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Effect of Sympathetic Stimulation and Blockade in Patients with Angina Pectoris
450
; ; CLINICAL CONFERENCE IN CARDIOLOGY
Effect of Sympathetic Stimulation and Blockade in Patients with Angina Pectoris A Clini~al Conference in Cardiology from the University of Kentucky Medical Center, Lexington, Kentucky
Moderator: Leonard S. Gettes, Al.D., Assistant Professor of Aledicine Karl F. Yoshonis, M.D., Cardiovascular Trainee; Instructor in Medicine Joseph R. Logic, A/.D., Assistant Professor of Aledicine and Physiology; American Heart Association Advanced Research Fellow Myron H. Luria, M.D., Assistant Professor of AJ edicine (lJresently at Cleveland, Ohio) Borys Surawicz, A/.D., Professor of Aledicine and Director, Cardiovascular Division
Dr. Gettes: For many years, Wilhelm Raab! has proposed that the sympathetic amines contribute to the development of angina pectoris. The reported effectiveness of the recently developed sympathetic blocking agent, propranolol, in the treatment of angina pectoris2 lends support to this hypothesis and makes important an understanding of the relationships between sympathetic amines, myocardial oxygen requirements, coronary blood How and angina pectoris. In 1948, Ahlquist3 separated the effects of catecholamines into two groups which he labeled alpha and beta. Catecholamines were considered to have an alpha stimulating effect \vhen they caused peripheral vasoconstriction, and to have a beta stimulating effect \vhen they caused peripheral vasodilitation, increased the heart rate, and increased the cardiac contractile force. Phenylephrine, which has only alpha stimulating effects, and isoproterenol, which has only beta stimulating effects, both increase myocardial oxygen consumption and increase coronary blood flow. The naturally occurring catecholamines, epinephrine and norepinephrine, possess both alpha and beta stimulating effects. Dr. Karl Yoshonis will present three patients \vith angina pectoris and abnormal electrocardiographic Study supported by N.I.H. Cardiology Research Training Grant HE 05598 and N.I.H. Cardiology Clinical Training Grant HE 05771.
52
responses to exercise in whom the ECG abnormalities of coronary insufficiency could be induced by the infusion of catecholamines. Two of these patients were women without demonstrable large vessel coronary artery disease and the third \vas a man \vith demonstrable large vessel coronary artery disease. Dr. Joseph Logic will then discuss the factors which determine myocardial oxygen consumption and coronary blood flow, and the effect of catecholamines on these factors. Dr. Myron Luria will relate these concepts to the patient with angina pectoris, and Dr. Borys Surawicz will summarize our clinical experience with propranolol in the treatment of angina pectoris. Dr. Yoshonis: Case 1: A 43-year-old white \vornan was first seen at University of Kentucky Medical Center in 1965 \vith a one and one-half year history of angina-like chest pain. The patient was premenopausal and had had migraine headaches in the past. The systolic blood pressure was 108 mm Hg and the diastolic blood pressure 65 mm Hg. The physical examination and roentgenograms of the chest, upper gastrointestinal tract and spine were normal. A complete blood count (CBC), urinalysis, t\vo-hour post-prandial blood sugar and cholesterol were \vithin normal limits. The resting ECG's were normal (Fig la, top). After three minutes of hvostep exercise, there \vas 2 mm S-T segment depresDIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
SYMPATHETIC STIMULATION AND BLOCKADE IN ANGINA
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1. Lead V4 recorded before (top), and after (bottom), the intravenous administration of propranolol 0.15 mg/kg. A, rest. B, after three minutes' two-step exercise. C, after intravenous isoproterenol infusion. D, after the intravenous administration of 0.8 mg atropine and 0.5 mg phenylephrine. Note the effect of propranolol therapy on heart rate and SoT segment changes.
FIGURE
sion in leads V 4 and Va (Fig Ib, top). Right and left ventricular pressures obtained during cardiac catheterization, and selective coronary arteriograms were normal. The intravenous infusion of isoproterenol (2 /Lg/ min) induced S-T segment changes similar to those observed after exercise (Fig Ie, top). Similar but less marked changes also occurred following the intravenous administration of 0.8 mg atropine and 0.5 mg phenylephrine, which increased the blood pressure to 180 mm Hg systolic and 120 mm Hg diastolic (Fig Id, top). All S-T segment abnormalities were prevented by the intravenous administration of 0.15 mg/kg of propranolol (Fig 1, bottom). Case 2: A 44-year-old white woman was first seen at our institution in 1967 with a one-year history of angina-like chest pain. Initially, the pains were precipitated by exertion, but subsequently occurred spontaneously. The patient had had a
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hysterectomy and oophorectomy performed in 1955. The systolic blood pressure varied from 140 to 160 mm Hg and the diastolic blood pressure varied from 95 to 110 mm Hg. The physical examination and roentgenograms of the chest, upper gastrointestinal tract, gall bladder and spine were normal. The CBC, serum cholesterol, glucose tolerance test, urinary vanillylmandelic acid and catecholamine determinations were within normal limits. A cold pressor test and histamine provocative test were also normal. Resting ECG's taken while the patient was having chest pain (Fig 2a) showed S-T segment depression in lead II and S-T segment elevation in lead V4. The blood pressure recorded at this time was 180 mm Hg systolic and 115 mm Hg-diastolic. ECG's taken after three minutes of two-step exercise showed similar S-T segment abnormalities. The patient experienced several episodes of spontaneous chest pain during cardiac catheterization.
