Variable susceptibility to dynamic coronary obstruction: An elusive link between coronary atherosclerosis and angina pectoris

Variable Susceptibilityto Dynamic Coronary Obstruction: An Elusive Link Between Coronary Atherosclerosis and Angina Pectoris AlTlLlO

MASERI, MD, SERGIO CHIERCHIA, MD, GRAHAfvl J. DAVIES, MB, MRCP, and KIM M. FOX, MB, MRCP

Growing evidence suggests that dynamic coronary obstructions play an important but elusive role in the genesis of ischemic events. Dynamic coronary obstructions can develop during certain phases of coronary disease as a result of a variable combi-

nation of vasoconstriction, arterial wall lesions, and increased thrombotic tendency. In a certain phase of their disease some patients develop dynamic coronary obstruction, while others with a similar degree of fixed atherosclerotic obstruction do not.

Myocardial infarction and sudden death are much more likely to occur in angina pectoris of recent onset and during the waxing of symptoms than in the stable phases. If patients are to be managed rationally, it is important to know whether the onset and spontaneous variability of angina is caused predominantly by the progression of atherosclerotic coronary obstructions or by dynamic events that only transiently interfere with regional myocardial oxygen supply. The investigators who specifically addressed themselves to this question favor the second hypothesis for most patients. Angiographic studies show that the severity of coronary atherosclerotic lesions is similar in stable and unstable angina.l-3 Further, the waning of symptoms is not associated with detectable development of collateral vessels.* Continuous hemodynamic monitoring”9 and pacing tests*JO showed that attacks at rest are not caused by an excessive increase of myocardial demand. The disparate coronary artery findings in patients with electrocardiographically documented angina at resPJ2 and, in particular, the recurring observation that about 10% of them have no detectable coronary stenosis13J4 lend support to the hypothesis that transient coronary obstructions caused by smooth muscle contraction or by transient intraluminal plugging by blood constituents, rather than the severity of atherosclerotic obstructions by itself, are the common denominator of the onset of angina and a sudden worsening of symptoms.

Dynamic stenosis occurs in some patients but not in others with comparable severity of atherosclerotic obstructions. Even in the same patient, there is variability from severe angina to improvement and even disappearance of pain for variable periods. These transient coronary obstructions are an elusive link between coronary atherosclerosis and clinical manifestations of ischemic heart disease. They are detectable at the very moment acute events take place, but not in routine angiograms or in postmortem studies. Together with the severity of fixed atherosclerotic coronary obstructions and with the impairment of contractile function, they determine both the symptoms and prognosis of ischemic heart disease. In this report, we discuss the possible mechanisms of transient coronary obstructions, the relation between the dynamic factors and fixed atherosclerotic plaques, and their clinical implications.

The Turning Point The major advance in our understanding of ischemic heart disease in the 1970s was the demonstration that decreased myocardial demand was not the only cause of angina.5-g Other mechanisms that only transiently interfere with myocardial oxygen supply can cause acute myocardial ischemia in the presence of an extremely variable degree of coronary atherosclerosis.15 The second important finding was the angiographic observations of transient obstruction or critical narrowing of apparently normal as well as of atheromatous epicardial coronary arteries during spontaneous angina1 episodes,16 and the progressive reduction in the incidence of total coronary occlusion in the immediate hours and days after acute infarction, suggestive of early spontaneous recanalization.

From the Cardiovascular Research Unit, Royal Postgraduate Medical School, Hammersmith Hospital, London, England. Address for reprints: Attilio Maseri. MD, Cardiovascular Research Unit, Hammersmith Hospital, Ducane Road, London W12 OHS, England.

