At the third annual postgraduate course of the

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1 CRITICAL REVIEWS Coronary Artery Spasm and Angina Pectoris* Goffredo G. Gensini, M.D., F.C.C.P. 00 Coronary artery spasm should now be considered a wedproven clinical entity which may or may not be associated with clinical symptoms and coronary atherosclerosis and may be either "spontaneous" or iatrogenicauy induced. The most important clinical entity associated with coronary spasm is that of Prinzmetal's angina. In patients with this "variant" form of angina, severe coronary spasm appears to be the cause of the acute reduction of myocardial blood supply leading to their transient ischemic episodes. Recent studies suggest that "spontaneous" coronary spasm may be related to increased parasympathetic activity and stimulation of a-adrenergic receptors and may be possibly associated with inappropriate phasing of circadian rhythms. These observations explain the failures of coronary bypass surgery in cases of Prinzmetal's angina and provide interesting leads for further investigations into the mechanism, significance, and pharmacodynamics of coronary vasomotion. "Spasm... of a coronary artery or even of one branch, may so modify the action of a section of the heart that it works with disturbed tension... and there are painful sensations." Sir William Osler, "This is a most interesting cause of angina pectoris in a person with little or perhaps no structural atherosclerotic coronary obstruction. It may, like atherosclerosis itself, become more common in these stressful days and years of today and tomorrow. It is a challenge to be met." The last published words of Paul D. White, At the third annual postgraduate course of the American College of Chest Physicians, PrinzmetaP in 1957 described a "variant" form of angina pectoris and reintroduced the concept of coronary spasm as the key factor in certain well-defined instances of rest angina. A few months after Prinzmetal's 4 first published report, we were able to document the appearance of spontaneously occurring coronary spasm associated with chest pain in a patient with angina pectoris and mild coronary artery disease, as well as the resolution of this spasm and the disappearance of the pain with the administration of a sublingual nitrate. Our first published report appeared in Earlier, West and Guzman 6 had demonstrated by selective coronary arteriography the effect of nitroglycerin, vasopressin (Pi tress in ), and epinephrine on the coronary arteries of dogs and had been able to show From the Msgr. Toomey Cardiovascular Laboratory and Research Department, St. Joseph's Hospital Health Center, and the Department of Medicine, Upstate Medical Center, State University of New York, Syracuse, NY. 00 Director, Msgr. Toomey Cardiovascular Laboratory and Research Department, and Clinical Professor of Medicine. Reprint requests: Dr. Gensini, St. joseph's Hospital Health Center, 301 Prospect Avenue, Syracuse dramatic examples of both coronary constriction and coronary vasodilatation. Ours, however, was the first clinical case in which the presence of spasm and its resolution had been documented with coronary arteriography. This concept then sounded quite controversial, as angina pectoris was thought to be consistently associated with either fixed coronary atherosclerotic obstructions or with other organic disease in which the demand could outstrip the capacity of the coronary vascular bed. The problem of symptomatic coronary artery spasm remained dormant or conveniently forgotten for almost a decade, but during the last few years, numerous reports have appeared documenting beyond all doubts the existence and clinical significance of this phenomenon. The report by Maseri et af in this issue is of special interest as it provides for the first time the missing correlation between the clinical, electrocardiographic, hemodynamic, and angiographic characteristics of "spontaneous angina." "REDISCOVERY" of CoRONARY SPASM AND SPASM-INDUCED ANGINA At this time, it may be interesting to question what made it possible for so many convincing studies to suddenly appear within the last three to four years. Selective coronary arteriography was described over 13 years ago 8 and has enjoyed widespread clinical application for well over a decade, yet with the exception of our report in and that of Demany et al 9 in 1968, no other arteriographic evidence of symptomatic coronary spasm had appeared prior to the one by Dhurandhar et al 10 in December of Worthy of note is that in their CORONARY ARTERY SPASM AND ANGINA PECTORIS 709