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2. Lead II (top) and V4 (bottom) recorded: A, during an attack of spontaneous chest pain. B, during an attack of chest pain precipitated hy the intravenous infusion of 1.5 mg phenylephrine. C, following the intravenous infusion of 3.0 mg phenylephrine. The patient was receiving 60 mg of orally administered phenoxybenzamine per day when C was recorded. FIGURE
DIS. CHEST, VOL. 54, NO.5. NOVEMBER 1968
53
452
GEnES ET AL
The left ventricular end-diastolic pressure was 15 mm Hg before chest pain and rose to 35 mm Hg when chest pain occurred. Selective coronary arteriograms were normal. The intravenous infusion of isoproterenol (4 JLg/ min) produced an increase in heart rate to 150, but did not produce S-T segment changes on the ECG or chest pain. When 1.5 mg of phenylephrine was infused intravenously, the blood pressure rose to 210 mm Hg systolic and 120 mm Hg diastolic. The patient developed chest pain and the S- T segments on the ECG became depressed in lead II and elevated in V4 (Fig 2b). The blood pressure elevation, development of chest pain, and S-T segment abnormalities did not accompany the intravenous administration of 3 mg phenylephrine when the patient was receiving 60 mg of orally administered phenoxybenzamine daily (Fig 2c). Case 3: A 48-year-old white man was first seen at the University of Kentucky Medical Center in 1967 with a two-month history of angina-like chest pain which was preceded by an acute myocardial infarction. The systolic blood pressure ranged from 130 to 150 mm Hg and the diastolic blood pressure ranged from 90 to 100 mm Hg. The physical examination and roentgenograms of the chest were normal. The CBC and urinalysis were within normal limits. A three hour glucose tolerance test was consistent with a diagnosis of diabetes mellitus and the serum cholesterol was 350 mg per cent. The resting ECG was consistent with an old inferior myocardial infarction. After three minutes of two step exercise there was 2 mm S-T segment depression in leads
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V4 (Fig 3b) and V 5. Right and left ventricular pressures obtained during cardiac catheterization were normal. Selective coronary arteriograms demonstrated almost complete occlusion of the right coronary artery and greater than 50 per cent occlusion of the left circumflex coronary artery. The intravenous infusion of isoproterenol (4 JLg/min) induced 1 mm S-T segment depression in V4 (Fig 3c) and V5 • The intravenous administration of 0.15 mg/kg propranolol (Fig 3, bottom) did not prevent the exercise-induced S- T segment changes, but did prevent the isoproterenol-induced S-T segment changes. Dr. Logic: The regulation of the coronary circulation is complex. Gregg and his associates 4 have clearly shown that coronary blood flow (CBF) is phasic. It decreases during isovolumetric systole, increases during ejection, and is maximal during diastole. This phasic pattern is a function of changes in aortic flow, arterial pressure, and in the resistance to blood flow \vithin the coronary circulation. The coronary vascular resistance is determined by the intramyocardial pressure and by neurohumoral and metabolic factors which act directly on the coronary arterioles. The most potent stimulus for decrease in coronary vascular resistance and an increase in CBF is a decrease in local p02' whether from systemic hypoxia or from factors which increase myocardial oxygen consumption (MV O 2 ), The precise determinants of MV O 2 have been difficult to denne. 5 It has been shown that the MV O 2 increases when the pressure- or time-tension per minute [time-ten-
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FIGURE 3. Lead V 4 recorded before (top) and after (bottom) the intravenous administration of propranolol 0.15 mg/kg. A, rest. B, after 3 minutes of 2-step exercise. C, after the intravenous infusion of isoproterenol.
54
DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
SYMPATHETIC STIMULATION AND BLOCKADE IN ANGINA
sion index (TTl)] increases. MV O 2 also increases when the velocity of shortening of the muscle fiber increases, even though the TTl may not change or may even decrease. Factors which increase arterial blood pressure will augment the after-load during systolic ejection, will prolong the TTl, and will increase the MV O 2 • Factors which enhance the intrinsic contractile state of the myocardium \viIJ increase the rate of development of tension in myocardial fibers and will also lead to an increase in MV O 2 • Thus, the MV O 2 may be regarded as a function of the rate of fiber shortening, the extent of fiber shortening, the duration of fiber shortening, and the frequency of fiber shortening. The concept of total contractile \vork, \vhich includes the external \vork performed during ventricular ejection and the work performed during the isovolumetric phase of systole, has been sho\vn to correlate well with MV0 2 • In the intact preparation both alpha and beta stimulating catecholamines increase the MV O 2 and increase coronary blood flow. The development of electromagnetic flow sensors has permitted the separation of the effects of the catecholamines on the coronary arteries from their effects on the myocardium. Catecholamines with beta stimulating effects directly enhance myocardial contractility and increase the rate of shortening of the myocardial fiber. Alpha adrenergic agents do not directly enhance myocardial contractility. Ho\vever, they do increase the arterial blood pressure, increase the after-load and prolong the TTl. The coronary arteries have been found to possess both alpha and heta receptors. The adrenergic neurotransmitter, norepinephrine, directly constricts the coronary arteries. This constriction can be prevented hy the alpha adrenergic blocking agent phenoxybenzamine and is therefore an alpha effect. Isoproterenol dilates the coronary arteries. This dilatation can be prevented by the beta adrenergic blocking agent propranolol and is therefore a beta effect. Zuberbuhler and Bohr6 have demonstrated both alpha and beta effects in the larger coronary arteries but only beta effects in the smaller coronary arteries. The sympathetic amines with beta stimulating effects increase coronary blood flow by increasing cardiac output and hy decreasing coronary vascular resistance. The decrease in coronary vascular resistance reflects not only the direct vasodilating effect of these amines, but also the indirect vasodilating effect \vhich accompanies the more rapid rate of fiber shortening and the increase in myocardial oxygen requirement. The sympathetic amines with alpha stimulating effects have a direct vasoconDIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
453
stricting effect and do not directly increase cardiac output. The increased CBF associated with administration of these amines results from an increase in arterial blood pressure which increases the gradient across the coronary vascular bed and from indirect dilitation of the coronary arteries. When the cardiac rate is constant, the indirect effect on the coronary arteries is secondary to the increase in myocardial oxygen requirement associated with prolongation of the TTl. Dr. Luria: The function of the coronary circulation is to supply an adequate amount of oxygen to the myocardium. Any increase in myocardial oxygen requirement must be associated with an increase in myocardial oxygen consumption if aerobic metabolism is to be maintained. Myocardial oxygen consumption is related directly to the coronary blood flow (CBF) and to the coronary A-V O 2 difference. In a wide variety of situations, the coronary A-V O 2 difference is maintained at a steady level. Therefore, any increase in myocardial oxygen consumption should be associated with a parallel increase in CBF. If the CBF is unable to increase sufficiently to meet the increased oxygen requirements, the coronary A-V O 2 difference will widen, anaerobic metabolism with the production of excess lactate may ensue, and eventually clinical angina may occur. Exercise and catecholamines increase the myocardial oxygen requirement and the CBF. As delineated above, there are several factors \vhich are responsible for the increased myocardial oxygen requirement. From a clinical standpoint, changes in the tension-time index, calculated from the ejection time, the ejection pressure and the heart rate, correlate well with change in myocardial O 2 consumption. An even more simple index, and one which can be employed at the bedside, is the product of the heart rate and hlood pressure (HR x BP). Although this index will reflect the increased myocardial O 2 requirement associated with agents which may increase the heart rate or the blood pressure without increasing the TTl, it is not an adequate measure of the myocardial O 2 requirement because it does not reflect the changes in the velocity of muscle shortening \vhich characterize agents with beta stimulating effects. Nonetheless, the clinical usefulness of HR x BP becomes evident \vhen experimental clinical angina is produced either by exercise or by increasing the heart rate with right atrial pacing. In either instance, there appears to be a certain level of HR x BP for each individual above which angina pectoris occurs. In each of the three patients presented in this
55
454 conference, angina and the ECG changes of coronary insufficiency occurred at a time when HR x BP increased. In two, HR x BP was increased via an increase in heart rate accompanying exercise and the administration of isoproterenol. In the third, HR x BP was increased by an increase in BP which occurred spontaneously and after the administration of phenylephrine.
