Vasotonic myocardial ischemia

CURRICULUM IN CARDIOLOGY

Vasotonic

myocardial

Tali T. Bashour, MD. Sun Francisco,

ischemia Calif.

The concept that myocardial ischemia can be directly related to enhanced coronary vasomotor tone is now widely accepted. Earlier skepticism has, to a large extent, been neutralized by a steady stream of convincing evidence. Doubts, however, remain as to the real incidence of this phenomenon and its precipitating factors. It is also not clear whether coronary vasoconstriction is a primary event or merely a by-product or secondary factor in a more complex histochemical disturbance afflicting atherosclerotic or nearly normal coronary arteries as a result of yet poorly understood mechanisms. Nevertheless, the simplistic view of ischemia as strictly a result of increased myocardial demand has been swept away by the expanding understanding of the dynamic nature of coronary supply. While primary focal spasm of large epicardial coronary arterial segments is admittedly infrequent, other forms of vasoconstriction are probably not. These include spasm superimposed over fixed obstruction, and that occurring during the “hot war” of unstable ischemia as a result of potent vasoactive by-products. Furthermore, reduced coronary flow as a consequence of constriction of smaller prearteriolar, arteriolar, and collateral beds is believed to play a major role in ischemia in the face of normal epicardial coronary arteries. The so called “syndrome X” is an example of ischemia related to increased coronary resistance. It can result from either reduced responsiveness to vasodilating stimuli or increased sensitivity to vasoconstricting stimuli. The role of stress-related release of catecholamines and its detrimental effect on coronary flow is undergoing serious assessment at present. Potential target sites of such a systemic outpouring can theoretically include the whole extent of the coronary vascular bed. Thus increased coronary vascular tone appears to be quite nonhomogeneous. Its causes, severity, From The Western Heart Institute, St. Mary’s Hospital and Medical Center; and the University of California, School of Medicine, San Francisco. Received for publication May 16, 1991; accepted July 1, 1991. Reprint requests: Tali T. Bashour, MD, Western Heart Institute, St. Mary’s Hospital and Medical Center, 450 Stanyan St., San Francisco, CA 94117. 4/1/33074

sites, and associated contributing and interdependent factors exhibit a remarkable degree of variation. A most dramatic form of vasoconstriction is total occlusion of a large epicardial coronary artery as a result of severe segmental spasm. This extreme reaction characterizes patients with variant angina. A less intense but more widespread constriction involves large as well as medium-sized arteries. A third less well-defined form involves intramyocardial branches and precapillary bed. Finally, some patients may suffer from increased coronary vascular resistance without demonstrable vasoconstriction, due presumably to obliterative changes within microvascular beds. The concept of a continuous spectrum presents a plausible approach to the understanding of the dynamic nature shared by these syndromes. On the other hand, viewing each as a separate clinical syndrome facilitates the understanding of the causes, consequences, and therapeutic options available. This review will include current concepts of the pathophysiology and clinical correlations of vasotonic ischemic syndromes. Provocative tests and treatment guidelines will also be addressed. HISTORICAL

PERSPECTIVE

The past decade has witnessed a redirection of thinking about the mechanism of ischemia, with greater emphasis on reduced supply vis-a-vis increased demand. Occurrence of coronary arterial vasoconstriction with or without intraluminal thrombosis has been the center of this thinking. However, to assume that this is a nouveau concept is historically incorrect. It was actually resurrected in modern times and was this time convincingly proven. The proposition that coronary spasm may represent an important mechanism of angina can be traced to work by Lathaml in the last century. Early in this century, Osler2 and later, Lewis3 called attention to the same concept. This sort of thinking later went into oblivion to be remembered only as the “resort of the diagnostically destitute.“4, 5 Thanks to the strong evidence that most patients with angina were found on necropsy to have atherosclerotic coronary artery disease, the increased myocardial demand concept 1701

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enjoyed a comfortable dominance. This quiescence was shattered in 1959 by Prinzmetal’s description of’ unprovoked angina occurring at rest and being associated with transient ST segment elevation, a condition he named “variant” angina.6 To explain this, he proposed coronary vasoconstriction at the site of an atherosclerotic lesion. Actual demonstration of coronary arterial spasm had to await the emergence of coronary arteriography and was first reported by Gensini et a1.7 Variant angina of Prinzmetal, as well as coronary spasm, however, remained as medical curiosities until the early 197Os, when more observations were reported. *-lo “Pure” spasm causing variant angina in patients with normal arteries was then described .by a group (which included the present author), and was called “variant of the variant.“l* At this point, the challenge to the established thinking seemed to be real, but it was nevertheless met by a few enthusiasts, and by many more skeptics and disbelievers. Since 1975, the concept of coronary vasospasm started to gain momentum, thanks largely to the remarkable work of Maseri et a1.12-14The weight of the evidence prompted Meller et a1.15 to declare coronary arterial spasm in Prinzmetal’s angina an all but “proved hypothesis.” Extensive evaluation of vasospastic ischemia followed, including clinical characteristics,16j lT pathophysiologic mechanisms,ls, lg and treatment,lg, so as well as vasospastic ischemia’s possible role in acute myocardial infarction. 21,22 A provocative test using ergonovine maleate was described for the induction of spasm in susceptible arteries.23, 24 The role of exercise was also investigated.25 For reasons that are still poorly understood, the disorder seemed to be substantially more prevalent outside the United States, especially in Italy and Japan. Actually, much of the investigative work in the 1980s was reported from these two countries. Parallel to the work on epicardial coronary artery spasm, interest in a puzzling syndrome of angina in patients with normal or near normal coronary arteriography was periodically surfacing.26, 27 A relationship to stressful life situations was proposed by Bashour et a12sAttention was gradually redirected to the small coronary arteries, as large artery spasm alone did not seem to explain ischemia in all patients with normal coronary arteriograms. The finding by Cannon et a1.2g of reduced vasodilator reserve in the small coronary arteries ushered in a new exciting concept of coronary microvascular dysfunction that dominated the late 1980s. Side by side with this line of thinking, a cardinal role for vasoconstriction was suggested as a catalyst in the vicious circle responsible for unstable angina, myocardial infarction, and