2 second edition of The Heart, Hurst and Logue 11 made no mention of either coronary spasm or of "variant" angina, whereas in their last edition, they C'Onsidered these phenomena in several chapters and concluded: "At the time of this writing the enigma of coronary spasm is again plaguing us. New syndromes are being elucidated that assign a significant role to coronary spasm." 12 Two reasons may be responsible for this "rediscovery" of the clinical role of coronary spasm in ischemic heart disease. First, coronary arteriography is often performed following administration of nitroglycerin or atropine, or both; the first is well known to produce vasodilatation and, thus, prevent or resolve spasm, and the second may prevent coronary spasm by a yet different mechanism. When arteriographers became aware of the existence of spasm-induced angina, they probably began to alter their protocol to increase the diagnostic yield of coronary arteriography. Secondly, the availability of coronary bypass surgery has led to a dramatic increase in the utilization of coronary arteriography and has extended the indication of this diagnostic procedure to cases with acute coronary insufficiency, a group which may very well include some patients with Prinzmetal's angina. Two additional reasons may be responsible for not identifying "spontaneously" occurring coronary spasm during coronary arteriography: ( 1) The natural tendency of most arteriographers has been to refrain from injecting, or even exploring with a catheter, the coronary arteries during episodes of pain, hypotension, severe arrhythmias, or other alarming electrocardiographic changes, all phenomena associated with the presence of Prinzmetal's angina. ( 2) There is a tendency for Prinzmetal's angina to occur in the wee hours of the morning, a rather unpopular time with most arteriographers and their stah. TYPES OF CoRONARY SPASM Our own experience and a review of the literature indicate that it is possible to describe at least four major types of coronary arterial spasm: Iatrogenically (Catheter) Induced Spasm Spasm induced by the mechanical stimulation of the catheter on the intima of the coronary artery appears more frequently ( 3 percent of the cases studied in our laboratory) during catheterization of the right coronary artery, probably because deep catheter penetration more easily occurs in this artery. A similar phenomenon involving the main left coronary artery is very rare; we have seen it only 710 GOFFREDO G. GENSINI once in over 3,000 coronary arteriograms. The following features are typical of iatrogenic spasm: ( 1) localization within the initial segment of a main coronary artery, at or within a few millimeters from the catheter tip; ( 2) no apparent hindrance to blood Bow; ( 3) no association with pain or ST-segment changes; and ( 4) tendency to spontaneous disappearance within about ten minutes, provided the catheter is removed from the coronary artery. The spasm may disappear sooner with administration of nitroglycerin or isosorbide dinitrate, even though the dilatation of the unaffected segments usually occurs prior to the disappearance of the constricting band. Coronary Spasm Superimposed on Well-Defined Coronary Obstructions We have observed a few cases in which coronary spasm was obviously superimposed on easily identifiable, fixed coronary narrowings but differed clinically and electrocardiographically from classical variant angina. These were four cases of unstable angina in which a major coronary artery appeared totally occluded during an episode of pain at the time of the first injection and became partially open, though still severely narrowed, after administration of nitroglycerin or isosorbide dinitrate. The role of spasm as a precipitating factor in some cases of unstable angina is further supported by recent hemodynamic studies of Berndt et al. 13 Coronary Spasm due to Nitrate Withdrawal Coronary spasm is known to occur in factory workers chronically exposed to nitroglycerin compounds. A recent publication by Lange et ap 4 describes the coronary arteriographic features of five such patients and provides an extensive review of the literature. Spontaneously Occurring Spasm Spontaneously occurring spasm (Prinzmetal's or variant angina) is the most interesting and now the best documented type of coronary spasm. Sufficient information has been gathered about this entity to describe in detail its clinical, electrocardiographic, hemodynamic, and arteriographic features and to use this term with precision and discrimination. I believe that the term, Prinzmetal's or variant angina, should be reserved for a clinical entity characterized by anginal pain occurring at rest and accompanied by transient ST-segment elevation. An exhaustive study of these patients will elicit most, if not all, of the following features: Clinical Presentation. The presenting symptom is