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Thus, routine angiographic studies performed when the patient is stable (and not during the acute episode) and postmortem examinat.ion may not necessarily reflect the state of the coronary arteries during acute events. The problem is even more complicated in the patient with typical angina pecto-ris, usually exertional, who shows ischemic electrocardiographic changes, coronary sinus lactate production and pain during pacing, but has a normal coronary angiogram.17 Such patients appear to have a reduced vasodilatory response to dipyridamole but no transient coronary obstruction. Thus, should this syndrome occur in patients who may have coronary plaques, one is tempted to attribute the cause of the ischemic episodes to these plaques without searching for other causes. The prevalence of the syndrome is unknown. Although clinically troublesome, it seems to have a good prognosis. Fixed and Dynamic Coronary Artery Obstructions Although either fixed or dynamic obstructions individually may be responsible for ischemic syndromes, their combination will have an enhanced influence on the symptoms and prognosis. A dynamic obstruction in a normal coronary tree is less likely to have devastating consequences than when thlere are multiple critical fixed obstructions. Conversely, even quite severe atherosclerotic narrowings may not cause symptoms if adequately compensated for ;bycollaterals and if there is not an excessive increase of myocardial metabolic requirement. Under certain conditions, atherosclerotic plaques may, however, favor the development of dynamic obstructions. Fixed !Stenosis An acute 85% diameter reduction of coronary lumen is required to reduce resting coronary flow.18 Poststenotic pressure is reduced; this favors collateral flow. The number of collaterals and their response to pressure gradients may vary considerably among persons. Thus, the same degree of stenosis may limit considerably coronary flow reserve in patients with poor collateral development, but may be compensated for in others who have adequate collateral development, as in dogs. This difference in development of collaterals is best appreciated angiographically when the collaterals are large; it may be missed when they are small but numerous. If stenoses and collateral development were fixed, the impairment of coronary flow reserve should also be constant and ischemia would occur only and every time myocardial demand exceeds coronary flow reserve. Clinically, this situation should correspond to a rather fixed, predictal& impairment of exercise tolerance and not to ischemia that occurs without detectable cause or at low levels of heart work. Dynamic Stenoses Dynamic stenoses are defined as changes in the caliber of epicardial coronary arteries that are transient, and therefore may not be detected postmortem or on routine angiography. We shall discuss the role of passive

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changes due to alterations in transmural pressure, of smooth muscle contraction, and of intravascular plugging. Passive changes in vessel caliber: A recent series of studies1gy20 examined passive rather than active changes in caliber at the site of coronary stenosis in response to changes in transmural distending pressure. This mechanism, described by Burton21 several years ago, predicts a decrease in lumen when transmural pressure is reduced and vessel closure when inflow pressure becomes lower than the critical closing pressure of the vessel. However, flow may not be influenced by the changes in lumen if the vessels are indeed collapsible. In the absence of active tone, a reduction of outflow pressure (pressure at the venous side) in a collapsible vessel does not result in cessation of flow because a waterfall, or sluice, phenomenon takes place and the vessels behave like Starling resistors. Thus, the difference between inflow pressure and extravascular pressure at the site of the collapsible vessels becomes the driving pressure, and the level of outflow pressure becomes irrelevant as long as it is lower than extravascular pressure. In dogs with acute coronary stenosis produced with a snare to the point of preventing reactive hyperemia, a decrease in flow was observed after distal arteriolar dilatation.22 We reproduced this phenomenon in carotid arteries of dogs without active tone only when the stenosis was produced by a snare: a decrease in flow was observed when distal pressure was reduced to low levels. The findings were opposite when comparable degrees of stenosis are produced by an intraluminal obstruction of similar degree (as it would be in the case of a subintimal plaque). We have shown that the difference in results was related to the inward protrusion of the intima caused by the snare, which is partially opposed by intraluminal pressure.23 Also, isolated human coronary arteries with severe eccentric stenoses in the absence of active tone do not exhibit closure for levels of inflow pressure as low as 50 mm Hg, but they exhibit a waterfall phenomenon when outflow pressure is reduced. The presence of active tone will simulate, to a large extent, an increased extravascular pressure surrounding the collapsible segment. Therefore, vessel occlusion with interruption of distal flow can occur only when smooth muscle tone results in a critical closing pressure higher than inflow pressure. This appears

unlikely unless tone increases.z4 However, a passive wall collapse in an elastic coronary stenosis secondary to a decrease in distending pressure was recently postulated by Ganz25 to explain vessel closure documented angiographically during spontaneous and exertional angina. This proposition appears untenable not only for the reasons discussed earlier, but also because if vascular occlusion were caused only by purely passive hydrodynamic phenomena, ischemic episodes should occur predictably every time perfusion pressure is lowered below a set level in any given patient. Nonetheless, during pacing-induced ischemia we could not find vessel occlusion in 10 consecutive patients (Fox KM, Davies GJ, Chierchia S, unpublished observations) .