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sudden death.t30-‘32The near future holds promise for further clarification of the mechanism of spasm, its role in the common ischemic syndromes, and the dynamic regulation of the coronary microcirculation. PATHOPHYSIOLOGY

The understanding of vascular reactivity in response to various stimuli has vastly expanded during the last decade. Biochemical reactions originating within the endothelial layer have been intensively investigated. A delicate balance seems to exist between different opposing chemicals released by endothelial cells. This balance can be disturbed by either the lack or the abundance of any of these, rendering the smooth muscle layer vulnerable to systemic and local vasoactive substances. A distinction should be made between the three components of the vascular wall on which different stimuli exert their effects. These include the endothelium, smooth muscle, and nerve endings.“” The net effect, whether vasodilation or vasoconstriction, is dependent on the dominance and overall potency of the particular stimulus. A “physiologic” systemic stimulus may exert an exaggerated action on a vessel rendered vulnerable by local factors. On the other hand, certain potent substances can cause severe myocardial ischemia at very low doses, even in intact coronary arteries. A distinction should also be made between focal or segmental reactivity and generalized constriction along the course of the artery.“‘i Systemic constricting stimuli tend to induce generalized vasoconstriction unless certain segments are “hypersensitive” to their action, in which case the effect is disproportionately strong. It has been established that endothelium-denuded arteries”” and those afflicted with atherosclerosis:“’ are not only more susceptible to vasoconstriction but may also exhibit paradoxical constriction in response to stimuli that normally cause vasodilatation. The cause of reduced coronary vasodilator response in the small coronary arteries is still not fully understood. In this syndrome termed “microvascular angina,” coronary resistance is increased in the absence of epicardial coronary constriction.“” The same systemic, endothelial, or smooth muscle factors discussed earlier may also be operative here. It is widely believed, however, that a yet undiscovered other mechanism may be playing the major role. Large epicardial artery segmental spasm has been implicated in the Prinzmetal variant form of angina,l” including the common form associated with atherosclerotic stenosis and the less common form encountered in angiographically normal arteries.” Arteriolar and small artery vasoconstriction, on the other hand, is considered the mechanism of ischemia

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in the absence of atherosclerosis and large artery spasm. In the following discussion, central and autonomic nervous system vasoactive substances in the circulation and those derived from the endothelium and the platelets will be considered. Central (systemic) vasoconstrictor stimuli. The actions of the three major catecholamines are mediated by the a- and P-receptors. 36 Norepinephrine working via al-receptors produces vasoconstriction in most organs. Epinephrine, on the other hand, while having a similar action in most organs, dilates blood vessels in skeletal muscles and the liver. The actions of dopamine are less well understood, but it seems to cause vasoconstriction by releasing norepinephrine. By contrast, dopamine induces renal and mesenteric vasodilatation caused presumably by a specific dopaminergic receptor. Vasopressin is secreted in the posterior pituitary gland and is a potent vasoconstrictor. Because of a direct myocardial depressant effect, it produces no appreciable increase in blood pressure. Conditions suspected of causing coronary spasm such as pain, emotion, “stress,” and exercise also increase vasopressin secretion. The octapeptide angiotensin II is a generalized vasoconstrictor. It is formed from angiotensin I by the action of renin on circulating angiotensinogen. Angiotensin II’s main function is to maintain adequate blood pressure. Neuropeptide Y is a polypeptide neurotransmitter produced in noradrenergic and adrenergic neurons in the medulla and hypothalamus. It is present in postganglionic sympathetic nerves and produces vasoconstriction. This substance was shown to produce severe myocardial ischemia in patients with angiographically normal coronary arteries. 37,38 On the opposing side, circulating vasodilator substances are also present in the circulation. They include the kinins, namely the nonapeptide bradykinin formed in the plasma by the action of kallikrein, and the atria1 natriuretic peptide (ANP) secreted by the heart. They antagonize the action of vasocontrictors and lower the blood pressure. Endothelium-derived vasoactive substances. The endothelium is the part of the vascular wall consisting of one layer of squamous cells in direct contact with circulating blood. The importance of the endothelial cells in regulating the contraction of the vascular smooth muscle has been the subject of great interest. By liberating several vasoactive substances, the endothelium plays a major role in the pathogenesis of several cardiovascular disorders, coronary vasospasm paramount among them. Endothelin is a recently discovered peptide derived from vascular endothelial cells.3g Its coronary

