Pathophysiology and differential diagnosis of cardiac pain

Progress in

Cardiovascular Diseases VOL. XIII, NO. 6

MAY, 1971

Pathophysiology and Differential Diagnosis of Cardiac Pain By JOHN J. SAM:PSON"AND MELVIN D. CHEITLIN

ARDIAC PAIN is the most important early clinical indication of coronary disease and thus its identification is essential. The purpose of this paper is to review the patterns of cardiac (myocardial hypoxic) pain of different etiologies and clinical classes as a basis for its differential diagnosis, and to present current theories and supporting evidence of its pathophysiology. Obtaining a clear clinical history unfortunately is fraught with the complexities inherent in physician to patient communication. These are failure of the questioner to seek the identifying qualities of the pain (or equivalent); inability of the patient to reply, (that is, psychotic, comatose, or narcotized); and inability of the patient to give an adequate history due to a poor memory, language defect, or devious or irrelevant responses which try the patience of the examiner, thus ending the session with the emotional breakdown of the patient and the exhaustion and mounting bias of the physician. 1 Sensitivity for discomfort is known to vary from person to person, probably from race to race, and from time to time. 2 Pain recognition and intensity may be partially quantitated by special testing, and by the simple clinical procedure of pressing on the styloid process of the subject and observing the intensity of reaction to pain. Evaluation of the severity or even the existence of pain is necessary to assay this important index of a serious disease. Sensitive and neurotic individuals may have attacks more frequently, more severe and more prolonged without the sinister prognosis such episodes would imply in a more stoic person2 Once the neural signal which results in cardiac pain is initiated, it passes along the sympathetic nerves to the eighth cervical and first five thoracic gan-

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From the Department of Medicine, University o[ California, Mt. Zion Hospital and Medical Center, and Letterman General Hospital, San Francisco, Calif. JoHN I- Sa~Pso~, M.D,, L.L.D,; Clinical Professor of Medicine, University of California Department of Medicine, San Francisco, Calif.; Senior Physician, Mt. Zion Hospital and Medical Center, San Francisco, Calif. MELVIND. CHEITLI~r,COL., MC, USA: Chief, Cardiology Service, Letterman General Hospital, San Francisco, Calif.

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glia and then to the lateral ascending pathways of the spinal cord. These impulses use similar pathways as somatic sensory return2 For this reason there may be overflow, or spread, at these spinal cord segments causing the phenomenon of somatic referral of pain to parts of the body whose sensory supply enters at the same spinal cord segment. Thus, the discomfort spreads or radiates from the chest to the arm to the side of the neck or jaw. Because of the similar pathways of return to the central nervous system, the intensity of stimuli returning from the heart can be amplified by heavy sensory traffic from the ann (bursitis, cervical osteoarthritis). This worsens the angina and explains why anginal pain is referred to body areas previously affected by other unrelated diseases, for example, an old healed rib fracture. Pain of somatic origin is usually limited to spinal segments serving areas where the exciting eause is located. The distribution of the pain of myocardial isehemia, as in characteristic angina peetoris and other visceral pain, is charaeteristieally referred to several cranial and spinal sensory nerve zones and may be diffuse.4,5 PATItOPHYSIOLOGY OF CAI~DIAC PAIN

Those clinical features which allow physicians to recognize angina pectoris give us clues to the pathogenesis of the discomfort. The feature which most suggests angina pectoris is the circumstance under which the chest discomfort occurs, such as physical effort and anxiety, which cause an increase in myocardial tension development and presumably the need for increased myocardial oxygen. It is also evident that whatever the cause for the discomfort it is certainly transient, since the angina lasts only a short time, almost always less than 15 to 20 min and its disappearance is frequently due to cessation of factors which caused the increased need for myocardial oxygen.

Supply and Demand Concepts The understanding of the pathogenesis of anginal pain demands the recognition that discomfort usually occurs in a setting where there is an acute disproportion between the need for myocardial oxygen and the ability of the coronary arterial system to supply enough oxygen-carrying blood to all parts of the myocardium to meet this demand. Certain spontaneous attacks are still unexplained. It is essential to examine the various factors influencing delivery of oxygenated blood. Coronary Blood Flow: Basic to the understanding of angina is the fact that normally the myocardium already extracts almost maximal amounts of oxygen from the coronary arterial blood, so any increase in oxygen delivery to the myocardium must be provided by an increase in myocardial blood flow. Normally, the myocardium extracts 70 to 75g of the available oxygen from the hemoglobin whereas the body as a whole extracts only about 20~.~ Flow through the coronary vascular tree, like flow through any organ bed, is determined by the pressure gradient from arteries to veins as affected by the total resistance to flow in the vessels. The vascular tree of the myocardium is unusual since the small resistance vessels are situated between contracting muscle fibers. During systole this force compresses intramural vessels and thus

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increases resistance to flow. The major portion of coronary flow occurs during diastole when resistance is minimal. 7 The factors which tend to decrease myocardial blood flow, either total or regional, and, therefore, can precipitate angina are: (1) increased resistance to flow through the coronary arteries, a. coronary atherosclerosis with or without coronary thrombosis, b. myocardial compressive effect of systole on intramyocardial arterioles in aortic stenosis or hypertension; (2) decrease of the driving pressure or mean aortic pressure (hypotension); (3) shortened diastolic portion of the cardiac cycle (aortic stenosis, tachycardias ); and (4) creation of a disproportion between capillary surface area and the mass of myocardial muscle fibers ( myocardial hypertrophy).

Oxygen Carrying Capacity of Hemoglobin and Oxyhemoglobin Dissociation Characteristics: The amount of hemoglobin per 100 ml of blood is an important determinant of the amount of oxygen the blood can carry per unit volume. Thus, in severe anemias, the marked decrease in oxygen carrying capacity of the blood can augment the tendency towards anginal pain. Recently a group of patients have been identified with typical angina pectoris and abnormal electrocardiograms consistent with myocardial ischemia, but "normal" coronary arteriograms by current standards, s,~ Several of these patients have died and have indeed had normal coronary arteries. Eliot and Bratt have demonstrated in these patients an abnormal hemoglobin-oxygen dissociation and have suggested the possibility that there is a decreased efllciency of oxygen release from their hemoglobin, thus causing myocardial hypoxia. ~~ Ayers et al. have shown that carbon monoxide hemoglobin levels on the order of those seen in cigarette smokers can change the oxyhemoglobin dissociation curve so that there is tighter binding of oxygen to hemoglobin and, therefore, less oxygen available to the tissues at any given coronary venous pO2.11 Patients dying of carbon monoxide poisoning may have left ventricular myocardial necrosisY Recently Shappell et al. la reported a "protective" stress phenomenon occurring during angina. This is a decreased hemoglobin affinity for oxygen at the tissue level. It occurs rapidly and is unaccompanied by changes in the concentration of erythrocytic 2, 3-diphosphoglycerate, adenosine triphosphate, or pH, all recognized factors altering the oxyhemoglobin dissociation curve. Disturbance of this causally unknown adaptive mechanism may distort the supply-to-demand ratio. 14,~5 Rheology: Unfavorably altered physical state of the circulating blood may be a factor in precipitation of angina either by directly increasing the viscosity of the plasma or by aggregation of the platelets or red cells. Perfusion may be diminished especially in narrowed channels as well as the rate of oxygen delivery to the tissues, z6 Burch and DePasquale, in 1962, reported high hematocrits in patients with myocardial infarction and suggested that the resultant high viscosity of the blood tended to induce coronary occlusion and myocardial infarction, x7 This observation lacks extensive confirmation. Dintenfass also reported a high blood

