentre International Study: improvement in prognosis of myocardial infarction by long-term beta-adrenoreceptor blockade using practolol, Br. Med. J. 3:735,1975. 42. Lovell, R. R. H.: Lessons about myocardial infarction from studies of longterm anticoagulation, Circulation 4OfSupp. IV):119,1969. 43. Borchgrevink, C. F.: Anticoagulant therapy in angina pectoris, Lancet 1:448, 1962. 44. Jackson, G., Atkinson, L., and Oram, S.: Reassessment of failed beta-blocker treatment in angina pedoris by peak exercise heart rate measurements, Br. Med. J. 3:616,1975. 45. Miller, R. R., Olson, H. G., Amsterdam, E. A., and Mason, D. T.: Propranolol-withdrawal rebound phenomenon, N. Engl. J. Med. 293:416, 1975. 46. Cannom, D. S., Miller, D. G., and Shumway, N. E.: The long-term follow-up of patients undergoing saphenous vein bypass surgery, Circulation 49:77, 1974. 47. Morris, G. C., Jr., Reul, G. J., and Howill, J. F.: Follow-up results of distal coronary artery bypass for ischemic heart disease, Am. J. Cardiol. 29180, 1972. 48. Alderman, E. L., Matlof, H. J., and Wexler, L.: Results of direct coronary artery surgery for the treatment of angina pectoris, N. Engl. J. Med. 288: 535,1973. 49. Kouchoukos, N. T., Kirklin, J. W., and Oberman, A.: An appraisal of coronary bypass grafting, Circulation 50:11,1974. 50. Caves, P. K., and Stinson, E.: Surgical Treatment, in Julian, D. G. (ed.1, Angina Pectoris (Edinburgh: Churchill Livingstone, 1977), p. 227. 51. Lesperance, J., Bourassa, M. G., Biron, P., Campeau, L., and Saltiel, J.: Aorta to coronary artery saphenous vein grafts, Am. J. Cardiol. 36459, 1972. 52. Vlodaver, Z., and Edwards, J. E.: Pathologic changes in aortic-coronary arterial saphenous vein grafts, Circulation 4&719, 1971. 53. Bruce. R. A.. and Hornsten. P. R.: Exercise stress testine in evaluation of patients with ischemic heart disease, Prog. Cardiovasc. Di; 11:37,1969. 54. Wallwork, J., Potter, B., and Caves, P. K.: Rehabilitation following coronary artery bypass grafting in angina: Return to work, Br. Heart J. (In press.) 55. Takaro, T., Hultgren, H. N., and Detre, K. M.: VA co-operative study of coronary arterial surgery in left main disease, Circulation 52fSupp. 11):143, 1975. 56. Mathur, V. S., and Guinn, G. A.: Prospective randomized study of coronary bypass surgery in stable angina: The first 100 patients, Circulation 516Supp. 1X133, 1975. 57. Kloster, F. E., Kremkan, E. L., Rahimtoola, S. H., Griswold, H. E., Ritxmann, L. W., and Starr, A.: Prospective randomized study of coronary bypass surgery for chronic stable angina, Eur. Cong. Cardiol., Abst. Book 1: 305,1976. 58. Sheldon, W. C., Rincon, G., Pichard, A. D., Raxari, M., Cheanvechai, C., and Loop, F. D.: Surgical treatment of coronary artery disease-“pure” graft operation, Prog. Cardiovasc. Dis. l&237, 1976. 59. Griffith, L. S. C., and Achuff, S. C.: Coronary Angiography, Julian, D. G. (ed.), Angina Pectoris (Edinburgh: Churchill Living&me, 1977). 60. M&leer, J. F., Starmer, C. F., Bartel, A. G., Behar, V. S., Kong, Y., Peter, R. H., and Rosati, R. A.: The nature of treatment selection in coronary artery disease, Circulation 49606, 1974. 52

61. Taiano, J. V., Scanlon, P. J., Meadows, W. R., Kahn, M., Pifarre, R., and Gunnar, R. M.: Influence of surgery on survival in 145 patients with left main coronary artery disease, Circulation 52(Supp. 1):105,1975. 62. Oberman, A., Kouchoukos, N. T., Harrell, R. R., Holt, J. H., Russell, O., and Rackley, C. E.: Surgical versus medical treatment in disease of the left main coronary artery, Lancet 2:591,1976. 63. Guthrie, R. B., Vlodaver, Z., Nicoloff, D. M., and Edwards, J. E.: Pathology of stable and unstable angina pectoris, Circulation 51:1059,1975. 64. Levy, H.: The natural history of changing patterns of angina pectoris, Ann. Intern. Med. 44:1123,1956. 65. Nichol, E. S., Philips, W. C., and Casten, G. G.: Virtue of prompt anticoagulant therapy in impending myocardial infarction, Ann. Intern. Med. 5611581959. 66. Duncan, B., Fulton, M., Morrison, S. L., Lutz, W., Donald, K. W., Kerr, F., Kirby, B. J., Julian, D. G., and Oliver, M. F.: New and worsening angina pectoris, Br. Med. J. 1:981, 1976. 67. Conti, C. R.: Personal communication. 68. Seldon, R., Neill, W. A., Ritzman, L. W., Okies, J. E., and Anderson, R. P.: Medical versus surgical therapy for acute coronary insufficiency, N. Engl. J. Med. 293:1329, 1975.

53