Dr. Gettes: It is clear from the preceding discussion that factors which have a positive increased inotropic or chronotropic effect and factors which increase the systemic blood pressure will also increase the myocardial oxygen requirement. Angina pectoris may be expected to occur if an increase in myocardial oxygen requirement were not associated with an increase in myocardial oxygen supply. As demonstrated by the two women presented in this conference, such an event may occur even in the absence of obstruction of the large coronary arteries. One of the possible explanations for the chest pain in these women is an excessive secretion of catecholamines or an undue sensitivity to the normal secretion of catecholamines. A possible approach to therapy of angina, either with or without large vessel coronary artery disease, would be to decrease the myocardial oxygen requirement. Indeed, it is this mechanism which has been postulated to explain the effectiveness of the beta sympathetic blocking agent, propranolol, in the treatment of angina. Propranolol decreases the heart rate at rest and during exercise, and thereby decreases the product of heart rate and blood pressure. In addition, propranolol slows the rate of shortening of the heart muscle fiber and decreases cardiac work. 7 These effects would decrease the myocardial oxygen requirement. On the other hand, propranolol prolongs contraction and may increase myocardial tension. These effects would increase the myocardial oxygen requirement. Propranolol also increases coronary vascular resistance and decreases coronary blood flow. It is therefore difficult to predict the net effect of propranolol therapy on the relationship between myocardial oxygen requirement and coronary blood How. Dr. Surawicz: Twenty-eight patients with coronary artery disease, angina pectoris and abnormal twostep exercise tests have been treated with orally administered propranolol in doses of 40-160 mg daily for periods of two months to three years.· Twenty-three of these patients (83 per cent) were symptomatically improved by therapy. In 19, we were able to compare the symptomatic improve°Supported by Ayerst Laboratories, New York.
56
GEnES ET AL ment, as determined by detailed questioning regarding the characteristics of the anginal attacks, to changes in the exercise ECG at each of several dosage levels. The purpose of this analysis was to establish the optimal dose of propranolol for each patient. We defined the optimal dose as the smallest dose associated \vith: (1) a negative double two-step Master exercise test; (2) the least abnormal ECG after exercise; (3) the maximal increase in the duration of exercise performed to the onset of S-T segment depression. In the absence of 1-3, we selected the maximal dose associated with a heart rate of more than 55 beats per minute at rest and more than 95 beats per minute during exercise. In three patients, the optimal dose \vas 40-60 mg per day. The dose was not increased in these patients because of slo\\ring of the heart rate. In 11 patients the optimal dose was 80 mg per day. In three of these patients larger doses \vere associated with less beneficial effects on symptoms and on the exercise ECC. In one patient the optimal dose was 120 mg per day, and in four 160 mg per day. Since 160 mg per day was the maximal dose used in this study, it is possible that this dose \vas not "optimal" in these four patients. In ten of the 19 patients there \vas less S-T segment depression following exercise, or an increase in the duration of exercise performed to the onset of S-T depression. The exercise ECG of the remaining nine patients was not improved. In both of these groups the slowing of the resting and exercise heart rates and the changes in the characteristics of the anginal attack were similar. Propranolol did not completely abolish exertional chest pain in anv of our patients. However, all patients required le;s nitroglycerine because the frequency and/ or the severity of the attacks decreased. Of greatest interest to us was a change in the pattern of the anginal attack itself. T\velve patients reported that hefore therapy with propranolol \vas instihlted, the intensity of the chest pain increased during each attack, whereas after therapy with propranolol \vas instituted, the intensity of the chest pain decreased during each attack. Our study confirmed the previously reported effectiveness of long-term propranolol therapy in the treatment of angina pectoris. Our study also confirmed the need to individualize the dose of propranolol, and sho\ved that the exercise ECG \vas helpful in determining the optimal dose in about 50 per ce'lt of patients. The symptomatic improvement associated with propranolol therapy reflected changes in the characteristics of the anginal attack. However, we were unable to ascribe the benencial DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
SYMPATHETIC STIMULATION AND BLOCKADE IN ANGINA
effect of propranolol to a significant decrease in myocardial oxygen requirement since the exercise ECG abnormalities were unchanged in 50 per cent of the patients who experienced subjective improvement. SU~IMARY
Dr. Gettes: We have presented three patients with angina pectoris in whom the S-T segment abnormalities of coronary insufficiency could be induced by the infusion of catecholamines. We have reviewed the factors which regulate coronary blood flow and have stressed the importance of the myocardial oxygen requirement in this regulation. We have considered the mechanisms by which the catecholamines increase myocardial oxygen requirements and have shown that the product of heart rate and blood pressure can be used at the bedside to assess a change in the myocardial oxygen requirement. Finally, we have reviewed our experiences with the beta adrenergic blocking agent, propranolol, in the treatment of angina pectoris and have confirmed the therapeutic effectiveness of the drug. However, we were unable to ascribe the propranolol induced changes in the characteristics of the anginal attack to a critical decrease in myocardial oxygen requirement. DISCUSSION