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vasoconstricting effect was later emphasized.40 Most recently,41 this substance was found to also inhibit myocardial function and contractility, probably by the release of oxygen-free radicals. The endotheliurn-deriued relaxing factor (EDRF) is another substance that still stimulates a great deal of interest and controversy. Its deficiency has been implicated in the pathogenesis of vasospasm. Experimental evidence from studies on porcine42 and canine43 coronary arteries suggests that ergonovine-induced spasm may be mediated by endothelial dysfunction. An intact endothelial function is probably necessary for acetylcholine to exert its relaxation of arterial smooth muscle.44 When damaged by atherosclerosis, the endothelium’s failure to release EDRF may result in acetylcholine-induced vasoconstriction.35* 45 In addition, EDRF inhibits platelet aggregation in vitro.46 This effect may be impaired in hypercholesterolemia47 and may be enhanced in a synergistic manner by prostacyclin. 48 It is almost certain that the loss of EDRF as a result of endothelial injury from balloon angioplasty renders the artery vulnerable to serotonin and other platelet products, with resultant vasoconstriction.4gp 5o The nature of EDRF remains unsettled. Some evidence51 suggests that it is nitric oxide (the final messenger responsible for arterial dilatation induced by nitrate compounds), while other evidence indicates that the two are not the same.52 The production of EDRF is augmented by cod liver oil 53 which may account for the beneficial effect of dietary fish oil on the atherosclerotic process. Platelet-derived vasoactive substances. Several vasoactive substances are released as a result of platelet adhesion and subsequent aggregation and the activation of certain biochemical pathways.54 Serotonin (5HT) is released from intracellular dense granules. It has been implicated alone or in combination with other platelet products in localized vasoconstriction. Activation of another pathway, the platelet membrane phospholipase AZ, leads to the release of arachidonic acid and eventually to the production of thromboxane A2 (TXAs), a process catalyzed by thromboxane synthetase. TXAs is a potent platelet aggregator and vasoconstrictor.55, 56 A still different pathway is stimulated by binding of activated coagulation factors V and X and calcium to the platelet membrane, which accelerates conversion of prothrombin to thrombin. Thrombin in turn catalyzes the conversion of fibrinogen to fibrin and is also implicated as a factor in the interplay of thrombosis and vasoconstriction. Two major horneostatic mechanisms operate to balance the active platelet furnace and to protect the patency of the involved vessel. The first results from

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stimulation of adenyl cyclase in adjacent intact endothelial cells with production of cyclic adenosine monophosphate (CAMP), which by inhibiting phospholipase As, limits the production of TXAs. The second mechanism involves stimulation by thrombin of the production of prostaglandin 12, a potent vasodilator and inhibitor of platelet aggregation. Only when these two and other balancing mechanisms are overwhelmed would thrombus formation and vasoconstriction continue unchecked and eventually result in vascular occlusion. This general presentation of biochemical processes implicated in coronary vasoconstriction provides clues as to the mechanism of coronary vasoconstriction in individual patients or in specific ischemic syndromes. In addition, other stimuli may induce or contribute to the induction of coronary vasospasm. Among these are hyperventilation, cold temperature, alkalosis, isometric exercise, and in certain conditions, the cholinergic neurotransmitter, acetylcholine. PROVOCATIONOFCORONARYSPASM

Based upon the recognized pathogenesis of coronary vasoconstriction, several means of provoking coronary vasospasm have been used for investigational or diagnostic purposes. The ergonovine maleate provocation test for coronary spasm was described in 1977 by Schroeder et a1.23 Subsequent experience by Heupler et al. 24 has established the test as being specific and sensitive for focal large coronary artery spasm. 57 The safety of the test was later questioned58-60 when reported instances of ventricular tachyarrhythmias, myocardial infarction, and even death began to appear. With the introduction of specific spasmolytic drugs, namely calcium channel antagonists, the applications of the ergonovine provocation test became limited. In patients with documented myocardial ischemia and normal coronary arteriography, a clear beneficial response to these drugs represents a therapeutic trial that strongly implies vasospasm as the mechanism for angina. Provoking spasm by hyperventilation-induced alkalosis was described with variable degrees of specificity and sensitivity.61v 62 The action may be potentiated if hyperventilation is performed in combination with Tris buffer infusion61 or with the cold pressor test.63 The test was found by different authors to be of value for detection of spasm64 as well as for assessment of the efficacy of treatment. 65 Sensitivity of hyperventilation was found to be significantly lower than that with ergonovine,@ while an equal sensitivity was found for the two tests when patients with active variant angina were tested.67 Despite the general