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Coronary smooth muscle contraction: Coronary spasm has become an accepted cause of variant angina26 and other ischemic syndromes.27 Recently, computerized measurements of coronary artery caliber on high-quality biplane angiography2s have proved that at the site of severe organic narrowings, considerable coronary artery constriction can occur. This was seen during physiologic stimuli such as isometric exercise or cold pressor, and, conversely, considerable dilatation was produced by nitroglycerin. Thus, smooth muscle contraction in epicardial coronary arteries appears to be a cause of transient impairment of coronary blood supply. As pointed out by Prinzmetal et al2g and theoretically discussed by Ma&pin, 3othe increase of smooth muscle tone required to impair flow in a coronary artery branch could be small at the site of a subintimal plaque which already critically encroaches upon the lumen. Eccentric stenoses represent >70% of obstructions in coronary arteries, and they retain sufficient flexibility to be constricted by smooth muscle contraction.31,32 Subintimal plaques can act as levers on the surrounding smooth muscle medial coat of the vessel so that even minimal changes in circumferential shortening can lead to a considerable reduction of the lumen. Conversely, the increase in smooth muscle tone must be considerable to impair flow in a normal segment of the vessel. On the basis of this consideration, MacAlpin suggested that normal changes in vasomotor tone may impair flow at the site of large subintimal plaques, whereas coronary spasm would more likely cause a reduction or impairment in the lumen in arteries without subintimal obstructions. On the basis of the present evidence we would, however, propose that both changes in vasomotor tone and spasm or abnormal changes in vasomotor tone can be responsible for vasoconstriction, but probably have different mechanisms. Physiologic changes in vasomotor tone mainly control increases in flow across a stenosis at any given time and modulate the threshold for spasmogenic stimuli.3s Increased vasomotor tone most likely contributes to the varying effort tolerance observed in patients in daily life, particularly in the cold or after meals, to the “walkthrough” phenomenon, and to ischemia that occurs or worsens immediately after strenuous exercise. We believe physiologic changes in vasomotor tone per se do not explain variant or spontaneous angina, because they are rare compared with the frequency of severe, obstructive plaques. These syndromes may occur only at certain times, and the constriction may not always occur at the site of the most severe atherosclerotic narrowing. Also, angiographic measurements during spasm do not support MacAlpin’s hypothesis, because the calculated increase in tone is greater at the site of spasm than in other segments of the vesse1.34 Coronary artery spasm may be caused by abnormal constrictive stimuli or by local supersensitivity to physiologic stimuli. These factors may explain the onset of spontaneous, unpredictable ischemic episodes more than passive changes in vessel lumen or physiologic changes in vasomotor tone alone for two reasons: (1) The spontaneous recurrence of angina interspersed with

relative asymptomatic phases of the disease, so often observed in patients with angina at rest, suggest waxing and waning of some transient pathophysiologic mechanism. (2) Should passive changes in the lumen or increase in physiologic vasomotor tone play a major role per se, “spontaneous” angina should be much more frequent than is usually observed in patients with severe atherosclerotic narrowings. Although coronary artery diameter may decrease on the average by about 20% after ergonovine35 or during handgrip exercise,2s ergonovine is only positive in a minority of patients and only when they are in a hot phase of their disease,36 independent of the severity of their organic coronary artery narrowings. The mechanisms of coronary smooth muscle control are still speculative. Multiple receptors responsible for vasoconstriction have been identified in normal and in atherosclerotic segments of human coronary arteries.37 Their role in the physiologic regulation of tone and in abnormal constriction is still poorly understood and is outside the scope of this report. Thrombosis, thrombolysis, and platelet activation: The relationship between thrombus and myocardial infarction has been questioned on the basis of the extremely variable frequency with which postmortem studies showed a fresh occlusion in patients who died after myocardial infarction.38 Postmortem studies represent a selection of large infarcts that are more likely to cause death and describe a static picture that may not reflect the situation at the very onset of myocardial infarction. Indeed, between the time of onset of infarction and that of the examination, thrombi can form or extend as well as undergo early lysis. Radiofibrinogen studies have indicated progressive late thrombus formation.3g*40 Conversely, angiography early after infarction showed complete vessel occlusion in 87% of cases within 4 hours of the onset of symptoms but in only 65% and in about 50% of cases when performed after 12 hours4i and after 2 weeks,42 respectively. The cause of occlusion and thrombus formation at a given moment in a given patient, which is the crux of the problem, remains speculative. The mechanisms of occlusion in infarction might be related to those of spontaneous angina, because infarction is frequent in angina of recent onset or during worsening of symptoms. Also, it usually occurs in the same vascular territory that undergoes transient ischemia caused by transient spasm.43-45 Platelet aggregation was shown to cause transient complete vascular occlusion in dogs at the site of an acute, severe stenosis.4a,47 We observed at postmortem examination a mural thrombus composed of platelets and fibrin about 1 cm distal to the site of a complete occlusion that had been shown angiographically to be irreversible.4s Platelet aggregation may be responsible for intraluminal plugging and may initiate thrombus formation, particularly when acute intimal damage is large, the balance between coagulation and lysis favors coagulation, and spasm is superimposed. Early lysis of thrombi or resolution of spasm, or both, can result in recanalization within a few hours or days; however, it may set the conditions for recurrent episodes of angina