3 chest pain with the following characteristics: ( 1) no relation to effort or excitement; ( 2) cyclic, rhythmic, and often recurrent pattern; ( 3) usually occurring at a predictable time, especially in the wee hours of the morning, waking the patient from sleep; ( 4) often accompanied by papitations, tachycardia, or syncope, singly or in combination; and ( 5) exhibiting prompt relief with administration of nitroglycerin. Laboratory Findings. Laboratory findings are entirely negative. Electrocardiogram. Transient ST-segment elevation during pain episodes is noted on the ECG ( STsegment elevation may occasionally occur unaccompanied by the feeling of pain). The ECG changes may involve the diaphragmatic wall (leads 2, 3, and avf), the lateral wall (leads 1, avl, and V6), and the anterior wall (leads V t to V s). Reciprocal changes are usually seen in the opposite leads. Ventricular arrhythmia and varying degrees of atrioventricular block may be detected. Hemodynamic Factors. Acute depression of left ventricular contractility, of aortic and left ventricular systolic pressure, and of cardiac index and elevation of left ventricular filling pressure and of peripheral vascular resistance 15 are the most common hemodynamic factors. Coronary Arteriography. Spasm of a coronary artery must precede and be present during the pain episodes, though it may at times be demonstrated in less severe forms without progressing to the point of pain. In order of increasing severity, the following three combinations may be observed: ( 1) spasm, no ST-segment elevation, and no pain; (2) more spasm, ST-segment elevation, and no pain; and (3) severe spasm, ST -segment elevation, and pain. The spasm often extends well beyond the arterial segment touched by the catheter, sometimes to include the entire vessel. There may be complete or nearly complete occlusion of the vessel with obvious hindrance to blood How. Nitroglycerin is highly effective in relieving the spasms; occasionally more than one tablet may be needed. Following the disappearance of the spasm, the coronary artery usually exhibits various degrees of irregularities at the affected level. In rare instances the artery appears entirely normal before and after the spasm. The other coronary branches may or may not be involved by fixed coronary obstructive lesions. MECHANISM OF SPASM-INDUCED ANGINA Beginning with Prinzmetal's observations3.4 and ending with the recent works of Y asue et al, of Berndt et al, 13 and of Maseri et af (in this issue), a number of apparently unrelated facts have been reported which, when properly evaluated, may shed an interesting and entirely new light on the mechanism of spasm-induced angina, unravel the "enigma" of coronary spasm, and even add a new time dimension to the study of many cardiocirculatory disorders. These facts can essentially be grouped under three major headings: ( 1) the typically cyclic pattern of spasm-induced angina in all its clinical, hemodynamic, and angiographic presentations; ( 2) the influence of the autonomic nervous system (or of its effector substances) on the caliber of the large coronary arteries, resulting in their vasomotion either toward the direction of constriction or of dilatation; and ( 3) the undisputed (but usually forgotten) presence of well-established circadian rhythms exercising a profound and only partially understood influence on all bodily functions, notably on sympathetic and parasympathetic activity. Essentially all reports on spasm-induced angina have stressed the cyclic rhythmic pattern of this phenomenon and its frequency during inactivity and in the early morning hours. Furthermore, as the attack begins and unfolds, there is no association with increased cardiac work as shown by little change of triple product; 13 in fact, there is a depression of myocardial contractility, 7 systemic pressure, and cardiac index. 