December 1991 American Hear1 Journal

safety of this test, the induced vasospasm may be refractory to nitroglycerin. 68 A recent study6g showed that magnesium suppresses angina1 attacks induced by hyperventilation in patients with variant angina. The authors hypothesized t,hat magnesium deficiency potentiates the contractile response of small and large coronary arteries. Stimuli causing generalized vasoconstriction may also unveil hypersensitivity of a coronary arterial segment to their action. They include the cold pressor test, which may potentiate the action of other stimuli6s or induce vasospasm and angina directly.“l Isometric exercise was found to cause reflex coronary vasoconstriction, therefore aggravating myocardial ischemia.70 The handgrip test was utilized as a provocative test for vasospasm in patients with variant angina. I1 The relatively low incidence of induction was appreciably increased after the intramuscular injection of phentolamine and was not lowered by atropine. The authors concluded that neither the sympathetic nor the parasympathetic system plays a major role in myocardial ischemia induced by isometric exercise. Provocation of coronary vasoconstriction by acetylcholine has been the subject of both interest and controversy. Yasue et al.i2 reported the coronary vasospastic action of acetylcholine in patients with variant angina. Since this action was blocked only by atropine, they concluded that it was not the result of reflex sympathetic reaction and suggested a possible direct role for the parasympathetic system in coronary spasm. Prior to this, the same group of investigators73 found a close relationship between the spasm of variant angina and stimulation of the sympathetic nervous system mediated by way of a-receptors present in large epicardial coronary arteries.7” Whether activation of parasympathetic receptors in large coronary arteries should induce spasm or relaxation of the arterial wall remained unclear. Ludmer et a1.74observed a paradoxical vasoconstrictive action of intracoronary acetylcholine in atherosclerotic arteries, while normal coronary arteries responded with dilation. Okumura et al.i5 later found that acetylcholine severely vasoconstricts coronary arteries involved in variant angina but at the same time causes less severe constriction of “control” arteries. This discrepancy may be related to the total dose and rate of intracoronary administration, with low doses causing dilation and higher doses causing constriction.‘6 The work of Kunihisa et al.” was in agreement with the theory of an enhanced selective action on the variant angina culprit vessel. They found a much less frequent vasoconstrictor effect in patients without coronary artery disease or in those with organic ath-

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erosclerotic disease. In another study, Okumura et a1.75 found intracoronary acetylcholine to be useful and reliable in provoking spasm in variant angina with multivessel involvement. In view of the favorable experience suggesting the reliability and safety of the intracoronary acetylcholine provocation test, it has been proposed as the test of choice in Prinzmetal’s angina. Because of the short half-life of acetylcholine, complications are predictably rare. Occasionally bradycardia occurs, especially when the right coronary artery is injected. Other agents capable of inducing coronary vasospasm include histamine,78 serotonin,7g epinephrine overdose,80 and L-thyroxine therapy.81 Spasm can also be stimulated by mechanical invasion of the coronary arteries as in diagnostic catheterizations27 83 or following percutaneous transluminal coronary angioplasty (PTCA).83,s4 CLINICAL CORRELATES VASOCONSTRICTION

OF CORONARY

About a decade ago, the pathogenesis of myocardial ischemia was viewed as primarily related to fixed stenosis of one or more coronary arteries. Ischemic syndromes solely due to severe dynamic obstruction in diseased or “normal” coronary arteries were recognized, but were felt to be uncommon. The two concepts of supply-side and demand-side ischemia, initially considered mutually exclusive, were merged into so-called “mixed angina.” The implication here is that vasoconstriction may be superimposed over organically stenosed arterial segments thus heightening the degree of obstruction, which if complete, can result in acute myocardial infarction. The relentless search for causes of total occlusion observed in over 85% of patients with acute myocardial infarction finally unveiled interacting components of vasoconstriction, plaque alteration, and white and red clot formation. A vicious circle is created that, unless broken by local defensive mechanisms or therapeutic interventions, can cause total cessation of blood flow in the afflicted vessel. While clot formation seems to be the ultimate process, little is known regarding the initial culprit trigger.85 In addition to spasm, possibilities include sudden change in pressure or velocity and hypercoagulability. Dynamic obstruction therefore appears to play a role in most myocardial ischemic conditions. It may also be involved in the pathogenesis of the enigmatic syndrome X. These clinical syndromes will be addressed in the following discussion. Also to be discussed are the relationship between spasm and exercise, the consequences of dynamic obstruction on myocardial function, and unusual forms of spasm, Microvascular

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angina or “syndrome X” will be considered, since most observers of this condition believe it is related to dynamic obstruction of small coronary arteries. Variant angina of PrinzmetaI. Before Prinzmetal characterized “variant angina” as a separate clinical entity,6 clinicians had observed that transient ST segment elevation similar to that of acute myocardial infarction could occur in angina pectoris.86, 87Despite subsequent reporting of this form of angina as a well-defined syndrome, 88-g1 its incidence was still considered low. The two basic characteristics of variant angina are the ST segment elevation and the fact that chest pain is unprovoked by a shift in the basic hemodynamic determinants of myocardial demand, which remains unchanged. Episodes tend to recur with identical intensity and duration. All this clearly implies a sudden reduction of coronary blood supply, with vasospasm being practically the only logical explanation. lo Recurrence at the same myocardial distribution and occasional progression to acute myocardial infarction were considered as indicative of superimposed vasospasm over a severe but still incomplete atherosclerotic obstruction. This limited conceptualization has later given way to a more polymorphic view of the syndrome. It became obvious that in certain patients the coronary arteries are angiographically normal, a condition termed “variant of the variant.“l’ More similar cases were reported as a separate entity with a generally benign prognosis.16 Both basic components of the variant angina syndrome (i.e., rest pain and ST elevation) were subsequently questioned. Is the ST segment always elevated in all ischemic episodes of this syndrome? Can ischemia, and for that matter coronary spasm, occur during effort? The answer to both questions lies in the fact that ST segment elevation is not synonymous with spasm but rather denotes rapid and complete occlusion of the artery, resulting in transmural myocardial ischemia. Spasm may well be the most common cause for such an occurrence. If spasm does not completely occlude the artery, one may expect ST segment depression or T wave inversion or pseudonormalization. On the other hand, if an embolism, a clot, or a balloon suddenly occludes a major coronary artery, the ST segment will be elevated. Therefore in patients with variant angina, the classical findings represent “one aspect of a continuous spectrum of vasospastic myocardial ischemia.“g2 These facts were clarified beyond doubt in the study by Maseri et a1.,g2 in which unprovoked angina1 episodes, presumably caused by spasm, were associated with either ST elevation, ST depression, or T wave changes. Pain occurred as a late phenomenon and in some patients it did not occur, an obser-