July 20. 1993

pectoris caused by spasm or by transient intraluminal plugging. Potential vicious circle: There may be a close interrelation between coronary smooth muscle constriction, intimal injury, and platelet activation and thrombosis. In normal arteries, intimal damage was documented after intense smooth muscle constriction.4s,4g In diseased arteries repeated or prolonged spasm under some circumstances may cause plaque rupture. The exposure of collagen elicits platelet activation and may initiate aggregation and thrombosis. Alternatively, platelet aggregation and thrombosis that forms because of a primitive intimal injury can result in intense coronary constriction because of the release of thromboxane AZ, serotonin and thrombin. The repeated observatmn that in patients with variant angina, spasm usually occurs several times a day for long periods of time without causing permanent occlusion, and that disruption of plaques by transluminal angioplasty causes severe coronary spasm or thrombosis in only about 5% of cases, suggests the existence of protective mechanisms. Thus, a vicious circle can develop only when a set of unfavorable circumstances converge to favor intimal damage, thrombosis and smooth muscle contraction. This concurrence of unfavorable circumstances can be expected to take place only in some patients and only at a particular time, making them particularly susceptible to dynamic occlusion.

Variable susceptibility to dynamic obstructions: With the exception of angina in stationary phases, ischemic events are typically episodic. Isolated angina1 attacks can occur occasionally, separated by months or years. Infarction can occur unheralded or preceded by few angina1 attacks. Recent-onset angina or worsening periods begin unpredictably, sometimes rapidly culminating in infarction, but more often diminish and even disappear for months or years.so-5s Waxing and waning periods are also common in stable exertional angina. Should ischemic events occur as a consequence of a slow, progressive atheroscllerotic narrowing, one might expect angina to appear for the first time during unusual increases of myocardial demand and, subsequently, progressively limit exercise tolerance. However, common clinical experience indicates that only occasionally does the first angina1 attack occur during unusually heavy exertion; most often it occurs without apparent cause or during activities well tolerated both before and after the attack. Although it is often assumed that waning of symptoms is largely due to the development of collaterals, this possibility could not be substantiated by repeated arteriography in the study of Neil1 et a1,4 specifically designed to te:st the hypothesis. There are several explanations as to why the individual susceptibility to dy:namic obstruction may vary. First, a particular phase of the development of the atherosclerotic plaque may favor both smooth muscle contraction and intimal lesions. Second, abnormal vasoconstrictor stimuli or an increased vasomotor tone or both are most likely to occur occasionally. Finally, the increased thrombotic tendency that may favor an ex-

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FIGURE 1. The possible determinants

of prognosis and symptoms in ischemic heart disease. The major determinant of prognosis are ventricular function, the severity of fixed atherosclerotic lesions, and the susceptibility to dynamic stenoses. Hypothetical alterations of the small vessels and of myocardial metabolism may be responsible for angina but probably do not affect prognosis.

aggerated response to intimal injury also seems to be transient.53 As discussed before, these conditions may occur in 1 person but not in another, and may be present only during certain periods of life.