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viscosity, probably due to increased red cell aggregation, in patients suffering from myocardial infarction. 18-2~ Postprandial hyperlipemia, according to some investigators, may precipitate angina pectoris by red cell aggregations which decrease oxygen transport to the tissue. 21'22 Regan et al. showed in 7 subjects a 20~ mean decrease in coronary blood flow during maximal lipemia after a fat meal, reversible with heparin clearanceY 8 Determinants of Myocardial Oxygen Consumption: Angina may be provoked by those activities which increase the demand of the myocardium for oxygen and involves those factors which determine myocardial muscle tension: the intraventricular systolic pressure, the diameter of the left ventricle, the heart rate, and the contractile state of the myocardinm. The first two of these are primary determinants of the myocardial muscle tension achieved, and their relationship is expressed in the law of LaPlace (for a cylinder) T a P.r. Where T ~ force per unit length of the circumference of the ventricle and the entire thickness of the wall; P ---- transmural pressure; and r radius of the ventricle. The heart rate expresses the number of times per minute this myocardial tension is achieved and the contractile state of the myoeardium is influenced by the sympathetic tone, the degree of cateeholamine stimulation~ and inotropic drugs. 2~ Boughgarden and Newman reported that most exertional anginal attacks and all spontaneous attacks in their series were preceded by a moderate rise in blood pressure and heart rate, emphasizing the importance of the above factors. 2~ Robinson quantitated this observation by inducing angina repeatedly irt 15 patients by various degrees of exerciseY 6 In every case the product of the heart rate and the intraarterial systolic blood pressure was nearly constant at the onset of angina. If systolic ejection time changes significantly, a correction should be made for this parameter. This "angina index" was observed to be the same despite large variations in the type, duration, and severity of the exercise as well as in patients with "spontaneous" and emotion induced pain. A critical level of myocardial tension development, essentially fixed for each patient, precipitated angina. The variation of facility with which pain can be provoked at different times in the same patient by a similar degree of stress is apparently due to the varying circulatory response to the precipitating stress. Therapeutic maneuvers favorably influence angina according to their reduction of myocardial oxygen consumption factors. Examples of this are Levine's observation 27 that carotid sinus stimulation with slowing of the pulse can cause cessation of angina. This has found clinical application in the implantation of an apparatus which electrically stimulates the carotid sinus nerves. 2s-~~ Currently, a well accepted explanation of the favorable hemodynamie effects of nitroglycerine in relieving angina is the reduction of arterial blood pressure and venous return and, therefore, size of the heart, thus decreasing the demand for myocardial oxygen. 3~ Additionally, nitroglycerine probably acts as a coronary vasodflator, especially on the more normal collateral "r 2 Beta adrenergic blocking agents reduce the frequency of angina by interfering with the inotropie and ehronotropie action of eateeholamines on the

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myocardium, thus decreasing the need for myocardial oxygen2 3'3~ The negative inotropie effect of propanolol which is undesirable in heart failure is not induced by Sotalol. 3~ It is evident that those factors which increase the size of the heart (congestive heart failure, increased blood volume, aortic insufficiency), those diseases that increase intraventricular pressure (hypertension, aortic stenosis, pulmonary valvular stenosis, pulmonary hypertension), and those situations which increase the heart rate or the level of sympathetic tone or catecholamine concentration (anxiety, exogenous epinephrine, pheochromocytoma, fever, pain), all are capable of increasing the demand for myocardial oxygen and precipitating angina. On the basis of this recognized interrelationship of supply and demand, it is possible to classify the pathogenesis of angina into those conditions which result in a reduction of coronary blood flow and those factors which result in the increased need for myocardial oxygen (Table 1 ). COLLATERAL VESSELS The fluctuating course of angina in many patients is attributable to the irregular advances of the occlusive disease and to the compensation for it by several factors of which expansion of a collateral circulation and recanalization are perhaps the foremost2 ~ Differences of opinion have long existed on the functional value of collateral vessels in normal mammalian hearts and whether the normal coronary arteries are "end" arteries2 6 The work of Prinzmetal and associates on injections of radioactive tagged erythrocytes and glass microspheres in dogs and by postmortem perfusions of human hearts indicated that in the normal heart there were functional co]lateral arteries and in the arterioTable 1 I. Angina Induced by Decreasing the Supply of Myocardial Blood (Major Examples) A. Occlusive arterial processes: atherosclerotic coronary arterial disease; other occlusive arterial diseases such as thrombosis, subendothelial-hyaline deposits and arteritis; coronary embolism; spasm of coronary arteries (dubious importance); dissection of the aorta with proximal coronary arter/al compression; dissection of a coronary artery; congenital abnormalities of the coronary arteries; syphilitic and atherosclerotic ostial occlusion. B. Changes in the quality of blood affecting fine vessel perfusion: polycythemia; hyperIipidemia; maeroglobulinemia. C. Inadequate coronary blood flow affecting oxygen carrying capacity: hypoxemia; cardias ). D. Changes in the quality of blood affecting oxygen carrying capacity: hypoxenfia; severe anemia; oxyhemoglobin dissociation curve abnormalities; carbon monoxide poisoning. II. Angina Induced by Increasing Need for Myocardial Oxygen A. Increased bodily metabolic demand: fever, hyperthyroidism, physical exercise, ambient temperature extremes, obesity. B. rncreased myocardial demand: aortic stenosis; aortic insufficiency; systemic arterial hypertension, especially of acute onset; excessive concentration of catecholamines, exogenous (that is, injected norepinephrine) or endogenous (pheochromocytoma) ; right ventriculat hypertension (pulmonary arterial hypertension, pulmonary stenosis); mitral insufl~cency, tricuspid disease, congenital shunting or obstructing defects.

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sclerotic coronary system by selective enlargement they served to prevent many catastrophiesY Recanalization of short coronary blocks was found by angiography in young men without symptoms 3 or more months after myocardial infarction. Factors recognized experimentally and clinically that enhance the size and competency of collateral coronary arteries are: progressive occlusive coronary disease, hypoxemia, anemia, exercise, and myocardial hypertrophy. Hearts of patients with severe coronary disease exhibited a massive, fine subendocardial anastomatic network at postmortem. 3s Coronary "steal" has been conceived as the robbing by collaterals of poorer per/used areas in favor of better vascularized myocardinm 3~ as suggested by the occasional increase of angina on use of nitroglycerine. CORONARY ARTERIAL INNERvATION AND REFLEXES

It has long been shown that coronary arteries and particularly the coronary arterioles are widely supplied with both afferent and efferent autonomic nerve fibers. 4~ Grayson and Lapin 44 found that after coronary occlusion in the untreated dog the coronary flow fell slowly and infarction ensued with little hyperemia in distant areas of the myocardium. When a coronary artery was occluded after adrenergic blockade, hyperemia was striking and no infarction occurred. This was excellent evidence of neurogenie vascular influences in the pathogenesis of myocardial infarction. .5,4~ Yurchak and associates, 4r studying the effects of norepinephrine infusion in man, conclude that eatecholamines and sympathetic neural stimulation appear to have two opposing effects: primary vasoconstriction of the coronary arterioles and increase in coronary perfusion pressure and increased positive inotropic and chronotropic effect causing a secondary increase in coronary blood flow. The usual sum of these effects is to increase coronary blood flow as arterial pressure rises, but the rise in coronary blood flow is suboptimal due to the competing vasoconstrictor effects. The role of sympathetic nervous system activity in response to emotions was measured by Nestel et al. in four groups of subjects who had had a myocardial infarction and who were subjected to a mental stress test. 4s Those without angina pectoris and those with atypical chest pain or no chest pain excreted far less VMA (3 methoxy hydroxy mandelic acid) in urine than those with a history of angina.