Dr. Jacqueline Noonan: Dr. Surawicz, how many patients in your study died during your period of observation? Dr. Surawicz: Two patients died during the period of observation. One was 38 and the other 46 years old. Both had severe exertional angina, both improved after propranolol therapy was instituted, and both died suddenly at home. Dr. Lester Bryant: Is it possible that these patients died as a result of propranolol therapy? Dr. Surawicz: This is, of course, possible. However, sudden death in patients with coronary artery disease is not uncommon and therefore two deaths in 28 patients, followed for three months to three years, is something that you would expect. The question is important because if one continued to increase the propranolol dose you would certainly reach a point where profound bradycardia and depression of contractility would counteract the beneficial effect of the drug. This is illustrated by the three patients in whom larger doses of propranolol were associated with a worsening of both their subjective and objective responses to the drug. For this reason, we initiated therapy with small doses and did not administer the drug in the high DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
455
doses (up to 400 mg per day), recommended by other investigators. Dr. Stephen Edelstein: By what postulated mechanism do you explain the beneficial effects of propranolol, if you do not accept a decrease in myocardial oxygen requirement as the mechanism of action? Dr. Gettes: As Dr. Surawicz has stated, the pattern of the anginal attack was changed by the administration of propranolol. Gazes and co-workers 8 pointed out that in patients with angina pectoris there \vas an abnormal increase in circulating catecholamines after exercise. It is possible that the increase in heart rate and blood pressure which Roughgarden9 has shown to accompany the development of angina pectoris may reflect this increase in circulating catecholamines. It is also possible that the progressive intensification of the anginal pain as experienced by our patients prior to therapy may reflect the further increase in myocardial oxygen requirement imposed by these changes in heart rate and blood pressure. Our patients stated that after propranolol therapy was instituted their pain did not intensify after its onset. This observation suggests that either the increase in the circulating catecholamines was prevented, or that the betastimulating effect of the increase in circulating catecholamines was blocked by propranolol therapy. An additional mechanism has been suggested by Wolfson and co-workers 1o who found that in one patient propranolol relieved coronary vasoconstriction during an attack of angina. Although this observation is not in keeping with experimental studies which have uniformly shown an increase in coronary resistance and a decrease in CBF, the relief of coronary vasoconstriction must be considered a possible mechanism of action. Dr. Armond Gordon: Did you perform any double blind studies? Dr. Surawicz: We did not. There are several double blind studies in the literature and all but one confirm the subjective improvement associated with the administration of propranolol. In addition, a long-term double blind study is very difficult to perform because the patients are aware of the slowed heart rate at rest and because their subjective improvement is so dramatic that they do not appreciate having the drug withdrawn. In ten patients we did discontinue the drug for two to four weeks. In all, the nitroglycerine requirement, resting and exercise heart rates, duration of two-step exercise and magnitude of post-exercise S-T segment depression returned to the pre-treatment values.
57
GETTES ET AL
456 REFERENCES
1 RAAB, W.: Hormonal and Neurogenic Cardiovascular Disorders, Williams and Wilkins, Baltimore, 1953. 2 Symposium on beta-adrenergic blockade, E. Braunwald, guest editor, Amer. ]. Cardiol., 18: 1966. 3 AHLQUIST, R. P.: Study of adrenotropic receptors, Amer. ]. Physiol., 153:586, 1948. 4 GREGG, D. E.: Physiology of the coronary circulation, Circulation, 27:1128, 1963. 5 BRAUNWALD, E., Ross, J. JR., AND SONNENBLICK, E. H.: Mechanisms of contraction of the normal and failing heart, New Eng. ]. Med., 277:794, 853,910,962, 1967. 6 ZUBERBUHLER, R. C .. AND BOHR, D. F.: Responses of coronary smooth muscle to catecholamines, Circulation Res., 26:431, 1965.
7 EpSTEIN, S. E., AND BRAUNWALD, E.: Beta-adrenergic receptor blocking drugs. Mechanisms of action and clinical applications, New Eng. ]. Med., 275:1106, 1175, 1966. 8 GAZES, P. C., RICHARDSON, J. A., AND WOODS, E. F.: Plasma catechol amine concentrations in myocardial infarction and angina pectoris. Circulation, 19:657, 1959. 9 ROUGHGARDEN, ]. W.: Circulatory changes associated with spontaneous angina pectoris, Amer. ]. Med., 41: 947, 1966. 10 WOLFSON, S., HEINLE, R. A., HERMAN, M. V., KEMP, H. G., SULLIVAN, J. M., AND GORLIN, R.: Propranolol and angina pectoris, Amer. ]. Cardiol, 18:345, 1966. Reprint requests: Dr. Gettes, Depamnent of Medicine, University of Kentucky, Lexington 40506
AMERICAN COLLEGE OF CHEST PIIYSI(:IANS 1969 ESSAY CONTEST Each year the College offers undergraduate medical students throughout the world the opportunity to submit manuscripts on any phase of the diagnosis and treabnent of cardiovascular or pulmonary disease, in open competition.
A sealed envelope bearing the same motto on the outside and enclosing the name and address of the author must accompany the essay. (Motto may be a word or brief phrase which has a significant meaning to the author.)
Medical students wishing to enter the 1969 Alfred A. Richman Essay Contest of the American College of Chest Physicians should observe the following rules:
The First Prize will be $500; Second Prize will be $300; Third Prize will be $200. Each winner will also receive a certificate of merit. A trophy, inscribed with the name of the First Prize winner and the name of his school will be awarded to the winner's school.
1) Complete application form in duplicate, have original copy signed by the dean of the medical school, and return original copy at once to the American College of Chest Physicians, 112 East Chestnut Street, Chicago, Illinois 60611. 2) Five copies of the manuscript, typewritten in English (double spaced) must be submitted to the American College of Chest Physicians offices in Chicago not later than April 15, 1969. 3) The length of manuscripts is optional; 2500-4500 words suggested. 4) The only means of identification of the author shall be' a motto or other device on the ·title page.
58
The winning contributions will be selected by a committee of chest specialists at the 35th Annual Meeting of the American College of Chest Physicians to be held in Chicago, Illinois in October, 1969. All manuscripts become the property of the American College of Chest Physicians and may be considered for publication in the College journal. It is suggested that applicants study the format of the College journal, DISEASES OF THE CHEST, to guide them in preparing the essay. A copy will be sent on request.
DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
; ; CLINICAL CONFERENCE IN CARDIOLOGY
Effect of Sympathetic Stimulation and Blockade in Patients with Angina Pectoris A Clini~al Conference in Cardiology from the University of Kentucky Medical Center, Lexington, Kentucky
Moderator: Leonard S. Gettes, Al.D., Assistant Professor of Aledicine Karl F. Yoshonis, M.D., Cardiovascular Trainee; Instructor in Medicine Joseph R. Logic, A/.D., Assistant Professor of Aledicine and Physiology; American Heart Association Advanced Research Fellow Myron H. Luria, M.D., Assistant Professor of AJ edicine (lJresently at Cleveland, Ohio) Borys Surawicz, A/.D., Professor of Aledicine and Director, Cardiovascular Division
Dr. Gettes: For many years, Wilhelm Raab! has proposed that the sympathetic amines contribute to the development of angina pectoris. The reported effectiveness of the recently developed sympathetic blocking agent, propranolol, in the treatment of angina pectoris2 lends support to this hypothesis and makes important an understanding of the relationships between sympathetic amines, myocardial oxygen requirements, coronary blood How and angina pectoris. In 1948, Ahlquist3 separated the effects of catecholamines into two groups which he labeled alpha and beta. Catecholamines were considered to have an alpha stimulating effect \vhen they caused peripheral vasoconstriction, and to have a beta stimulating effect \vhen they caused peripheral vasodilitation, increased the heart rate, and increased the cardiac contractile force. Phenylephrine, which has only alpha stimulating effects, and isoproterenol, which has only beta stimulating effects, both increase myocardial oxygen consumption and increase coronary blood flow. The naturally occurring catecholamines, epinephrine and norepinephrine, possess both alpha and beta stimulating effects. Dr. Karl Yoshonis will present three patients \vith angina pectoris and abnormal electrocardiographic Study supported by N.I.H. Cardiology Research Training Grant HE 05598 and N.I.H. Cardiology Clinical Training Grant HE 05771.
52
responses to exercise in whom the ECG abnormalities of coronary insufficiency could be induced by the infusion of catecholamines. Two of these patients were women without demonstrable large vessel coronary artery disease and the third \vas a man \vith demonstrable large vessel coronary artery disease. Dr. Joseph Logic will then discuss the factors which determine myocardial oxygen consumption and coronary blood flow, and the effect of catecholamines on these factors. Dr. Myron Luria will relate these concepts to the patient with angina pectoris, and Dr. Borys Surawicz will summarize our clinical experience with propranolol in the treatment of angina pectoris. Dr. Yoshonis: Case 1: A 43-year-old white \vornan was first seen at University of Kentucky Medical Center in 1965 \vith a one and one-half year history of angina-like chest pain. The patient was premenopausal and had had migraine headaches in the past. The systolic blood pressure was 108 mm Hg and the diastolic blood pressure 65 mm Hg. The physical examination and roentgenograms of the chest, upper gastrointestinal tract and spine were normal. A complete blood count (CBC), urinalysis, t\vo-hour post-prandial blood sugar and cholesterol were \vithin normal limits. The resting ECG's were normal (Fig la, top). After three minutes of hvostep exercise, there \vas 2 mm S-T segment depresDIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
SYMPATHETIC STIMULATION AND BLOCKADE IN ANGINA
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1. Lead V4 recorded before (top), and after (bottom), the intravenous administration of propranolol 0.15 mg/kg. A, rest. B, after three minutes' two-step exercise. C, after intravenous isoproterenol infusion. D, after the intravenous administration of 0.8 mg atropine and 0.5 mg phenylephrine. Note the effect of propranolol therapy on heart rate and SoT segment changes.
FIGURE
sion in leads V 4 and Va (Fig Ib, top). Right and left ventricular pressures obtained during cardiac catheterization, and selective coronary arteriograms were normal. The intravenous infusion of isoproterenol (2 /Lg/ min) induced S-T segment changes similar to those observed after exercise (Fig Ie, top). Similar but less marked changes also occurred following the intravenous administration of 0.8 mg atropine and 0.5 mg phenylephrine, which increased the blood pressure to 180 mm Hg systolic and 120 mm Hg diastolic (Fig Id, top). All S-T segment abnormalities were prevented by the intravenous administration of 0.15 mg/kg of propranolol (Fig 1, bottom). Case 2: A 44-year-old white woman was first seen at our institution in 1967 with a one-year history of angina-like chest pain. Initially, the pains were precipitated by exertion, but subsequently occurred spontaneously. The patient had had a
A
II
hysterectomy and oophorectomy performed in 1955. The systolic blood pressure varied from 140 to 160 mm Hg and the diastolic blood pressure varied from 95 to 110 mm Hg. The physical examination and roentgenograms of the chest, upper gastrointestinal tract, gall bladder and spine were normal. The CBC, serum cholesterol, glucose tolerance test, urinary vanillylmandelic acid and catecholamine determinations were within normal limits. A cold pressor test and histamine provocative test were also normal. Resting ECG's taken while the patient was having chest pain (Fig 2a) showed S-T segment depression in lead II and S-T segment elevation in lead V4. The blood pressure recorded at this time was 180 mm Hg systolic and 115 mm Hg-diastolic. ECG's taken after three minutes of two-step exercise showed similar S-T segment abnormalities. The patient experienced several episodes of spontaneous chest pain during cardiac catheterization.