Clinical Implications Symptoms and coronary atherosclerosis: The large variability in the relationship between severity of atherosclerotic coronary narrowings and symptoms may be explained to a considerable extent by 2 additional variables. On the 1 side, the individual response of collateral development for a given fixed,stenosis conditions the severity of impairment of coronary flow reserve and, therefore, maximal exercise tolerance. On the other side, the variable susceptibility to dynamic stenosis conditions the appearance of ischemic episodes for levels of heart work, hence of myocardial oxygen requirement, which are well within the possibilities of the actual residual coronary flow reserve of the patient. This latter form of angina, also called “primary,“N,55 may be caused also by mechanisms other than dynamic stenosis, namely by alterations of the small vessels or the myocardium or both (Fig. 1). Determinants of prognosis: Although the relationship between severity of coronary stenosis and symptoms is quite variable, both elements appear to influence prognosis. In all published series the mortality at 5 years increases progressively with the number of diseased vessels found at arteriography, but mortality and infarction are higher among patients with unstable than with stable angina, in spite of no detectable differences in the severity of coronary atherosclerosis. We propose that this difference is largely related to the role of dynamic coronary stenoses. A greater susceptibility to dynamic stenoses could account, at least in part, for the mortality rate reported for patients with good ventricular function by Bruschke et a1,56which was twice as high as that of the Coronary Artery Surgery Study57 (Fig. 2). Patients referred to the Cleveland Clinic in the 1960s must have been much more symptomatic than those included in the CASS study (and not operated upon) in the 1970s. The &year mortality rate increases progressively with the degree of impairment of exercise

CORONARY ATHEROSCLEROSIS AND VASOSPASM

80

60 50 40 FIGURE 2. Five-year mortality in the series of Bruschke

30

et al5s (severely symptomatic patients, closed symbols) and in the Coronary Artery Surgery Study (CASSy7

20

disease; squares, P-vessel disease; triangles, 3-vessel

(nonoperated patients, open symbols). (Circles, l-vessel

10 0

I

I

I

J

Normal I nfaret Cond. Repot. Dist. Dist.

1 Normal

tolerance assessed by stress testing58; we interpret this as a more severe fixed impairment of coronary flow re-

serve (resulting from the balance between severity of stenoses and development of collaterals). Therefore, among patients with good ventricular function, it may become possible to identify subsets with an unfavorable prognosis because of poorer collateral development, greater susceptibility to dynamic obstructions, or both. The role of these prognostic determinants may be obscured by the presence of poor left ventricular function, which is, by itself, the major determinant of prognosis and was not appreciably different in the series of Bruschke et aP and in the Coronary Artery Surgery Study.57 Rational basis for therapy and prevention: Therapy of angina is still largely dominated by the primary aim of reducing myocardial oxygen requirements. The favorable response to beta blockers is used to validate this concept, but it is naive to assume that beta blockers have only this effect or that they act only through this mechanism. This attitude is reminiscent of that in the 195Os, when nitrates were thought to be effective because they increased myocardial blood flow. The hypothesis of an increase of myocardial demand exceeding coronary flow reserve was not supported by objective measurements, not only in patients with angina at rest but also for most episodes that occur during ambulatory monitoring of the electrocardiogram5g*60 in patients with stable angina. Thus, a transient impairment of myocardial oxygen supply may play a dominant role in angina. The role of dynamic stenosis in angina is beginning to be appreciated,61,s2 but it may have multiple mechanisms.63 The identification of the role and varied mechanisms of dynamic stenoses help prevent angina1 attacks caused by a transient impairment of flow rather than by an excessive increase of demand.

I Poor L.V.

disease.) Although the mortality rate is similar in both studies for patients with poor left ventricular function, it is about one half in patients with normal ventricular function in the CASS study. Although the effects of changing medical therapy cannot be excluded, part of the difference may be that the patients in the series of Bruschke et al56 were more symptomatic for comparable severity of coronary atherosclerosis because susceptibility to dynamic obstructions.