Visceral Reflexes and Angina It has been known for many years that visceral distention including distension of the bile ducts and the gall bladder can produce reflex changes affecting the heart, usually of the cardiac rhythm, but also of the electrocardiogram. 4~'51 Gastric distension in dogs has been shown to produce reflex constriction of the coronary arteries 52 (Table 1).

Mechanism for the Production of Cardiac Pain Since the classical paper of Keefer and Resnik, 53 it has been agreed that the common denominator of the various circumstances associated with angina is

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myocardial ischemia (or hypoxia), but the medium by which the pain is elicited is as yet in dispute. A rapid rate of induction of hypoxia is apparently more conducive to pain than the depth of hypoxia. Where there is no definitely known pathophysiologie explanation there are a number of theories. Pain Producing Factor: Myocardial ischemia seems to cause the release of a "pain-producing factor" similar to Lewis' P factor of ischemic contracting skeletal muscle 5~ which stimulates sensory nerve endings in either perieoronary or paracoronary vessel sites. Its conversion or wash out with restoration of blood flow would expla/n the brevity of anginal episodes. The nature of this factor is unknown. Lactic acid has been suggested as the factor since this substance is a product of metabolism oeeurring under anaerobic conditions, that is, in the presence of myocardial ischemia, 5~ but this substance eannot be a major factor since, in Parker's studies on 14 patients there was no consistent correlation of angina with lactate release2 * Also, in MeArdle's syndrome (hereditary absence of muscle phospholylase), a disease characterized by marked weakness and muscle pain on exereise~ there is no increased formation of lactic a c i d s Plasma "kinin", probably largely bradykinin, a polypeptide, has been shown to be formed in the plasma in the presence of isehemie tissue. ~s The kinins among other properties stimulate pain fibers and may be the pain producing factor in angina, although the experimental relation of the mass of isehemie muscle to the induction of angina is not as yet demonstrated25 Myocardial Failure: M/iller and ttOrvik described a rise in the pulmonary wedge pressure during exercise preceding the onset of anginal pain. as They suggested that the pain may be associated with sudden congestion of the lungs. Parker et al. also described an increase in left ventricular end diastolic pressure (LVEDP) which nearly para}}eled in time the onset of angina and the degree of depression of the ST segment, aa Thus, in some instances of myocardial isehemia and angina there is evidence of transient and reversible left ventrieular failure. 6~ Clinical evidence of this is the development of third and fourth heart sounds with angina. There are, however, many examples of stress induced angina not associated with an increase in LVEDP or other signs of cardiac failure2 ~ Dimond suggests that decreased compliance of the ischemic left ventriele causes the rise of LVEDP. 6~ It is well recognized that some patients treated with digitalis and/or diuretics will experience a decrease in the incidence of anginal episodes especially nocturnal angina. In other patients, as congestive heart failure develops, the frequency of anginal attacks decrease. Certainly the pain and the failure are not interdependent since there are many instances where the two are dissociated. Dyskinesia: Isehemic areas of ventricular walls may exhibit constant dyskinesia after myocardial infarction. The systolic expansion or inaction can appear transiently with the anginal attack during exercise. Stimulation of pain receptors is possible in the wall by this distortion of the muscle fibers. ~--~ Coronary Spasm: Latham and Gardner, in 1847~7 /~rst suggested coronary spasm as the instigator of anginal pain but currently it is believed to be only contributory. Coronary arteriography substantiates the existence of coronary spasm with and without catheter contact 68 and generally without concomitant angina. Prinzmetal's explanation for his variant type of angina 69 assumes that

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spasm in an area of severe proximal coronary arterial disease is partially responsible for the anginal pains. Whiting et al. reported an instance of variant angina without angiographic evidence of coronary disease7 ~

Stimuli Arising from the Interface between Normal and Ischemic Myocardium: Anoxie areas of myocardium caused by local ischemia presumably generate stimuli which result in angina. The nature of these stimuli is unknown. It can be demonstrated that there is a local drop in temperature of the myocardinm when the arterial supply is suddenly cut off. Electrieal disturbances at this interface are possibly related to loeal release of intracellular potassium, fall in pH, or other physiochemieal change. ~1 Sympathogenie Biochemical Trigger Mechanism of Angina Pectoris: tlaab has theorized that a discrepancy exists between a sudden excessive sympathetic stimulation and catecholamine release and the inability of the diseased coronary arteries to dilate sufficiently to meet this increased demand which includes elevation of blood pressure. 72 The catecholamine-indueed local hypoxia causes intramyoeardial electrolyte shifts. The depletion of myocardial potassium is further aggravated by superimposed corticosteriod release. The understanding of the pathophysiology of an episode whatever it is termed and the physicians' response by appropriate patient care is required in the high-risk acute coronary insufficiency attack.

Angina Pectoris The term "angina pectoris" should be reserved for recurrent short attaeks of cardiac pain generally induced by physical or psychic stress, but often occurring spontaneously. The pattern may vary from time to time in cause, intensity, and frequency or can remain stable. Though spontaneous or more prolonged attacks are rightfully considered serious, they may occur repeatedly in some patients without grave sequelae. Blumgart, Schlesinger, and Davis ~a demonstrated by roentgenograms of postmortem radioopaque injections of the coronary arteries that nearly all patients with angina pectoris had occlusion of at least one major coronary artery branch even without a clinical history of myocardial infarction. Riseman and Brown ~* reported high erythrocyte sedimentation rates in patients examined shortly after the first attack of anginal pain. They suggested that angina was largely indueed by coronary occlusion with minor infarction. Permanently abnormal and asymptomatie abrupt changes in electrocardiograms of patients with angina peetoris suggest the advent of "silent infarctions" and resultant chronic ischemic areas. Several postmortem studies 7~ have revealed approximately 2(G~ of the myocardial infarctions were "silent''. Similar evidence of unsuspected severe coronary disease in young or middle-aged men were reported by Enos and by Spain and others. 7s,~7 The pain of angina pectoris may be superficial or deep and located in the substernal or transverse anterior or upper posterior ehest. It may arise in or radiate to the neck, jaws, throat, bregma, occiput, brows, cheeks, below the ear pinna, the mastoid processes, the external auditory canal, shoulders, upper and/or lower arms, hands, and to the epigastrium but rarely, if ever, lower in the body. It may be right or left sided or bilateral in any of the above locations.