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2. Lead II (top) and V4 (bottom) recorded: A, during an attack of spontaneous chest pain. B, during an attack of chest pain precipitated hy the intravenous infusion of 1.5 mg phenylephrine. C, following the intravenous infusion of 3.0 mg phenylephrine. The patient was receiving 60 mg of orally administered phenoxybenzamine per day when C was recorded. FIGURE
DIS. CHEST, VOL. 54, NO.5. NOVEMBER 1968
53
452
GEnES ET AL
The left ventricular end-diastolic pressure was 15 mm Hg before chest pain and rose to 35 mm Hg when chest pain occurred. Selective coronary arteriograms were normal. The intravenous infusion of isoproterenol (4 JLg/ min) produced an increase in heart rate to 150, but did not produce S-T segment changes on the ECG or chest pain. When 1.5 mg of phenylephrine was infused intravenously, the blood pressure rose to 210 mm Hg systolic and 120 mm Hg diastolic. The patient developed chest pain and the S- T segments on the ECG became depressed in lead II and elevated in V4 (Fig 2b). The blood pressure elevation, development of chest pain, and S-T segment abnormalities did not accompany the intravenous administration of 3 mg phenylephrine when the patient was receiving 60 mg of orally administered phenoxybenzamine daily (Fig 2c). Case 3: A 48-year-old white man was first seen at the University of Kentucky Medical Center in 1967 with a two-month history of angina-like chest pain which was preceded by an acute myocardial infarction. The systolic blood pressure ranged from 130 to 150 mm Hg and the diastolic blood pressure ranged from 90 to 100 mm Hg. The physical examination and roentgenograms of the chest were normal. The CBC and urinalysis were within normal limits. A three hour glucose tolerance test was consistent with a diagnosis of diabetes mellitus and the serum cholesterol was 350 mg per cent. The resting ECG was consistent with an old inferior myocardial infarction. After three minutes of two step exercise there was 2 mm S-T segment depression in leads
A
V4 (Fig 3b) and V 5. Right and left ventricular pressures obtained during cardiac catheterization were normal. Selective coronary arteriograms demonstrated almost complete occlusion of the right coronary artery and greater than 50 per cent occlusion of the left circumflex coronary artery. The intravenous infusion of isoproterenol (4 JLg/min) induced 1 mm S-T segment depression in V4 (Fig 3c) and V5 • The intravenous administration of 0.15 mg/kg propranolol (Fig 3, bottom) did not prevent the exercise-induced S- T segment changes, but did prevent the isoproterenol-induced S-T segment changes. Dr. Logic: The regulation of the coronary circulation is complex. Gregg and his associates 4 have clearly shown that coronary blood flow (CBF) is phasic. It decreases during isovolumetric systole, increases during ejection, and is maximal during diastole. This phasic pattern is a function of changes in aortic flow, arterial pressure, and in the resistance to blood flow \vithin the coronary circulation. The coronary vascular resistance is determined by the intramyocardial pressure and by neurohumoral and metabolic factors which act directly on the coronary arterioles. The most potent stimulus for decrease in coronary vascular resistance and an increase in CBF is a decrease in local p02' whether from systemic hypoxia or from factors which increase myocardial oxygen consumption (MV O 2 ), The precise determinants of MV O 2 have been difficult to denne. 5 It has been shown that the MV O 2 increases when the pressure- or time-tension per minute [time-ten-
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FIGURE 3. Lead V 4 recorded before (top) and after (bottom) the intravenous administration of propranolol 0.15 mg/kg. A, rest. B, after 3 minutes of 2-step exercise. C, after the intravenous infusion of isoproterenol.
54
DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
SYMPATHETIC STIMULATION AND BLOCKADE IN ANGINA
sion index (TTl)] increases. MV O 2 also increases when the velocity of shortening of the muscle fiber increases, even though the TTl may not change or may even decrease. Factors which increase arterial blood pressure will augment the after-load during systolic ejection, will prolong the TTl, and will increase the MV O 2 • Factors which enhance the intrinsic contractile state of the myocardium \viIJ increase the rate of development of tension in myocardial fibers and will also lead to an increase in MV O 2 • Thus, the MV O 2 may be regarded as a function of the rate of fiber shortening, the extent of fiber shortening, the duration of fiber shortening, and the frequency of fiber shortening. The concept of total contractile \vork, \vhich includes the external \vork performed during ventricular ejection and the work performed during the isovolumetric phase of systole, has been sho\vn to correlate well with MV0 2 • In the intact preparation both alpha and beta stimulating catecholamines increase the MV O 2 and increase coronary blood flow. The development of electromagnetic flow sensors has permitted the separation of the effects of the catecholamines on the coronary arteries from their effects on the myocardium. Catecholamines with beta stimulating effects directly enhance myocardial contractility and increase the rate of shortening of the myocardial fiber. Alpha adrenergic agents do not directly enhance myocardial contractility. Ho\vever, they do increase the arterial blood pressure, increase the after-load and prolong the TTl. The coronary arteries have been found to possess both alpha and heta receptors. The adrenergic neurotransmitter, norepinephrine, directly constricts the coronary arteries. This constriction can be prevented hy the alpha adrenergic blocking agent phenoxybenzamine and is therefore an alpha effect. Isoproterenol dilates the coronary arteries. This dilatation can be prevented by the beta adrenergic blocking agent propranolol and is therefore a beta effect. Zuberbuhler and Bohr6 have demonstrated both alpha and beta effects in the larger coronary arteries but only beta effects in the smaller coronary arteries. The sympathetic amines with beta stimulating effects increase coronary blood flow by increasing cardiac output and hy decreasing coronary vascular resistance. The decrease in coronary vascular resistance reflects not only the direct vasodilating effect of these amines, but also the indirect vasodilating effect \vhich accompanies the more rapid rate of fiber shortening and the increase in myocardial oxygen requirement. The sympathetic amines with alpha stimulating effects have a direct vasoconDIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
453
stricting effect and do not directly increase cardiac output. The increased CBF associated with administration of these amines results from an increase in arterial blood pressure which increases the gradient across the coronary vascular bed and from indirect dilitation of the coronary arteries. When the cardiac rate is constant, the indirect effect on the coronary arteries is secondary to the increase in myocardial oxygen requirement associated with prolongation of the TTl. Dr. Luria: The function of the coronary circulation is to supply an adequate amount of oxygen to the myocardium. Any increase in myocardial oxygen requirement must be associated with an increase in myocardial oxygen consumption if aerobic metabolism is to be maintained. Myocardial oxygen consumption is related directly to the coronary blood flow (CBF) and to the coronary A-V O 2 difference. In a wide variety of situations, the coronary A-V O 2 difference is maintained at a steady level. Therefore, any increase in myocardial oxygen consumption should be associated with a parallel increase in CBF. If the CBF is unable to increase sufficiently to meet the increased oxygen requirements, the coronary A-V O 2 difference will widen, anaerobic metabolism with the production of excess lactate may ensue, and eventually clinical angina may occur. Exercise and catecholamines increase the myocardial oxygen requirement and the CBF. As delineated above, there are several factors \vhich are responsible for the increased myocardial oxygen requirement. From a clinical standpoint, changes in the tension-time index, calculated from the ejection time, the ejection pressure and the heart rate, correlate well with change in myocardial O 2 consumption. An even more simple index, and one which can be employed at the bedside, is the product of the heart rate and hlood pressure (HR x BP). Although this index will reflect the increased myocardial O 2 requirement associated with agents which may increase the heart rate or the blood pressure without increasing the TTl, it is not an adequate measure of the myocardial O 2 requirement because it does not reflect the changes in the velocity of muscle shortening \vhich characterize agents with beta stimulating effects. Nonetheless, the clinical usefulness of HR x BP becomes evident \vhen experimental clinical angina is produced either by exercise or by increasing the heart rate with right atrial pacing. In either instance, there appears to be a certain level of HR x BP for each individual above which angina pectoris occurs. In each of the three patients presented in this
55
454 conference, angina and the ECG changes of coronary insufficiency occurred at a time when HR x BP increased. In two, HR x BP was increased via an increase in heart rate accompanying exercise and the administration of isoproterenol. In the third, HR x BP was increased by an increase in BP which occurred spontaneously and after the administration of phenylephrine.