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vation compatible with recent knowledge about the sequence of events in the ischemic cascadeg3 and in silent ischemia.g4 The authors concluded that spasm occurs with variable intensity in the presence of variable degrees of atherosclerosis and collateral circulation. The resultant ischemia would therefore exhibit a spectrum of intensity with trivial transient asymptomatic episodes on the one end, and with severe unrelenting spasm resulting in myocardial infarction on the other. Another feature of variant angina is the tendency for spasm to recur in the same coronary segments,@ especially at a site of organic stenosis,g5 indicating localized hypersensitivity to vasoconstricting stimulation. Furthermore, certain data tend to suggest an even greater sensitivity to vasodilators in coronary arteries of patients with variant angina.g6 The vasoactive responses of segments not involved directly with spontaneous spasm was evaluated in several studies. In patients with atypical chest pain in the absence of documented focal spasm or typical variant angina, ergonovine was found to produce mild diffuse coronary vasoconstriction.g7, gs In a recent study,gg Hoshio et al. compared vasomotor responsiveness with both ergonovine and nitrates in segments with and without spasm in patients with vasospastic angina, as well as in a control group without ischemic heart disease. They found that responses to both ergonovine and nitrates were greater in the spastic segments than in other segments, and responses in arteries not involved with spasm were greater than responses in arteries of individuals without ischemic heart disease. Kaski et al.loo arrived at similar conclusions after evaluating the response to ergonovine in patients with variant angina. They measured coronary diameters at the site of spontaneous spasm and a nonspastic segment after intravenous ergonovine. The reduction was maximal in spastic segments, suggesting that spontaneous spasm in variant angina results from a local exaggerated response to a generalized stimulus that produces only mild constriction in other segments. These findings clearly support the concept of a spectrum of vasoreactivity and lend credence to the frequent observations of symptomatic diffuse or sporadic spasm involving multiple segments. Despite a strong suspicion that variant angina may have a genetic predisposition,lO’ only a few reports of occurrence in siblings have been published.lo2, lo3 It is clear, however, that vasospastic ischemia is more frequently encountered in certain geographic locations such as Italy and Japan. Circadian variation of coronary artery tone and therefore of the ischemia threshold was evaluated by Yasue et a1104,io5 in patients with variant angina.

December 1991 hmerlcan Heart Journal

They observed a peak increase in coronary artery tone in the early morning and a reduction of this tone in the afternoon. By performing coronary angiography and exercise tests, they found coronary arterial diameter to be small in the morning with readily inducible spasm and angina, with mild exercise and marked dilatat,ion following the administration of nitroglycerin. By contrast, the artery was usually dilated in the afternoon and exercise could induce only mild spasm and no angina1 attacks except in patients with severe organic obstruction, in whom only a slight degree of spasm was necessary to occlude the artery. The influence of a rapid eye movement (REM) pattern of sleep on coronary vasomotor tone may explain some of this circadian variation of the ischemia threshold. Nowlin et al.‘O” observed an association between REM sleep and nocturnal angina. Otsuka et a1.‘07 were able to confirm this association in patients with variant angina by simultaneous sleep pattern and electrocardiographic monitoring. They observed extreme bradyarrhythmias followed by angina with ST segment elevation. This occurred not only during REM sleep, but also for a period of time after arousal. During this early morning period, only a slight effort could induce the attack. These observations and those of Yasue et a1.io4 provide support for the general finding of a higher rate of angina frequency and acute myocardial infarction in the early morning hours. Therefore sleep is associated with significant alterations in coronary hemodynamics and autonomic nervous function.‘Ox Coronary vasospasm and exercise. Since variant angina typically occurs at rest, the role of exercise in coronary arterial spasm was for some time ignored. A common belief was that when the exercise test was positive, it indicated severe underlying organic obstruction. However, exercise-induced ST segment elevation has been reported with relative frequency in patients with ischemia caused predominantly by coronary spasm. log, 11° Fig. 1 shows severe segmental ischemia with marked ST segment elevation and a large thallium-201 defect induced by exercise in a patient with a normal coronary arteriogram who had effort angina. Exercise later failed to induce ischemia in the same patient after he was effectively treated with nifedipine. That exercise can induce spasm in susceptible patients is therefore undeniable. Actually, the report of ST segment elevation induced by exercisel’i, i12 has preceded the full understanding of the relationship between spasm and ST segment elevation. This relationship is only compatible with the known role of sympathetic discharge in the induction of coronary vasoconstriction. Why this relationship is not frequently demonstrable remains unclear. In-