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This multisegmental distribution of pain has certain unexplained limits in pattern of both origin and radiation. Thus, whereas almost any zone in the chest, arms, neck, and head seems subject to anginal pain, certain areas are much more often affected such as the ulnar side of the forearm and hand. Angina with pain radiating exclusively to the radial side of the left hand and thumb was observed in only one of our series of 150 cases and was reported in one patient of MacKenzie's series of 160 cases, s Pain was referred to the left leg in two patients concomitant with angina and in one patient to the umbilicus. The pain has been vividly described as expansive, constricting, compressive, aching, or burning. Numbness or paresthesias of the arms, hands or other primary or referred areas may accompany the angina or occur independently. The sense of impending death or of strangling seems to have been observed more often from reports in past decades than in our current experience. Pains are unlikely to be anginal if stabbing or catching or if influenced by posture, breathing, or motion of the trunk or arms. Occasionally eructation of gas or swallowed air seems to relieve angina. The feeling of inability to fill the lungs with a breath, a "block of breathing", first described by Gallavardin and called by him "blockpnea" is difficult to differentiate from true dyspnea, hyperpnea, or panting but appears anginal2 8-s~ Sharma and Taylor have reported an increase of ventilation occurring concomitantly with the development of angina on leg exercise with patients undergoing left heart catheter study. The dyspnea seems to be evidence of promptly developing congestive failure which terminates within 1 to 2 min of the test and is accompanied by increased heart rate, decreased stroke volume output, increased left ventricular end diastolic pressure, and increased arteriovenous oxygen difference, s0a "Anginal equivalents", most notably numbness of the upper trunk and arms, faintness, or general weakness, arise in some patients with physical or psychic stress, supplanting anginal pain. Some patients automatically "freeze" when severe pain is induced by effort though many patients may continue to exercise. The "walk-through" or "second wind" phenomenon is an anomalous ability to recover from the pain and continue with the same exercise, s~ Three patients in our series exhibited second wind (Fig. I). 150 Cases of Angina Pectoris Analyzed for Sites of Pain and Patterns of Onset, Cessation, and Becurrence: Many comprehensive collections of case studies of angina peetoris have been published since Heberden's first description. sl'5's2-s5 Our 150 consecutive ambulatory patients with angina peetoris presented in Fig. 1 illustrate the frequency of different distribution patterns; and the different temporal courses of the anginal periods. These patterns probably reflect the changing balance of the occlusive disease and the compensatory processes as discussed previously. The diagnosis of angina peetoris was made on our personal clinical judgment. The clinical data is presented in Fig. 1 and Table 2. In Fig. 1 the central chest symbol includes transverse or substernal areas. In approximately half the myocardial infarction cases "premonitory" pain developed. Unusual sites of anginal pain in certain patients were the tip of the nose, brows, bregma, oceiput, palate, tip of tongue, solely in the

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Fig. 1.-Sites of pain of angina pectoris ha 150 successive ambulatory patients.

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elbows, wrists, mastoid processes and both ear lobes with the throat. Although 9470 had anterior chest pain at some time, origin in the arms, throat, or back occurred, radiating later to the chest. Of the first 100 of these 150 cases, 63% had documented histories of myocardial infarction. Of those without history of myocardial infarction, 3970 exhibited E C G abnormalities such as conduction defects and abnormal T waves and Q waves. In these 100 patients, 1370 had not required nitroglycerine. Of those who had used it, 6870 had p r o m p t relief of angina, 227o inconsistent effects, and 10% found it valueless. (1) Physical effort of varying levels of intensity. (2) Other excessive metabolic demands such as: fever and thyrotoxicosis which may induce angina in patients previously free of it. 86 Severely

FactorsInfluencingAnginaPectoris:

Table 2.-Time Patterns of Angina Pectoris-100 Cases A. Angina pectoris persistent and stable in intensity for over 1 year without initial documented myocardial infarction. B. Spontaneous recurrent episodes of angina pectoris for longer than 2 weeks and less than 2 month. C. Angina pectoris preceding myocardial infarction and terminating thereafter. D. Angina pectoris persisting after one or more myocardial infarctions with or without preceding anginal period or premonitory pain. E. Angina pectoris after two or more myocardial infarctions, initial period of angina subsiding within 1 yea~.

31% 16% 2%

38% 13%

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Fig. 2.-Diagram derived from Paturet (520) illustrating the relations of the intercostal nerve and the dorsal nerve root branches to the ligaments, ribs, and vertebrae (pattern T 3 to T~0). Note the possible compression of the nerves between the costotransverse ligaments with kyphotic posture and forward motion of the ribs. (Arrow indicates anterior motion of ribs.)

hypothyroid patients are highly sensitive to small variations in thyroid extract dosage. Obesity increases demands on the cardiac output due to the work load of transporting the weight, and the oxygen demands of actively metabolizing excessive fatty tissue. (3) Taehycardia from whatever cause can induce anginaY Anginal pain may start with the onset of paroxysmal arrhythmia and persist through long periods of tachyeardia or may subside during the paroxysm, sa A recent report deseribes anginal pain during the flushing and taehyeardia episodes of the earcinoid syndrome, s9 (4) Bradyeardia caused by sinus nodal slowing or atrioventrieular block can initiate angina2 ~ (5) Severe anemia tends, in some patients, to induce angina on effort. Adaptation occurs probably from improved qualities of blood flow. A patient recovered from myocardial infaretion who had nephritis and whose hemoglobin was under 4.0 g~o did not develop angina on moderately heavy physical exertion but did have dyspnea. 9~,~2 (6) Conversely, polycythemia seems to increase sensitivity to angina23 (7) Hypoglycemia, either spontaneous or after insulin, with or without hypotension, can precipitate angina. A 56-year-old man had repeated angina at 4 a.m. when serum glucose fell to 30 mgg. (S) Congestive heart failure. (9) Emotion, for example, anger or excitement as in testifying in a court procedure, arguments by telephone, or even watching a boxing match on television often precipitate angina. Monitored electrocardiograms while automobile driving reveal inversion of T waves and depression of S - T segments 94 with or without concomitant angina. Nowlin monitored sleeping subjects to find that often rapid eye movements, indicating dreaming, immediately preceded awakening with angina25 (10) Exposure of the face to cold air with or without effort. 96'97 (11) Hot, humid environment can precipitate angina and electrocardiographic changes, presumably due to increased demand by elevated cardiac output, as (19.) Influence of recent food intake? 2,99 (13) The time of day, as exhibited by a tendeney toward an attack of angina at eertain times, for example, in the morning after breakfast, at night on retiring to bed. 1~176 (14) Oral intake of alcohol seems to relieve some anginal episodes despite lack of experimental evidence of reduction of cardiac work load or increased coronary blood flow. (15) Tobaeeo. 1~176 (16) Altitude. Some patients will develop angina when active at altitudes of over 5000 feet and others seem tolerant of 12,000 feet. ~~ (17) Nitrites: sublingual nitroglycerine or inhaled amyl nitrite, when effective

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abolishes or diminishes angina in 1 to 5 rain with flushing, ff the drug is potent. Pain of the premonitory syndrome or of the onset of myocardial infarction is generally not diminished or dispelled by nitrites. Use of nitroglycerine for angina in the postmyocardinal infarction period is controversial because of the danger of a hypotensive reaction but is probably safe when the blood pressure is satisfactory and stable. 1~ (18) Posture, specifically bending forward, may induce pain. Variant Angina Pectoris: Variant angina is the infrequently occurring form of angina first described by Prinzmetal and co-workers in 19597 ~ It arises spontaneously with elevation of S-T segment frequently at rest and is generally relieved by nitroglycerine. Occlusive proximal coronary disease and possibly an element of coronary spasm accounts for the angina. 7~176 ACUTE CORONARYINSUFFICIENCYWITHOUT MYOCARDIALINFARCTION PREMONITORY MYOCARDIALINFARCTIONSYNDROME: PREINFARCTtON ANGINA PECTORIS