Dr. Gettes: It is clear from the preceding discussion that factors which have a positive increased inotropic or chronotropic effect and factors which increase the systemic blood pressure will also increase the myocardial oxygen requirement. Angina pectoris may be expected to occur if an increase in myocardial oxygen requirement were not associated with an increase in myocardial oxygen supply. As demonstrated by the two women presented in this conference, such an event may occur even in the absence of obstruction of the large coronary arteries. One of the possible explanations for the chest pain in these women is an excessive secretion of catecholamines or an undue sensitivity to the normal secretion of catecholamines. A possible approach to therapy of angina, either with or without large vessel coronary artery disease, would be to decrease the myocardial oxygen requirement. Indeed, it is this mechanism which has been postulated to explain the effectiveness of the beta sympathetic blocking agent, propranolol, in the treatment of angina. Propranolol decreases the heart rate at rest and during exercise, and thereby decreases the product of heart rate and blood pressure. In addition, propranolol slows the rate of shortening of the heart muscle fiber and decreases cardiac work. 7 These effects would decrease the myocardial oxygen requirement. On the other hand, propranolol prolongs contraction and may increase myocardial tension. These effects would increase the myocardial oxygen requirement. Propranolol also increases coronary vascular resistance and decreases coronary blood flow. It is therefore difficult to predict the net effect of propranolol therapy on the relationship between myocardial oxygen requirement and coronary blood How. Dr. Surawicz: Twenty-eight patients with coronary artery disease, angina pectoris and abnormal twostep exercise tests have been treated with orally administered propranolol in doses of 40-160 mg daily for periods of two months to three years.· Twenty-three of these patients (83 per cent) were symptomatically improved by therapy. In 19, we were able to compare the symptomatic improve°Supported by Ayerst Laboratories, New York.
56
GEnES ET AL ment, as determined by detailed questioning regarding the characteristics of the anginal attacks, to changes in the exercise ECG at each of several dosage levels. The purpose of this analysis was to establish the optimal dose of propranolol for each patient. We defined the optimal dose as the smallest dose associated \vith: (1) a negative double two-step Master exercise test; (2) the least abnormal ECG after exercise; (3) the maximal increase in the duration of exercise performed to the onset of S-T segment depression. In the absence of 1-3, we selected the maximal dose associated with a heart rate of more than 55 beats per minute at rest and more than 95 beats per minute during exercise. In three patients, the optimal dose \vas 40-60 mg per day. The dose was not increased in these patients because of slo\\ring of the heart rate. In 11 patients the optimal dose was 80 mg per day. In three of these patients larger doses \vere associated with less beneficial effects on symptoms and on the exercise ECC. In one patient the optimal dose was 120 mg per day, and in four 160 mg per day. Since 160 mg per day was the maximal dose used in this study, it is possible that this dose \vas not "optimal" in these four patients. In ten of the 19 patients there \vas less S-T segment depression following exercise, or an increase in the duration of exercise performed to the onset of S-T depression. The exercise ECG of the remaining nine patients was not improved. In both of these groups the slowing of the resting and exercise heart rates and the changes in the characteristics of the anginal attack were similar. Propranolol did not completely abolish exertional chest pain in anv of our patients. However, all patients required le;s nitroglycerine because the frequency and/ or the severity of the attacks decreased. Of greatest interest to us was a change in the pattern of the anginal attack itself. T\velve patients reported that hefore therapy with propranolol \vas instihlted, the intensity of the chest pain increased during each attack, whereas after therapy with propranolol \vas instituted, the intensity of the chest pain decreased during each attack. Our study confirmed the previously reported effectiveness of long-term propranolol therapy in the treatment of angina pectoris. Our study also confirmed the need to individualize the dose of propranolol, and sho\ved that the exercise ECG \vas helpful in determining the optimal dose in about 50 per ce'lt of patients. The symptomatic improvement associated with propranolol therapy reflected changes in the characteristics of the anginal attack. However, we were unable to ascribe the benencial DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
SYMPATHETIC STIMULATION AND BLOCKADE IN ANGINA
effect of propranolol to a significant decrease in myocardial oxygen requirement since the exercise ECG abnormalities were unchanged in 50 per cent of the patients who experienced subjective improvement. SU~IMARY
Dr. Gettes: We have presented three patients with angina pectoris in whom the S-T segment abnormalities of coronary insufficiency could be induced by the infusion of catecholamines. We have reviewed the factors which regulate coronary blood flow and have stressed the importance of the myocardial oxygen requirement in this regulation. We have considered the mechanisms by which the catecholamines increase myocardial oxygen requirements and have shown that the product of heart rate and blood pressure can be used at the bedside to assess a change in the myocardial oxygen requirement. Finally, we have reviewed our experiences with the beta adrenergic blocking agent, propranolol, in the treatment of angina pectoris and have confirmed the therapeutic effectiveness of the drug. However, we were unable to ascribe the propranolol induced changes in the characteristics of the anginal attack to a critical decrease in myocardial oxygen requirement. DISCUSSION