of greater

The prevention of dynamic stenoses and the assessment of coronary flow reserve by stress testing should help to identify the subset of patients who will benefit most from revascularization. References 1. Eetes EH, Entman HL, Dixon HB, Hackel DB. The vascular supply of the left ventricular wall. Anatomic observations plus a hypothesis regarding acute events in coronary artery disease. Am Heart J 1966;71:58-67. 2. Fuater V. Fwe RL. Connollv DC. Danielson MA. Elveeack LR. Kurland LT. Arteriogiaphic pakerns eaily in.the onset of the coronary syndromes. Br Heart J 1975:37:1250-1255, 3. Neil1 WA! Rlizmann LW, Selden R. The pathophysiologic basis of acute coronary Insufficiency. Observations favoring the hypothesis of intermittent reversible coronary obstruction. Am Heart J 1977;94:439-444. 4. Nell1 NE. Wherton T, Flurl-Lumdeen J, Cohen I. Acute coronary insufficiency. Coronary occlusion after intermittent ischemic attacks. k Engl J Med 1980;302:1157-1162. 5. Mawr1 A, Mlmmo R, Chierchia S, Marchesi C, Peeola A, L’Abbate A. Coronary spasm as a cause of acute myocardial ischemia in man. Chest 1975;68:625-633. 6. Guazzi M. Polese A. Fiorentinl C. Maarini F, Olivari MT. Bartorelll C. Left and right. heart ha&nodynamic$ duiing spontaneous- angina pectoris. Comparison between angina with ST segment depression and angina with ST segment elevation. Br Heart J 1975; 37:401-413. 7. Flgueras J, Singh BN, Ganz W. Mechanisms of rest and nocturnal angina; ObSeNatiOnS during continuous hemodynamic and electrocardiographic monitoring. Circulation.1979;59:955-968. 8. Figueras J, Singh BN, Ganz W. Haemodynamic and electrocardiographic accompaniments of resting postprandial angina. Br Heart J 1979:42: 402-409. 9, Chierchia S, Lazxarl M, Simonettl I, Maaeri A. Haemcdynamic monitoring in angina at rest. Herz 1980;5:189-193. : 10. Berndt TB, Fitzgerald J, Harrison DC, Schroeder JS. Hemodynamic changes at thg onset of spontaneous versus pacing-induced angina. Am J Cardiol 1977;363784-788. 11. King SB, Douglas JS. Coronary arteriography and left ventriculography. In: Hust JW. Logan RB, Jeffert RC. Wen&n NR. eds. The Heart. 4th ed. New York: McGraw-Hill, 1978:397-416. 12. Papapletro SE, Nleae OS, Paine TD, Mantle JA, Rackley CE, Rueaell RO, Rogers WJ. Transient electrocardiographic changes in patients with unstable angina: relation to coronary arterial anatomy. Am J Cardiol 1980; 48:28-33. 13. Bertolasl CA, Tronge JE, Carreno CA, Jalon J, Ruda Vega Y. Unstable angina--prospective and randomized study of its evolution. with and without surgery. Am J Cardiol 1974;33:201-208. 14. Nat&l Cooperative Study Group to Compare Medical and Surgical Therapy in Unstable Anaina Pectoris. I. Reoort of orotocol and oatient oooulation. Am J Cardiol 1376:37:896-902. 15. Chlerchla S. Brunelli C. Slmonetti I. Lazzari M. Maseri A. Seauence of events in anbina at rest! primary reduction in cbronary flow. Cjrculation