The abrupt onset of pain with difference in form, duration, severity, frequency, or spontaneity from that of previous anginal pains indicates a new occlusive process and when no objective evidence of myocardial infarction develops it can be called acute coronary insufficiency. Such acute change may be due to mural thrombosis, subintimal hemorrhage, or a trap door displacement of an endothelial plaque. Continued observation of the patient for a week is recommended because the episode may be the forerunner of a serious myocardial infarct2 ~176 The duration of a "premonitory period" of a threatened infarct is arbitrarily suggested as 14 days, a period determined experimentally and elinieally for development of reparative and compensating factors under customary or average circumstances. ~~

Myocardial Infarction Acute coronary insufficiency resulting in myocardial infarction as diagnosed by electrocardiographic, clinical, and laboratory evidence exhibits at onset more severe and prolonged pain at times lasting from 2 to 5 days dependent on the size of the infarct. A narcotic is generally needed and preferably by intravenous injection ff the pain is severe. ~~ Periearditis secondary to myocardial infaretion may become apparent within 48 hr of the onset and may induce the characteristic pain of that entity possibly superimposed on coronary pain. The postmyocardial infarction syndrome resembles relapsing benign viral periearditis with pneumonia and pleurisy and the pain is similar to that of infectious percarditis and pleuritis, m-~t* The shoulder-hand syndrome described in 19421~ is a rare sequel of myocardial infarction but not likely to be confused with cardiac pain. Persistent pain and swelling of the left arm may continue for weeks. 17

Other Entities Causing C.ardiac Pain Aortic Insufficiency: The angina of severe aortic insufficiency, especially in the young, differs from that of coronary disease 1~6 in that: attacks at rest are

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frequent, episodes often may last for 1 to 3 hr, fluctuating in intensity, and nitroglycerine often is ineffective or the relief may be transient. Aortic Stenosis: Patients having aortic stenosis with high intraventricular pressures and large ventricular/aortic gradients frequently exhibit angina (70% in Wood's series). Spontaneous anginal pains are not common and the development of pain may more consistently occur with lesser degrees of physical effort than in coronary disease. Syncopal episodes may ensue after giving a nitrite and large doses must be avoided. 117

Obstructive Hypertrophic Cardiomyopathy Including Idiopathic Hypertrophic Subaortic Stenosis (IHSS): Anginal pain due to outflow obstruction of the left (IHSS) or right ventricle does occurY s Despite known increase of left ventricular-aortic gradient by nitrites these drugs may promptly terminate the angina. Propranolol can prevent angina as well as decrease evidence of heart failure. Noncoronary Nonobstructive Primary Myocardial Disease: This is a heterogenous group of diseases which are characterized by congestive heart failure without known etiologic agent, and part of the pathologic process can include coronary disease. The anginal attacks have no unique character. 11s ~o Pulmonic Valvular Stenosis and Right Ventricular Strain: Pulmonic valvular stenosis and other lesions inducing right ventricular strain can produce angina indistinguishable from that of coronary disease cured by removing obstruction to right ventricleY 1 ADJUNCTS IN THE DIFFERENTIAL DIAGNOSIS OF CHEST PAIN

Risk Factors: The greater the number of abnormalities of the following elements in a patient's history or examination, the greater the chance of excessive or precocious coronary atherosclerosis. These include obesity, high levels of serum cholesterol, triglycerides and uric acid, hypertension, abnormal resting ECG, positive family history of precocious or severe arterial disease, diabetes mellitus, cigarette smoking, highly competitive personality, mesomorphic genotype, and a sedentary life. In any individual the assessment of the number of risk factors can do no more than raise the index of suspicion in differentiating anginal pain from other types of chest pain. The ECG Before and After Stress: There are no changes in an ECG which are pathognomonic of coronary artery disease. Despite a negative history an ECG showing initial QRS force changes of an old myocardial infarction is probably indicative of myocardial damage secondary to coronary arterial diseaseY 2 However, small myocardial infarctions may leave no evidence, electrocardiographic, clinical, or even angiographic, in their wake; and other destructive myocardial disease "cardiomyopathy" can duplicate the electrocardiographic pattern of the necrosis following coronary occlusion. During repolarization, the reconstitution of electrical forces is very sensitive to anoxia, and so the most common abnormality in patients with ischemic heart disease is ST-T wave depression. Unfortunately, this is a nonspecifie change and may be found with many benign or serious influences.

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Tests exist to assay coronary competence by challenging the myocardinm by a work load which is predetermined or until dangerous signs develop such as angina, extreme dyspnea, fatigue, or arrhythmia (Master's test). 8~ The validity of the "positive stress test" in the detection of coronary artery disease may be indicated by the long term followup studies of Mattingly. 12~ They have shown a high correlation of definite clinical coronary disease with an abnormal test and a very low ineidence of positive tests among patients without coronary disease. Coronary Arteriography: Coronary artery obstruction is the most likely reason for angina peetoris, and eoronary arteriography is the best means for accurately demonstrating signifieant obstructive lesions during life in large and to a lesser degree in small extramural and intramural arteries. In Proudfit's 122 series the story of typical angina pectoris was 93.77o predictive of significant obstructive coronary arterial disease. Unfortunately the incidence of occlusive atheroselerotie lesions is so high in men over the age of 50 years that some occlusive disease will be found in almost all. Little is gained in attempting to substantiate a diagnosis of angina in middle-aged patients by demonstrating a partially obstructive lesion. However, absence of arterial narrowing is valuable in excluding angina. There have been several small series 8-1~of patients with angina who do not exhibit occlusive coronary disease by angiography. The possibility has been presented above that angina has been induced by oxyhemoglobin dissociation defects. ~24 It is probable that lack of technical perfection of angiography and of skill in interpretation of the angiogram of small vessels are more plausible explanations of the negative findings22s

Differential Diagnosis of Cardiac Pain Diseases of the chest that have prolonged and fluctuating courses may cause pain resembling angina pectoris, for example, prolonged pulmonary and/or pleural disease including multiple pulmonary emboli with or without infarction, prolonged pericarditis, thoracic aortic aneurysm, and tumors of the lung and mediastinum. Especially confusing are the thoracic radicular and other chest wall syndromes, such as acute traumatic or inflammatory disease of the chest wall, xiphoid syndrome, myositis, and acute rib or cartilage pain. At times the pain of abdominal disease may resemble anginal pain as in esophageal, gastric, biliary tract, and pancreatic dysfunction. More acutely developing entities may be confused with myocardial infarct or acute myocardial isehemia. These include dissecting aneurysm of the thoracic aorta, acute pericarditis, pulmonary embolism, pneurnothroax, pneumomediastinum, acute pleuritis, and airway obstruction. Although occasional instances arise in which upper abdominal disease and various diseases of the chest, especially with abrupt onset, may present features resembling chronic or acute coronary insumeieney, distinguishing elements are identifiable. For this reason the discussion of differential diagnosis will be limited to those entities which, in our experience, have led to the greatest problems of differentiation from coronary disease.

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Chest Wall Syndromes Chest wall syndromes, especially the radicular syndromes, are the commonest causes of chest pain requiring differentiation from cardiac pain. Tietze's syndrome although relatively rare, is a localized inflammatory disease of the upper central ribs or cartilages and intercostal muscles causing pain. lz~ "Xyphoidalgia" is a persistant xiphoid pain after injury. 128 Precordial catch is a short painful condition caused by presumably a displacement of a rib or cartilage resulting in impingement of sensitive periosteal or perichondral surfaces. Tussic rib fractures are unlikely to present diagnostic problems. Impingement of the thoracic 8th to 10th rib margin on the crest of the ilium in kyphotic patients can cause pain and local tenderness. Rarer entities and those readily identified include post herpetic neuralgia, tumors of the ribs or chest wall, and acute phlebitis of a superficial vein of the chest wall (Mondor's syndrome).