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Fig. 1. A, Exercise-induced ST segment elevation and angina in a 70-year-old patient with effort angina and a normal coronary angiogram. Notice the gradual return of ST-T changes to baseline within 3 minutes of rest. Repeat exercise test of the same patient while he was being treated with nifedipine. No evidence of ischemia has developed despite a higher level of exercise. 6, Thallium-201 scintigrams in the same patient. Notice the large reversible defect before treatment.

versely, the role of coronary spasm in classic exerciseinduced angina was felt to be insignificant.i13 With more understanding of spasm as a spectrum,g2 the sharp distinction between effort angina and coronary spasm became gradually more blurred. Occasionally coronary spasm with a normal coronary angiogram was reported to manifest as exertional angina indistinguishable clinically from that caused by organic stenosis.i14 Circadian variation in exercise capacity was proposed by Yasue et a1.1°4 to explain the spasm-mediated angina occurring in the early morning but not in the afternoon. The value of exercise testing in patients with spontaneous or provoked

spasm during angiography was recently evaluated by Caste110 et a1.115in an attempt to assess the value of ST segment changes in predicting underlying fixed stenosis. ST segment elevation occurred in a small percentage of patients and was not predictive of fixed stenosis, indicating a very active spasm component in these patients. On the other hand, ST segment depression, despite a very active functional component, was highly predictive of underlying fixed organic lesions. In patients with classic variant angina, the incidence of exercise-induced ST segment elevation may be higher in those who have active disease with frequent spontaneous episodes.l16 Furthermore,

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in patients with “pure” spasm and a normal coronary arteriogram, both ergonovine provocation57 and continuous electrocardiographic monitoringl” were found to be superior to exercise testing for the diagnosis of coronary artery spasm. When thallium-201 scanning was added, the yield of exercise-induced ischemia was significantly increased,‘18 as defects on the scan were observed in patients who had neither chest pain nor ST changes. Coronary vasospasm and silent ischemia. Silent, myocardial ischemia is frequently present in patients who also manifest stable angina. A possible role for coronary vasospasm in silent ischemia can be suspected from the fact that these patients tend to have a higher incidence of acute myocardial infarction and sudden death.rig Biagini et a1.120 implicated vasospastic ischemia as the mechanism of frequent asymptomatic ST-T changes in selected patients with unstable angina.lZO Continuous electrocardiographic monitoring in patients with vasospastic ischemia has shown that over 70 COof ischemic ST-T changes were silent.g2, 121In 25 patients with angiographically documented coronary spasm, exercise tests with thallium computed tomography revealed perfusion defects in 11 patients; only four of them had angina during exercise. 118 The explanation for painless ischemia in most cases lies in the fact that pain is usually a late manifestationg2 and that many of the spastic episodes are not intense or prolonged enough to cause pain. In some patients at least, a defective mechanism of pain perception of the type described in stable anginalZ2 may be implied. These findings tend to support and widen the scope of earlier observations of repetitive Prinzmetal’s type myocardial ischemia without angina pect0ris.l”” They also indicate that silent ischemia is as frequent-if not more so-in vasospastic vis-a-vis fixed coronary artery disease. Coronary vasospasm and arrhythmia. Both tachyarrhythmias and bradyarrhythmias have been uniformly reported in variant angina and in vasospastic ischemia in general.* Profound sinus bradycardia or sinus arrest may occur and may result in syncope.16* 128,12gHeart block at the level of the atrioventricular node or distal to the bundle of His has also been observed.16, 28,125 Ischemia of the sinoatrial or atrioventricular nodes provides an explanation for these complications. Bradyarrhythmias were more frequently noticed when spasm occurred in a dominant right coronary artery’“, 128commonly providing blood supply to both nodes. Frequent premature ventricular beats as well as life-threatening ventric*References

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11, 16, 28, 92, and 124 to 127.

ular arrhythmias have also been frequently reported,ll, 127,130,131 occasionally as the mechanism (it death. There is a suspicion that at least. in some cases, coronary spasm may be responsible for “primary” paroxysmal ventricular tachycardia occurring in the absence of detectable organic heart disease. Serious arrhythmia may also complicate experimental or inadvertent provocation of spasm.‘5g, 128Syncope caused by arrhythmia may be the presenting symptom of coronary vasospasm before angina is observed, and may account for some cases of “painless” ischemic episodes. 12s Arrhythmic syncope should whenever possible be distinguished from hemodynamic syncope that results from sudden stunning of left ventricular function (electromechanical dissociation) caused by left main or multivessel spasm.‘TZ Atria1 arrhythmias are probably less common in vasospastic ischemiai3” and are clearly less consequential. Several explanations have been offered for the high preponderance of arrhythmias in coronary spasm. The intensity and suddenness of both occlusion and reperfusion are more dramatic in coronary spasm and therefore are more likely to result in dispersion of repolarization and reentrant circles. This is probably more true when occlusion and reperfusion occur in a previously normal artery. This hypothesis was experimentally proven.134, ls5 Arrhythmias both of ischemic or reperfusion origin are less likely to occur with brief ischemic periods.‘“’ Occlusion arrhythmias seem to be more frequent and more malignant than reperfusion arrhythmias in coronary spasm. 137,1x6 The role of the R-on-T phenomenon may also be more prominent during the ischemic occlusion phase. ‘a9 Finally, a potential source of ventricular arrhythmias in vasospastic ischemia may be related to t,he magnesium deficiency recently observed in many patients with variant angina.14* This deficiency can usually be corrected after treatment with calcium antagonists. Myocardial

dysfunction

in

vasospastic

ischemia.