15 It appears that, contrary to effort-induced angina, the Prinzmetal's variety occurs at a time in which the metabolic, and thus, the myocardial oxygen demand is at its lowest point. As part of a study on the effect of a placebo on the coronary arteries of dogs and men, we demonstrated, to our surprise, that the caliber of the epicardial coronary arteries of both species decreased appreciably and reached its lowest point after 90 minutes of observation, 17 pari passu with either deepening of the anesthesia (dogs) or increased relaxation of the patient, phenomena which are known to be associated with a reduction in myocardial oxygen demand. This observation suggests that during sleep in the early morning hours, at a time in which the myocardial oxygen demand is at its lowest ebb, the diameter of the large coronary arteries is at its narrowest point. Significantly, the attacks of Prinzmetal's angina peak at precisely this time. The significance of body rhythms on the pathogenesis of human ailments has been largely neglected in clinical medicine, perhaps especially so in the study of ischemic heart disease; yet astute physicians have readily recognized not only the influence of weather, but also a puzzling variation in the frequency and severity of anginal attacks in many of their patients. In cases of effort-induced angina, these variations are usually difficult to iden- CORONARY ARTERY SPASM AND ANGINA PECTORIS 711

4 Table 1-Action of Coronary J' a omotor Sub tance Aetion on Coronary Artery Class of Effects Drug Used References Promotes Vasodilatation or prevents spasm, or both Cholinergic blocking a-adrenergic blocker,s-adrcnergic stimulator Smooth-muscle relaxant Atropine Phenoxybenzamine Nylidin Nitroglycerin 4 5,17 Promotes vasoconstriction or spasm, or both Parasympathomimetic a-adrenergic stimulator,s-adrenergic blocker Pure vasoconstrictor Methacholine Epinephrine Propranolol Ergonovine 19 tify, as the increase in metabolic demand caused by efforts or emotional stresses overshadows the humoral or autonomic makeup of the body at that point in time. This is not so with the Prinzmetal's variant. A dynamic study of man's response to his environment has demonstrated the marked circadian variations exhibited by catecholamine excretion, cardiac output, body temperature, arterial pressure, pulse rate, and left ventricular function. 18 These studies show that the slowest heart rate, the lowest systolic and diastolic systemic pressures, the most prolonged left ventricular ejection time and preejection period, and the lowest urinary excretion of catecholamines occur between 12 o'clock midnight and 6 A.M. According to Wertheimer et al: 18 "Associated with the reduced nocturnal catecholamine secretion, there is a significant fall in myocardial functional capacity, with an increased vulnerability of the heart to stress, particularly from 12 midnight to 6 a.m.... nocturnal cardiac decompensation, including acute congestive failure, arrhythmia and sudden death, is an observed frequent occurrence in patients with significant heart disease. Circadian changes in ventricular function may play an important role in the occurrence of these events... " These studies underscore the role of fluctuating changes of autonomic activity in the production of, or the response to, noxious internal or environmental stimuli. The role of the autonomic nervous system in the pathogenesis of Prinzmetal's angina has been extensively investigated by Y asue et al. These authors demonstrated that the pain episodes and their concomitant electrocardiographic manifestation could be reproduced by the administration of a parasympathomimetic agent (methacholine), by an a adrenergic stimulator (epinephrine) and aggravated by a.b-adrenergic blocker (propranolol). Conversely, a parasympatholytic agent (atropine) and an a-adrenergic blocker ( phenoxybenzamine) suppressed or prevented the attacks. Furthermore, contrary to the effect of the a-adrenergic stimulator, a.b-adrenergic stimulator (isoproterenol) did not elicit pain or ST-segment changes. Additional in- 712 GOFFREDO G. GENSINI formation scattered in the literature complements the observations of the Japanese authors. For instance, Prinzmetal et al 4 were able to prevent the pain episodes with a.b-adrenergic stimulator ( nylidrin). The efficacy of a "pure" smooth-muscle relaxant, nitroglycerin, in preventing or suppressing the attacks, or both, is universally recognized. Recently, E. K. Shirey (personal communication, 1974) and Hanna 19 have reproduced the pain and the arteriographic evidence of spasm with a "pure" vasoconstrictor, ergonovine (Table 1). I believe that sufficient information has been gathered at this time to fit together all the many pieces of the puzzle and build a working hypothesis, based on factual evidence, for the pathophysiology of spasm-induced angina. During periods of inactivity, but more markedly so between 12 o'clock midnight and 6 AM, there is a diminution of circulating catecholamines and an increase in parasympathetic activity. Concomitant with the