Radicular Syndrome Neuroses underlay this entity frequently and require recognition. The pain which characterizes cervico-dorsal spinal nerve root involvement may be deep and compressive or a prolonged dull ache with momentary recurrent darting or stabbing. The segments involved and most often confused with cardiac pain are C~ through TG and particularly in the precordinm (see Fig. 2). The pain is likely to last for hours but may be briefer. It may accompany physical effort, but more frequently follows it. Fatigue and/or "slouched" or kyphotic posture, as in leaning over a desk or being curled up in a large chair tends to induce pain then or subsequently. Pressing or constrictive nature of pain in the chest or throat, or aching of the jaws is quite unusual. Consciousness of breathing and hyperventilation may exaggerate the discomfort as part of an anxiety state, as in inappropriate fatigue. Tenderness of the upper trapezius and lateral pectoral muscles is common and occasionally spasm of paraspinal muscles and hyperesthesia is noted in the involved zones. Bilateral areas of tenderness may be elicited by heavy pressure over the T3 to T~ cartilages especially and ribs adjacent to the sternum and on the corresponding posterior spinous processes. The demonstration that there is noncardiac cause for the chest pain is reassuring and aided by aspirin, local heat on the upper back, advice on posture and avoidance of fatigue can effect a striking improvem e n t . ~29

Spinal defects, inc/uding arthritis, were thought to be the basic cause for the radicular syndrome, but fatigue with anxiety and defective posture are sufficient.* Sudden lancinating pain in the affected zone can be precipitated by coughing or sneezing. 13~ A plausible explanation of the mechanism distorting nerve roots is presented by Raney. T M The posterior rami of the spinal roots from T3 to Tie lie between the anterior and posterior divisions of the superior costotransverse (C-T) ligament. If the rib head is displaced postero-laterally and the adjacent vertebrae move toward each other as by kyphotic posture, the superior C-T ligament is tensed and impinges on branches of the posterior spinal nerve root or intercostal nerve ( Fig. 2).

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Pericarditis

As is well known, the pain of acute pericarditis has a sharp "catching" quality exaggerated by inspiration and motion of the trunk and relieved by bending forward. Catching pain does not suggest a cardiac origin but underlying such pain a dull, prolonged and fluctuating pressure or ache may develop deep in the chest and can be referred to the neck, throat, back, or arms. Barnes and Burchell report 14 such problem cases. Similar pains appear with massive pericardial effusion or pericardial tamponade. 1~2 The pain so resembles angina that a decrement of coronary flow in this disease seems likely. In almost all instances the pericardial rub, the fever (temperature over 38.5~ oral) and leukocytosis are accompanied by little or no rise in serum enzymes, less than expected with a sizeable myocardial infarct. 133 In pericarditis T-wave inversion as a rule follows the S-T segment elevation by 2 to 4 days in contrast to the sequence in myocardial infarction. T-wave inversion may be the only abnormality and may persist indefinitely. Esophageal and Hiatus Hernia Pain 1~4-136 Upper Gastrointestinal Tract and Other Upper Abdominal Diseases: Peptic ulcer, gastritis, and functional (neurogenic) pylorospasm rarely induce pain of "cardiac" quality. Indefinite epigastic aching, nausea, pyrosis, and sensations of bloating (with eructation), boring or cramping, often related to meals are not likely to be confused with angina. However, notoriously the cardiac pain of myocardial infarction may be accompanied by just such symptoms and prior to 1924 was often diagnosed "acute indigestion." Pains of hiatus hernia strikingly imitate cardiac pain but the epigastric and substernal distress is more likely to appear in a supine posture, especially during the night. T-wave abnormalities may be induced by distention of a hiatus hernia. A review of 214 patients with this disease by Palmer 134 gave the following significant findings: in about 570 the picture resembled angina pectoris, even precipitated by physical effort or straining as in lifting a weight. The symptoms often come and go in cycles of days or weeks. The smaller the hernia, that is, 2-3 cm, the more likely it was to induce severe symptoms and the less likely to be demonstrated roentgenographically. In our experience a 57-year-old man was hospitalized five times for suspected myocardial infarction. The pain onset was eventually identified as accompanying abrupt massive gastroesophageal reflux above a small hiatus hernia. Bennett and Atkinson13~ reported in 124 patients that of patients with esophagitis, esophageal spasm and other esophageal defects, or gastroduodenal disease, about 1870 had concomitant coronary disease; of patients with esophageal dysfunction, the peak decade of presenting symptoms was from 50-60 years. The distribution of pain was invariably substernal but in one-third was epigastric and in appreciable numbers in areas commonly identified with referred cardiac pain. Esophageal pain was induced by exercise such as walking in 24%, by stooping or bending in 4370, by emotion in 2470, and by meals in 30% of this series. The differentiation of most upper abdominal disease from coronary disease

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may be simple but is rendered difficult when qualities of pain resembling angina or coronary disease also exist. Gall bladder disease, other than the colic of cholelithiasis, seems to produce symptoms similar to functional gastroesophageal disturbances. Despite overlapping symptoms patterns, the diagnosis was incorrect in less than 157o of our patients when thoroughly studied, as proven by the test of time.

Pulmonary Embolism Puhnonary embolism with infarction pursues four clinical and pathologic forms: 136 (1) multiple small emboli that can cause cardiac type of pain only when pulmonary hypertension is induced (right ventricular strain), (2) the "medium sized" emboli with systemic reactions, hemoptysis, and pleuritis. Pleural pain, although generally "catching" may be dull and located substernally or diffusely deep in the chest. In 90 cases reported by Israel and Goldstein 13~ pleural pain occurred in 5670 and true angina in 24%. Angina may be caused by hypoxemia and diminished coronary perfusion in patients with pulmonary embolism. Pleural rub with occasional pericardial extension and rub strengthens the diagnosis. Electrocardiographic changes are discussed below. (3) Large emboli obstructing one or more major pulmonary arterial trunks frequently induced an anginal-like sense of obstruction to breathing (blockpnea) or more severe painful compressing discomfort substernally or diffusely in the anterior chest. The occurrence of shock, cyanosis, and tachycardia and the Q3-T3 pattern of the electrocardiogram in inferior leads simulates the reactions to a large inferior myocardial infarction. Myocardial necrosis has been reported with large pulmonary embolism, confirming the probability of accompanying coronary insufficiency. Chest roentgenograms are often not diagnostic and pulmonary angiography l~s and chest scanning for the radioactivity of injected " I macroaggregates of tagged serum albumin are necessary for diagnosis. 1~9 The electrocardiographic changes may be diagnostically valuable if a series of records are started soon, that is, 4 to 12 hrs after onset with over 8070 correlation, otherwise specific value may be low. Summary of electrocardiographic changes: clockwise rotation of the anterior chest leads; serial inversion of the T waves in leads V~, 2, 3; tall peaked P waves with prominent S in I and AVL and occasionally right bundle branch block; right ventricular strain patterns; T wave inversion and Q wave prominence in leads III and AVF but not generally in II. 1.~ Elevation of SLDH (serum lactic dehydrogenase) activity and serum bilirubin with normal SGOT (serum glutamic oxalacetic transaminase) activity is not specifically diagnostic for pulmonary embolism. Massive pulmonary infarcts may exhibit elevated serum bilirubin levels as high as 20 mg/lO0 ml, accompanying right heart strain and resultant congestion of the liver. Moderate to large infarcts with acute "cor pulmonale" and hepatic congestion often induce elevation of both SLDH and SGOT ~4~ (hepatic origin).~37 Of recent interest is the rise in some patients with pulmonary embolism or pneumonia of serum SCPK (serum creatinephosphokinase) activity to modest heights, that is, 50-70

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U/100 ml, proportionately greater than the SGOT rise in uncomplicated pulmonary infarction.