Clinical and experimental observations have produced evidence that ischemic myocardial dysfunction is different between reduced supply and increased demand types of ischemia. The former can result clinically from severe coronary spasm and is believed to produce more profound left ventricular dysfunction than the latter.14rT 142This probably reflects an abrupt transmural reduction of blood flow in sudden total occlusion as opposed to reduction of perfusion of mainly subendocardial layers in demand ischemia. As a result of transmural ischemia, the whole myocardial segment becomes dyskinetic with markedly increased diastolic stiffness. The so-called ischemic cascade reflects the temporal sequence of

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2. A, Spontaneous extensive multivessel spasm (left main, left anterior descending, and circumflex arteries) during cardiac catheterization in a 56-year-old man. Chest pain and hypotension with multivessel spasm occurred following left ventricular angiography. 6, Reversal of spasm after the intracoronary injection of nitroglycerin. Fig.

events that follows rapid interruption of coronary 143,144 B iochemical abnormalities are followed by impairment of diastolic properties and left ventricular compliance, then by systolic dysfunction with segmental wall motion abnormalities, then by

supply.93,

ST segment changes, and finally by chest pain. These changes translate into depression of ventricular ejection fraction and stroke index as well as an increase in end-diastolic pressure and chamber stiffness.144 Unless coronary spasm is rapidly released, more pro-

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found ischemia would result with a greater chance of reperfusion sequelae including arrhythmias, myocardial stunning caused by depleted adenosine triphosphate (ATP) stores, or myocardial injury by oxygen free radicals. Using continuous hemodynamic monitoring and ventricular angiography, Maseri et a1.g2 observed a reduction in left ventricular relaxation and contraction during vasospastic ischemia. The onset of ST segment elevation and pain was associated with increased end-diastolic pressure and diminished peak dP/dt of the left ventricle. Two-dimensional echocardiography and radionuclide ventriculography have since been extensively used to assess ischemic ventricular dysfunction. Left ventricular impairment was found to vary according to the location of the spastic segment and the duration of spasm.145T 146Selective spasm of the right coronary artery tends to produce predominantly right ventricular impairment.‘47 The extent of left ventricular involvement depends on whether septal ischemia is present or not.14s On the other hand, selective spasm of the left anterior descending coronary artery148 produces left ventricular impairment without associated effects on the right ventricle. More extensive multivessel spasm and especially left main spasm may cause syncope13” or cardiogenic shock (Fig. 2) as a consequence of global ischemia of the left ventricle. Coronary

vasospasm

and acute myocardial

infarction.

The initiation and continuance of coronary arterial occlusion is believed to be responsible for myocardial infarction. An interplay of vasoconstriction and thrombus formation seems to fuel the occlusion by creating a vicious circle with mutual enhancement between spasm and thrombosis. Vasoconstriction, by slowing or interrupting flow, creates a favorable environment for white and red thrombus formation. The liberated products such as TXAs, serotonin, and thrombin all tend to aggravate vasoconstriction. The event or events that trigger this interplay are, however, more controversial. There is currently sporadic evidence that, at least in some cases, vasospasm is demonstrable at the very early phase of acute myocardial infarction.30, ‘4g, ‘So The success of thrombolytic therapy in establishing recanalization of the occluded artery in the majority of patienm presents, however, an argument against a major role for spasm.151-153 In these studies, only a low incidence of recanalization was observed following the administration of intracoronary nitroglycerin. It is still possible that the role of spasm diminishes as a thrombus is formed, and its possible contribution as a triggering event in the very early minutes cannot therefore be excluded. Other potential causes include plaque fissuring’s4 with subsequent thrombosis, critical