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1980;61:759-768. 16. Maseri A, L’Abbate A, Pesola A, Baiieetra AM, Marrlili M, Meltinti G, Severi S, DeNes DM, Parodi 0, Biagini A. Coronary-vasospasm in angina pectoris. Lancet 1977;1:713-717. 17. Opherk D, Zebe Ii, Welhe E, MelI G, Durr C, Graverl B, Mehmel HC, Schwarz F, Kubler W. Reduced coronary dilatory capacity and ultrastructural changes of the myocardium in paltients with angina pectoris but normal coronary arteriograms. Circulation 1981:63:817-825. 16. Gould KL, Llpscomb K, Hamllton SW. Physiologic basis for assessing critical coronary stenosis. Am J Cardiol 1974;33:87-94. 19. Santamore WP, Walk&y P. Altered coronary flow responses to vasoactive drugs in the presence of coronary internal stenosis in the dog. Am J Cardiol 1980;45:276-285, 20. Swarlz J, Carlyle P, Cohn JW. Effect of dilatation of the distal coronary bed on flow and resistance in severety stenotic coronary arteries in the dog. Am J Cardiol 1979;43:219-224. 21. Burton AC. Physical principles of circulatory phenomena: the physical equilibria of the heart and blood vessels. In: Hamilton WF, Dow P. eds. Circulation, Handbook of Physiology. Washington, DC: American Physiological Society, 1962:85-106. 22. Walinsky P, Santamore WP, Wiener L, Breet A. Dynamic changes in the haemcdynamic severity of coronary artery stenosis in a canine model. Cardiovasc Res 1979;13:113-118. 23. van Arnim T, Crea F, Chlerchla S, MaserI A. Influence of the type of stenosis on passive luminal changes in the dog carotid artery. Proceedings of the 4th International meeting on Atherosclerosis. Bologna: 1981;187-189. 24. Logan S. On the fluid mechanisms of human coronary artery stenosis. IEEE Trans Biomed Eng 1975;22:327-334. 26. Ganz W. Coronarv soasm in mvocwdial infarction:fact cr fiction? Circulation 1981;63:487-488. ’ . 26. Meller H, Pkhard A! Da& S. Coronary arterial spasm in Prinzmetal’s angina: a proved hypotheses. AmJ Cardiol 1976;37:938-940. 27. Hlllls LD, Braunwald E. Coronary artery spasm. N Engl J Med 1978;299: 695-702. 26. Brown BG, Solson E, Petersen RB, Rlever CD, Dodge HT. The mechanisms of nitroglycerin action: stenosis vasodilatation as a major component of the drug response. Circulation 19131;69:1089-1097. 29. Prinzmetal M, Kennamar R, Merliss R, Wada T, Bor N. Angina pectoris. 1. A variant form of angina pectoris. Am J Med 1959;27:375-88. 30. MacAipin RN. Contribution of dynamic vascular wall thickening to luminal narrowina durina coronarv arterial constriction. Circulation 1980:61: 296-301: . 31. Leary T. Coronary spasm as a possible factor in producing sudden death. Am Heart J 1935:10:338-344. 32. Vlodaver Z, Edwards JE. Pathology of coronary atherosclerosis. Prog Cardiovasc Dis 1971;14:256-259. 33. Yasue H, Omote S, Taklzawa A, Nagao M, Ylwa R, Tanaka S. Circadian variation of exercise capacity in patients with Prinzmetal’s variant angina: the role of exercise-induced coronary arterial spasm. Circulation 1979; 59:938-948. 34. Freedman SB, Rkhmond DR, Kelly DT. Pathophysiologyof coronary artery spasm. Circulation 1982:66:705-709. 35. Curry RC, Pepine CJ, Sabom BM, Feldman RL, Chrlstle LO, Contl CR. Effects of ergonovine in patients with and without coronary artery disease. Circulation 1977;56:803-809. 36. Bertrand ME, Lablanche JM, Tllmant PY, Thleuleex FA, Delferge YR, Carre AG, Asseman P, Berrin B, Llbersa C, Laurent JM. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation 1982;6!%1299-1306. 37. Ginsburg R, Brlstow MR, Harrison DC, Stlnsten EB. Studies with isolated human coronary arteries: some geineral observations, potential mediators of spasm, role of calcium antagonists. Chest 1980;78(suppl):180-186. 36. Baroldl G. Acute coronary occlusion as a cause of myocardial infarct and sudden coronary heart death. Am J Cardiol 1965;16:859-880. 39. Erhardl LR, Lundman T, Mellstedt Ii. Incorporationof 1251-labelledfibrinogen into coronary arterial thrombi in acute myocardial infarction in man. Lancet 1973;1:387-390. 40. Fulton WFM. Does coronary thrombosis cause myocardial infarction or vice-versa? In: Weatherall DJ, ed. Advanced Medicine, Royal College of Physicians, London: Pitman Medical, 1978:14-15.