Dissecting Aneurysm Dissecting aneurysm of the aorta often is difllcult to distinguish from the onset of acute myocardial infarction. Whereas silent dissections have been reported, the pain generally is extremely severe as the aortic wall layers forcibly are separated and reaches a peak more rapidly than in myocardial ilffarction. 143 If the tear is in the ascending aorta or proximal arch, pain will be referred to the retrosternal region. The pain is more severe and intractable than that ill most myocardial infarctions and often requires repeated doses of narcotics for several days. It often has a ripping or cutting quality unlike cardiac pain. The pain is disproportionately severe and lacks signs of heart failure which would be expected in a large myocardial infarction. Pain will march as in two-thirds of the series of Hirst and associates 143 invading a new area and receding from a previous one. The progress will be from the anterior chest or deep abdomen to the head and neck, shoulders, and arms, but more often arises in upper back (intereapular) and travels to the lumbosacral region. If the aol~c intima tears elsewhere than the proximal aorta, the pain starts often in the back or abdomen with less likely confusion with a myocardial infarct. A chest roentgenogram and, more positively, an aortogram may lead to the diagnosis. The result of successive occlusions of the arteries arising from the aorta give much information on the diagnosis of dissecting aneurysm. Procession of encroachment on aortic branches induce signs as follows: the carotid and vertebral arteries lead to syncope, decrease of vision, hemiplegia, and coma; the mesenteric arteries cause diffuse abdominal pain and ileus; renal arteries induce an acute renovaseular hypertension and anuria; the arteries of the arms and legs cause decreased pulse volume and blood pressure and occasionally threat of gangrene (these arterial compressions are irregular in lateralization and sequence); encroachment in the proximal coronary arteries may lead to coronary insufficiency; alteration of the aortic ring (not dearly understood) leads to aortic valve incompetence; and slow leakage into the pericardium may cause periearditis and changes in the electrocardiogram or fatal tamponade ff rapid. The differentiation from cardiac pain must be made by the whole picture since coronary insufficiency and pericarditis arise in both diseases. CONCLUSIONS AND SUMMARY

Cardiac pain, as the most important early clinical index of coronary disease, is identified by the clinical history which must be obtained by searching questioning. The differential diagnosis is difficult ff other diseases present similar patterns of the precipitating factors: quality, location, and radiation. Such noncardiac pain can be precipitated by physical or emotional stress, last a short time, and even be relieved by nitrites. Rarely do all of these elements duplicate the picture of anginal pain when the history is accurate. At other times, and especially when coronary surgery is considered, other

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adjuncts will be required either to appraise the distribution of flow or to anatomically assay the degree and location of the coronary disease. These are coronary angiography and stress tests inducing clinical dynamic and electrocardiographic abnormalities. The pathophysiology of cardiac pain is reviewed and although the actual pain producing substances and the location of pain sensors are not known, accepting their existence seems valid. The role of factors unfavorably altering the ratio of coronary oxygenated blood supply to myocardial demand in causing cardiac pain has become increasingly clear. Of great importance is the avoidance of the fallacious diagnosis of clinical coronary disease with its serious impact on the psychic and social aspects of the patient's future life. Such a fallacy cannot readily be dispelled. The eccentricities of the patterns of angina and of other more atypical, acute patterns of coronary disease cannot be thoroughly explained but their clinical significance is increasingly recognized. It is important that appropriate patient observation and care follow recognition by the physician of the threat of a major myocardial infarction when indicated by a change in the pattern of cardiac pain. Nothing is of greater importance in the clinical consideration of cardiac pain than the recognition of this situation. ADDENDU2V~

Since this paper was submitted for publication, there have been several articles of importance which should be included. Vokonas et a1144have studied oxyhemoglobin dissociation curves from 15 patients with anginal pain and normal coronary arteries by eineangiography and find no abnormalities of hemoglobin affinity for oxygen at rest. Glancy et al. 14~ found that ouabain in patients with angina pectoris increased ventricular contractility without increasing either exercise tolerance or the pressure-rate product at which angina occurred. Detry and Bruce 146 found that nitroglycerine in patients with angina pectoris increased exercise tolerance and raised the threshold of angina onset above the prior heart rate-blood pressure product. This response was attributed to decrease in myocardial oxygen consumption resulting from the lowering of LVEDP and cardiac volume produced by the nitroglycerine. Beeker et al. 1~7 demonstrated in dog experiments that nitroglycerine selectively increased blood flow to subendocardial areas relative to the epicardium in both ischemic and nonischemic areas of the myocardium. Nitroglycerine did not materially increase total blood flow to the ischemic area. The selective increase in subendocardial blood flow after nitroglycerine was attributed to the decrease in heart size as well as developed myocardial tension. This resuited in a reduction in the gradient of tension within the ventricular wall and permitted increased endocardial blood flow. A direct action on the larger vessels to the subendocardial area could not be ruled out. REFERENCES

1. Loan, W. B., and Dundee, J. W.: The clinical assessment of pain. Practitioner 198: 759, 1967. 2. Keys, A.: Coronary heart disease in

sevencountries. Circulation Suppl. 41, 1970. 3. Procacci, P.: A survey of modem concepts of Pain. In Vinken, P. J., and Bruyn,G. W. (Eds.): Handbook of Clinical

526 Neurology, Vol. I, Distm'bances of nervous function. Amsterdam, North Holland, 1969, p. 137. 4. Gunther, L., and Smnpson, J. J.: The radicular syndrome in hypertrophic osteoarthritis of the spine, root pain and its differentiation from heart pain. ].A.M.A. 93: 514, 1929. 5. McKenzie, J.: Angina pectoris. In Fraude, H., Oxford Medical Publications. London, Hodder and Stoughton, 1927. 6. Ecken_hoff, J. E., Hafkenschie], J. H., Landmesser, C. M., and Harme], M.: Cardiac oxygen metabolism and control of coronary circulation. Amer. J. Physiol. 149: 634, 1947. 7. Gregg, D. E., and Fisher, L. C.: Blood supply to the heart. In Handbook of Physiology Vol. I1. Washington, D.C., American Physiological Society, 1963, pp. 1533-1536. 8. Likoff, W., Segal, B. L., and Kasparian, H,: Paradox of normal selective coronary arteriograms in patients considered to have unmistakable coronary heart disease. New Eng. ]. Med. 276:1063, 1967. 9. Dwyer, E. M., Jr., Wiener, L., and Cox, J. W.: Angina pectoris in patients with normal and abnormal coronary arteriograms. Amer. J. Cardiol. 23:639, 1969. 10. Eliot, R. S., and Bratt, G.: The paradox of myocardial ischemia and necrosis in young women with nornaal coronary arteriograms. Amer. J. Cardiol. 23:633, 1969. 11. Ayers, S. M., Mueller, H. S., Gregory, J. J., Gianelli, S., Jr., and Penny, J. L.: Systemic and myocardial hemodynamie responses to relatively small concentrations o[ earboxyhemoglobin ( COHb ). Arch. Environ. Health (Chicago) 18:699, 1969. 12. Anderson, R. F., Allewirth, D. C., and DeGroot, W. J.: Myocardial toxicity from carbon monoxide poisoning. Ann. Intern. Med. 67:1172, 1967. 13. ShappeU, S. D., Murray, 1. A., Nasser, M. G., Wills, R. E., Tolxance J. D,, and Lenfant, C. J. : Acute change in hemoglobin affinity for oxygen during angina pectoris. New Eng. J. Med. 282:1219, 1970. 14. Astrup, P.: Bed-cell pH and oxygen affinity of hemoglobin. New Eng. J. Med. 283:202, 1970. 15. Torrance, J., Jacobs, P., Restrepo, A., Eschbach, J., Lenfant, C., and Finch, C. A.: Intraerythrocytic adaptation to anemia. New Eng. J. Med. 283:165, 1970. 16. Wells, R.: Current concepts. Syn-