reduced metabolic demand and the diminished coronary blood flow, there is a reduction in caliber of the large coronary arteries, possibly related to the low level of circulating.b-adrenergic stimulator (vasodilator) substances. According to Y asue et al, the enhanced parasympathetic activity may, upon reaching a given threshold, produce an acetylcholine-mediated release of norepinephrine from the postganglionic sympathetic nerve terminals of the heart, acting on the a-adrenergic ( vasoconstrictor) receptors of a large coronary artery and resulting in its spasm. Another possible explanation is the existence of well-proved sympathetic-parasympathetic interactions;20 inappropriate phasing in the blood levels of the sympathetic and parasympathetic substances may potentiate vasoconstrictor stimuli and trigger vasospasm in susceptible portions of the coronary arteries. This phenomenon could occur simply because of a temporarily inappropriate onset in the rising phase of catecholamine production or be triggered by the same mechanism associated with the onset of the rapid eye movement period of sleep. 21

5 Interestingly, all of these phenomena are triggered by acetylcholine and suppressed by atropine and by a-adrenergic blockers. The lead provided by these preliminary observations and hypotheses should indicate the need for further investigations into the mechanisms and pharmacodynamics of coronary vasomotion and of sympathetic-parasympathetic interactions. The poor results obtained with coronary bypass surgery in cases of Prinzmetal's angina 22 should stimulate efforts directed toward the prevention of clinically significant coronary spasm by pharmacologic means or, failing those, toward the exploration of innovative surgical approaches. REFERENCES 1 Osler W: The Lumlein lectures on angina pectoris. Lancet 1:839, White PD: The historical background of angina pectoris. Mod Concepts Cardiovasc Dis 43: 109, Prinzmetal ~ I: Coronary artery disease. Presented at the third annual postgraduate course of the American College of Chest Physicians, Los Angeles, Dec 11, Prinzmetal M, Kennamer R, ~ 1 e r lr, i set s al: Angina pectoris: l. A variant form of angina pectoris: Preliminary report. Am J Med 27:375, Gensini GG, Di Giorgi S, Murad-Netto S, et al: Arteriagraphic demonstration of coronary artery spasm and its release after the use of a vasodilator in a case of angina pectoris and in the experimental animal. Angiology 13:550, West JW, Guzman SV: Coronary dilatation and constriction visualized by selective angiography. Circ Res 7 :527, Maseri A, Mimmo R, Chierchia S, et al: Coronary artery spasm as a cause of acute myocardial ischemia in man. Chest 68: , Sones FM Jr, Shirey EK: Cine coronary arteriography. Mod Concepts Cardiovasc Dis 31 :735, Demany MA, Tambe A, Zimmerman HA : Coronary arterial spasm. Chest 53: , Dhurandhar RW, Watt DL, Silver MD, et al: Prinzmetal's variant form of angina with arteriographic evidence of coronary arterial spasm. Am J Cardiol 30:902, Hurst JW, Logue RB : The Heart (2nd ed). New York, McGraw-Hill, Hurst JW, Logue RB, Schlant RC, et al: The Heart, Arteries and Veins (3rd ed). New York, McGraw-Hill, 1974, p Berndt TB, Fitzgerald JW, Harrison DC, eta!: Coronary artery spasm in unstable angina? Comparison of hemodynamic changes during pacing-induced and spontaneous pain. Circulation 50 ( suppl 3) : 215, Lange RL, Reid MS, Tesch DD, et al: Nonatheromatous ischemic heart disease following withdrawal from chronic industrial nitroglycerin exposure. Circulation 46:666, Guazzi M, Polese A, Fiorentini C, et al: Left ventricular performance and related hemodynamic changes in Prinzmetal's variant angina pectoris. Br Heart J 33:84, 1971 Yasue H, Touyama M, Shimamoto M, et al : Role of automatic nervous system in the pathogenesis of Prinzmetal's variant form of angina. Circulation 50:534, Gensini GG, Kelly AE, DaCosta BCB, et al: Quantitative angiography: The measurement of coronary vasomobility in the intact animal and man. Chest 60: , Wertheimer L, Hassen A, Delman A, et al : Cardiovascular circadian rhythm in man. In Chronobiology ( Scheving LE, Halberg F, Pauly JE). Tokyo, lgaku Shoin, Hanna MA : Prinzmetal angina and coronary artery spasm. Presented at the Scientific Session of the Cardiac Laboratory Fellows Reunion, Cleveland, Oct 18, Levy MN: Sympathetic-parasympathetic interactions in the heart. Circ Res 29:437, Jouvet M: Biogenic amines and the states of sleep. Science 3:32, Gaasch WH, Lufschanowski R, Leachman RD, et al: Surgical management of Prinzmetal's variant angina. Chest 66: , 1974 CORONARY ARTERY SPASM AND ANGINA PECTORIS 713