Dr. Jacqueline Noonan: Dr. Surawicz, how many patients in your study died during your period of observation? Dr. Surawicz: Two patients died during the period of observation. One was 38 and the other 46 years old. Both had severe exertional angina, both improved after propranolol therapy was instituted, and both died suddenly at home. Dr. Lester Bryant: Is it possible that these patients died as a result of propranolol therapy? Dr. Surawicz: This is, of course, possible. However, sudden death in patients with coronary artery disease is not uncommon and therefore two deaths in 28 patients, followed for three months to three years, is something that you would expect. The question is important because if one continued to increase the propranolol dose you would certainly reach a point where profound bradycardia and depression of contractility would counteract the beneficial effect of the drug. This is illustrated by the three patients in whom larger doses of propranolol were associated with a worsening of both their subjective and objective responses to the drug. For this reason, we initiated therapy with small doses and did not administer the drug in the high DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968
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doses (up to 400 mg per day), recommended by other investigators. Dr. Stephen Edelstein: By what postulated mechanism do you explain the beneficial effects of propranolol, if you do not accept a decrease in myocardial oxygen requirement as the mechanism of action? Dr. Gettes: As Dr. Surawicz has stated, the pattern of the anginal attack was changed by the administration of propranolol. Gazes and co-workers 8 pointed out that in patients with angina pectoris there \vas an abnormal increase in circulating catecholamines after exercise. It is possible that the increase in heart rate and blood pressure which Roughgarden9 has shown to accompany the development of angina pectoris may reflect this increase in circulating catecholamines. It is also possible that the progressive intensification of the anginal pain as experienced by our patients prior to therapy may reflect the further increase in myocardial oxygen requirement imposed by these changes in heart rate and blood pressure. Our patients stated that after propranolol therapy was instituted their pain did not intensify after its onset. This observation suggests that either the increase in the circulating catecholamines was prevented, or that the betastimulating effect of the increase in circulating catecholamines was blocked by propranolol therapy. An additional mechanism has been suggested by Wolfson and co-workers 1o who found that in one patient propranolol relieved coronary vasoconstriction during an attack of angina. Although this observation is not in keeping with experimental studies which have uniformly shown an increase in coronary resistance and a decrease in CBF, the relief of coronary vasoconstriction must be considered a possible mechanism of action. Dr. Armond Gordon: Did you perform any double blind studies? Dr. Surawicz: We did not. There are several double blind studies in the literature and all but one confirm the subjective improvement associated with the administration of propranolol. In addition, a long-term double blind study is very difficult to perform because the patients are aware of the slowed heart rate at rest and because their subjective improvement is so dramatic that they do not appreciate having the drug withdrawn. In ten patients we did discontinue the drug for two to four weeks. In all, the nitroglycerine requirement, resting and exercise heart rates, duration of two-step exercise and magnitude of post-exercise S-T segment depression returned to the pre-treatment values.
57
GETTES ET AL
456 REFERENCES
1 RAAB, W.: Hormonal and Neurogenic Cardiovascular Disorders, Williams and Wilkins, Baltimore, 1953. 2 Symposium on beta-adrenergic blockade, E. Braunwald, guest editor, Amer. ]. Cardiol., 18: 1966. 3 AHLQUIST, R. P.: Study of adrenotropic receptors, Amer. ]. Physiol., 153:586, 1948. 4 GREGG, D. E.: Physiology of the coronary circulation, Circulation, 27:1128, 1963. 5 BRAUNWALD, E., Ross, J. JR., AND SONNENBLICK, E. H.: Mechanisms of contraction of the normal and failing heart, New Eng. ]. Med., 277:794, 853,910,962, 1967. 6 ZUBERBUHLER, R. C .. AND BOHR, D. F.: Responses of coronary smooth muscle to catecholamines, Circulation Res., 26:431, 1965.
7 EpSTEIN, S. E., AND BRAUNWALD, E.: Beta-adrenergic receptor blocking drugs. Mechanisms of action and clinical applications, New Eng. ]. Med., 275:1106, 1175, 1966. 8 GAZES, P. C., RICHARDSON, J. A., AND WOODS, E. F.: Plasma catechol amine concentrations in myocardial infarction and angina pectoris. Circulation, 19:657, 1959. 9 ROUGHGARDEN, ]. W.: Circulatory changes associated with spontaneous angina pectoris, Amer. ]. Med., 41: 947, 1966. 10 WOLFSON, S., HEINLE, R. A., HERMAN, M. V., KEMP, H. G., SULLIVAN, J. M., AND GORLIN, R.: Propranolol and angina pectoris, Amer. ]. Cardiol, 18:345, 1966. Reprint requests: Dr. Gettes, Depamnent of Medicine, University of Kentucky, Lexington 40506
AMERICAN COLLEGE OF CHEST PIIYSI(:IANS 1969 ESSAY CONTEST Each year the College offers undergraduate medical students throughout the world the opportunity to submit manuscripts on any phase of the diagnosis and treabnent of cardiovascular or pulmonary disease, in open competition.
A sealed envelope bearing the same motto on the outside and enclosing the name and address of the author must accompany the essay. (Motto may be a word or brief phrase which has a significant meaning to the author.)
Medical students wishing to enter the 1969 Alfred A. Richman Essay Contest of the American College of Chest Physicians should observe the following rules:
The First Prize will be $500; Second Prize will be $300; Third Prize will be $200. Each winner will also receive a certificate of merit. A trophy, inscribed with the name of the First Prize winner and the name of his school will be awarded to the winner's school.
1) Complete application form in duplicate, have original copy signed by the dean of the medical school, and return original copy at once to the American College of Chest Physicians, 112 East Chestnut Street, Chicago, Illinois 60611. 2) Five copies of the manuscript, typewritten in English (double spaced) must be submitted to the American College of Chest Physicians offices in Chicago not later than April 15, 1969. 3) The length of manuscripts is optional; 2500-4500 words suggested. 4) The only means of identification of the author shall be' a motto or other device on the ·title page.
58
The winning contributions will be selected by a committee of chest specialists at the 35th Annual Meeting of the American College of Chest Physicians to be held in Chicago, Illinois in October, 1969. All manuscripts become the property of the American College of Chest Physicians and may be considered for publication in the College journal. It is suggested that applicants study the format of the College journal, DISEASES OF THE CHEST, to guide them in preparing the essay. A copy will be sent on request.
DIS. CHEST, VOL. 54, NO.5, NOVEMBER 1968