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dromes of hyperviscosity. New Eng. J. Med. 283:183, 1970. 17. Burch, G. E., and DePasquale, N. P.: Tho hematocint in patients with myocardial infarction. J.A.M.A. 180:63, 1962, 18. Dintenfass, L.: Thixotropy of blood and proneness to thrombus formation. Circ. Res. 11:233, 1962. 19. - : Viscosity and clotting of blood in venous thrombosis and coronary occlusion. Circ. Res. 14:1, 1964. 20. - , Julian, D. G., and Miller, G. E.: Viscosity of blood in normal subjects and in patients suffering from coronary occlusion and arterial thrombosis. Amer. Heart J. 71:587, 1966. 21. Williams, A. V., Higginbotham, A. C., and Knisely, M. H.: Increased blood cell agglutination following ingestion of fat, a factor contributing to cardiac ischemia, coronary ins:d~ciency, and anginal pain; a contribution to the biophysics of disease. Angiology 8:1020, 1957. 22. Kuo, P. T., and Joyner, C. R., Jr.: Angina pectoris induced by fat ingestion in patients with coronary arrest disease; ballistocardiographio and electrocardiographic findings. J.A.M.A. 158:1008, 1955. 23. Began, T. J., Binak, K., Gordon, S., DeFazio, V., and Hellems H. K.: Myocardial blood flow and oxygen consumption during postprandial lipemia mad heparin-indueed ]ipolysis. Circulation 23:55, 1961. 24. Sonnenblick, E. H., Ross, J., Jr., and Brannwald, E.: Oxygen consumption of the heart. Newer concepts of its multifactoral determination. Amer. ]. Cardiol. 22:328, 1968. 25. Roughgarden, J. W., and Ne~rnaan, E. V.: Circulatory changes during the pain of angina pectoris, 1772-1965-A critical review. Amer. ]. Med. 41:935, 1966. 26. Robinson, B. F.: l~elation of heart rate and systolic blood pressure to the onset of pain in angina pectoris. Circulation 35: 1073, 1967. 27. Levine, S. A.: Some notes concerning angina pectoris. J.A.M.A. 171:1838, 1959. 28. Braunwald, E., Epstein, S. E., Glick, G., Wechsler, A. S., and Brannwald, N. S.: Relief of angina pectoris by electrical stimulation of the carotid-sinus nerves New Eng. J. Med. 277:1278, 1967. 29. Levy, J. V., and Richards, V. Inotropic and metabolic effects of three adrenergic receptor blocking drugs on isolated

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527 onary vessels in the pathogenesis of coronary insufficiency, (in Russian). Leningrad, 1953. Cited in Tyavorkin, V.V.: Reproduction of atherosclerosis in rabbits by limitation of mobility. Bull. Exp. Biol. Med. 63:112, 1967. 44. Grayson, J., and Lapin, B. A.: Observations on the mechanisms of infarction in the dog after experimental occlusion of the coronary artery. Lancet 1:1284, 1966. 45. Way, H. H., Frank, C. W., Kanter, D. M., and Wegria, R.: Experimental studies on intercoronary reflexes. Circ. Res. 5:91, 1957. 46. Opdyke, D. F., and Selkurt, E. E.: Study of alleged intercoronary reflexes following coronary occlusion. Amer. Heart J. 36:73, 1948. 47. Yurchak, P. M., Rolett, E. L., Cohen, L. S., and Gorlin, R.: Effects of norepinephrine on the coronary circulation in man. Circulation 30:180, 1964. 48. Nestel, P. J., Verghese, A., and Lovell, R. R. H.: Catecholamine secretion and sympathetic nervous responses to emot.ion in men with and without angina peetoffs. Amer. Heart J. 73:227, 1967. 49. Bettman, R. B., and Rubinfeld, S. H.: Gallbladder-heart reflexes in man under spinal anesthesia. Amer. Heart J. 10:550, 1935.

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59,8 ventricular function and S-T segment depression during angina precipitated by exercise. Circulation 40:97, 1969. 57. McArdle, B.: Myopathy due to a defect in muscle glycogen breakdown. Clin. Sei. 10:13, 1951. 58. Guzman, F., Braun, C., and Lira, i~. K. S.: Visceral pain and the pseudoaffective response to intra-arterial injection of bradykinin and other algesic agents. Arch. Intern. Pharmacodyn. 137:353, 1962. 59. MUller, O., and Borvik, K.: Hemodynamie consequences of coronary heart disease with observations during anginal pain and on the effect of nitroglycerin. Brit. Heart J. 20:302, 1958. 60. Dimond, E. G., Duenas, A., and Benehimol, A.: Apex cardiography. Amer. Heart J. 72:124, 1966. 61. Linehart, J. W., Hildner, F. J., Barold, S. S., Lister, J. W., and Samet, P.: Left heart hemodynamics during angina pectoris induced by atrial pacing. Circulation 40: 483, 1969. 62. Tennant, 11., and Wiggers, C. J.: The effect of coronary occlusion on myocardial contraction. Amer. J. Physiol. 112:351, 1935. 63. Elliott, W. C., and Gorlin, R.: Coronary circulation, myocardial isehemia and angina peetoris. I Mod. Cone. Cardiovasc. Dis. 35:111, 1966. 64. Herman, M, V., Heinle, B. A., Klein, M. D., and Gorlin, R.: Localized disorders in myocardial contraction. Asynergy and its role in congestive heart failure. New Eng. J. Med. 277:222, 1967. 65. Eddleman, E. E., Jr., and Langley, J. O.: Paradoxical pulsation of the preeordimn in myoeardial infarction and angina pectoris. Amer. Heart J. 63:579, 1962. 66. Sampson, J. J., Felton, L. lt., Goetz, A. A., Soloman, B. and Alexrod, B.: Portable serial roentgenkymography in acute myocardial infarction. Circulation 13:729, 1956. 67. Fothergill, J. M.: The Heart and Its Diseases. Philadelphia, Lindsay and Blakiston, 1879. 68. Demany, M. A., Tambe, A., and Zimmerman, H. A.: Coronary arterial spasm. Dis. Chest 53:714, 1968. 69. Prinzmetal, M., Kennamer, R., Merliss, R., Wada, T., and Bor, N.: Angina pectoris, I. A. variant fmTn of angina pectoris. Amer. J. Med. 27:375, 1959. 70. Whiting, 11. B., Klein, M. D., Vanderveer, J., and Lown B.: Variant angina pec-

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CARDIAC PArrr

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531

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147. Becker, L. C., Fortuin, N. J., and Pitt, /3.: Effect of ischemic and antianginal drugs on the distribution of radioactive rnicrospheres in the canine left ventricle. Circ. Res. 28:263, 1971.