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41. De Wood M, Spores J, Noteke R, Mweel L, Burroughs R, Goiden M, Lang H. Prevalence of total coronary occlusion during the early hours of transmural myocardial infarction. N Engl J Med 1980;303:897-902. 42. Bertrand ME, Lelebvre JIM, Laiene CL, Rousseau MF, Carre AG, LekieBre JP. Coronary arteriography in acute transmural myocardial infarction. Am Heart J 1978;97:61-69. 43. Maseri A, L’Abbate A, Baroidi G, Chlerchla S, Marziiii M, Baiieetra AM, Sever1 S. Parodl 0, Blaelnl A, Metante A, Pesoia A. Coronary vasospasm as a possible cause of myocardial infarction: a conclusion derived from the study of preinfarction angina. N Engl J Med 1978;299:1271-1277. 44. Maser1 A, Chierchla S, L’Abbate A. Pathogenetic mechanisms underlying the clinical events associated with atherosclerotic heart disease. Circulation 1980:62:SuooI V:V-3-V-13. 45. Mad& JE. The syndrome of variant angina culminating in acute myocardiil infarction. Circulation 1979;59:297-306. 46. Folis JD, Crowell EB, Rowe GG. Platelet aggregation in partiilly obstructed vessels and its elimination with aspirin. Circulation 1976:54:365-370. 47. Alken JW, Gorman RR, Shebuekl RJ. Prostacyclin prevents blockage of oartiallv obstructed coronarv arteries. In: Vane JR. Berastrom S, eds. Prostacyclin. New York: Raven Press, 1979:65-67. 46. Gertz DS, Uretsky 0, Rebecka S, Wajnberg M, Navot N, Gotsman MS. Endothelial cell damaae and thrombus formation after oartial arterial constriction:relevance to Iti role of coronary artery spasm’in the pathogenesis of myocardial infarction. Circulation 1981;63:476-466. 49. Jorls I, Majno G. Endothelial changes induced by arterial spasm. Am J Physiol 1980;102:346-358. 50. Duncan 8, Fulton M, Morrison SL, Lutz W, Donald KW, Kerr F, Kirby BJ, Julian DG, Oliver MF. Prognosis of new and worsening angina pectoris. Br Med J 1976;1:961-985. 51. Sever1 S, Davies GJ, Maser1 A, Marzullo P, L’Abbate A. Long term prognosis of variant angina with medical treatment. Am J Cardiol 1980;46: 226-231. 52. Kannel WB, Sorlle PD. Remission of clinical angina pectoris: the Framingham study. Am J Cardiol 1978;42:119-123. 53. Nerl Sernerl GG, Genslnl GF, Abbot1 R, Mugenelnl C, Fevllla S, Bruneiil C, Chlerchla S, Parodl 0. Increased fibrinopeptide A formation and thromboxane A2 production in patients with ischemic heart disease: relationships to coronary pathoanatomy, risk factors and clinical manifestations. Am Heart J 1981;42:185-194. 54. Maser1 A. Preface. In: Maseri A, Klassen GA, Lesch M. eds. Primary and Secondary Angina Pectoris. New York: Grune & Stratton, 1978:X111-XIV. 55. Maser1 A. Pathogenetic mechanisms of angina pectoris: expanding views. Br Heart J 1980;43:648-660. 56. Bruechke AVG, Proudflt WL, Sones FM. Progress study of 590 COnSeCutive ,non-surgtcal cases of coronary, disease followed 5-9 years. 11. ~~$culographtc and other correlabons. Circulation 1973:57:t t5457. Mock MB, Flrher L, Kllllp T, Alderman EL, Aueten WG, Bouraesa MA, Brooks H, Cohen LS, Frommer PL, Frye RL, Giaeeman E, Goeeeiin AJ, Harlhorne JW, Judkins MP, Kaiser GC, Kemp HG, McKneaily MF, Mudd JG, Myers W, Paeeamanl E, Rlngqvlel I, Rogers WJ, Rueeeii RO, Ryan TJ, Sautter RD, Sheffleld T, Sosa JA, Trietanti F, Fray D. The natural history of non-ooeratecloatients with ischemic heart disease: the CASS exoerience. in press: 56. Elleslad MH. Prognostic value of stress testing. In: Loogen F, Seipel L, eds. Detection of lschemic Myocardium with Exercise. New York: Springer Verlag, 1982:77-83. 59. Schang SJ Jr, Peplne CJ. Transient asymptomatic S-T segment depression during daily activity. Am J Cardiol 1977;38:396-401. 60. Deanfield JE, Fox KM, Rlbelro P, Crean P, Chlerchla S, Maeerl A. Instability of stable angina pectoris. Clin Sci, in press. 61. Brown BG. Coronary vasospasm: observations linking the clinical spectrum of ischemic heart disease to the dynamic pathology of coronary atherosclerosis. Arch Intern Med 1981;141:716-722. 62. EpQteln SE, Talbot TL. Dynamic coronary tone in precipitation, exacerbation and relief of angina pectoris. Am J Cardiol 1981;46:797-803. 63. Wolf NM, Mandelkorn J, Slngh S, Leo LR, LaPorte S, Barrett M, Melster S. Evidence for thrombosis in acute ischemic syndromes other than transmural infarction (abstr). Circulation 1981:84:Suppl IV:IV-197.