stenosis resulting in high shear stress sufhcient to damage platelets and red cells, and a hypercoagulable state. Intense sudden spasm may by itself cause plaque fissuring, and persistent severe spasm caused by supersensitivity to vasoconstrictor stimuli may be refractory to vasodilators, which may explain the failure of these medications to reestablish vessel patency. The complexity of the interactions between all these factors, especially their synergistic adverse et’fects, explains the difficulty in determining the initial culprit. Maseri et al.““” proposed a “unifying hypothesis” to explain the relative rarity of acute myocardial infarction despite severe coronary arterial stenosis. According to this hypothesis, all three major processes, i.e., plaque rupture, supersensitivity to vasoconstrictor stimuli, and displacement of the thrombolytic equilibrium toward thrombosis, may be simultaneously and equally operative. However, an extremely powerful presence of one or two of them may suffice to cause the occlusion.‘“5 In severe cases of vasospasm, a clot formation may take place with subsequent total occlusion and myocardial infarction.21, 8’, 156-160Occasionally an infarction can be prevented by prompt intervention with vasodilator and anticoagulant therapy.‘“’ Vasoconstriction may be frequently involved in the pathogenesis of reocelusion after initially successful thrombolysis. Intracoronary isosorbide dinitrate was found to be effective in resolving ST segment elevation and in restoring coronary patency in many cases.162 We found sublingual nifedipine combined with an intravenous infusion of nitroglycerin to be effective in similar cases (Fig. 3). The facts about spasm and infarction are clearly not out yet, but most probably they lie somewhere in t,he middle between the suggestions of proponents and skeptics.‘“” Coronary vasospasm and angioplasty. It is generally accepted that coronary vasospasm frequently follows percutaneous transluminal coronary angioplasty (PTCA) and may compromise the success of this therapeutic intervention ‘K *esby increasing the rates of immediate reocclusion’6’ and long-term stenosis. 168 The potential mechanisms responsible for PTCA-induced uasoconstriction include release of vasospastic substances (TXAz, serotonin) from platelet aggregates,“” endothelial damage with loss of EDRF, release of endothelium-derived constrictor substance (endothelin) ,4’ and local adrenergic nerve dysfunction. lsg This vasoconstriction should be distinguished from the passive elastic recoil that. promptly follows balloon deflation.17’ The incidence of this complication is not directly related to the degree of pressure, the length of inflation, or oversizing of the balloon.“’ It mav he prevented by pretreat-

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myocardial

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Fig. 3. Left panel, One day following successful thrombolysis, chest pain and ST segment elevation recurred, indicating reocclusion. Right panel, Following sublingual nifedipine combined with intravenous infusion of nitroglycerin, pain subsided and the ST segment returned to baseline.

ment with intracoronary

verapamil17i or nitroglycerin 172 or may be aggravated by vasopressors such as ddpamine17” and by excessive manipulation. Early observations indicate a higher prevalence with atherectomy and rotational devices. The role of vasospasm in restenosis after PTCA is more controversial. Failure of conventional doses of diltiazem174 or nifedipine 175 to influence the rate of this frustrating complication seems to argue against a major role played by vasospasm in its production. The frequency and extent of vasoconstriction late after PTCA is still not fully determined. There is available evidence for both a higher and lower incidence.168, 176 Some animal studies177 even suggested that an angioplastied artery is incapable of undergoing vasoconstriction. In a study by Leisch et a1.,r7s arterial spasm at the site of dilatation was found to be significantly more frequent in patients who developed restenosis in clinically matched groups. Others17g found a high incidence of provoked spasm after successful PTCA. The relationship between the presence and absence of provoked vasospasm before and 6 months after PTCA was assessed by Bertrand et al.168 in four groups of patients. Those who had spasm before and after the procedure were found to have the highest rate of restenosis (55 %), followed by those who demonstrated spasm only after PTCA (38%). The lowest rates were found in patients who had spasm before but not after PTCA (19 % ) and in those who did not have it either before or after the procedure (20 % ). The restenosis rate was even higher when spasm was observed in the same dilated coronary segment. The authors concluded that provoked spasm after PTCA is frequently associated with res-

tenosis. Whether more than conventional doses of calcium antagonists, a combination of these drugs, or newer agents will help in reducing the rate of restenosis after PTCA is still unsettled at this time. The efficacy of PTCA and its potential adverse effects in patients with classic variant angina are also of particular interest. Earlier reportslEo, ‘sl considered patients with coronary artery spasm as poor candidates for the procedure because of a higher rate of complication and because of the emergency bypass salvage procedures. While the rate of restenosis was clearly increased when PTCA was used for the treatment of variant angina, serious complications were uncommon.lE2, ls3 Since most of these patients tend to have severe organic stenosis and many of them have single-vessel disease, PTCA appears to be indicated in a high proportion of them. Caution and close follow-up seem to be warranted after the procedure in addition to keeping a high expectation index for the development of restenosis. Coronary

vasospasm

in mental

and emotional

stress.

A relationship between emotional stress and spasmmediated myocardial ischemia has been suspected for more than a decade.l&, lE5 a-Adrenergic or serotoninergic-mediated spasm was referred to as a possible mechanism. An angina1 syndrome with a normal coronary angiogram was described earlieGE and was found to be more frequent in women. After evaluation of nine middle-aged women with profound emotional stress, manifest ischemia, and documented or strongly implied coronary spasm, we proposed that spasm was directly related to sudden worsening of a tense but contained emotional imbalance (Fig. 4) commonly centered around sexuality.28 Since then,

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Fig. 4. Left panel, Evidence of inferoposterior transmural myocardial ischemia in a &year-old during severe emotional stress. Right panel, Changes were normalized after intravenous infusion glycerin. Coronary angiography was later found to he normal.

several investigators have observed a relationship between ischemia and the stress of daily life. Deanfield et a1.187described recurrent episodes of ST segment depression during daily life in patients with stable angina. Episodes were elicited by ordinary tasks without an increase in heart rate, indicating impairment of coronary blood flow, presumably spasm-mediated rather than as a result of increased myocardial metabolic demand. A link between silent myocardial ischemia and mental stress was later found by the same grouplag with objective evidence? using rubidium-82 with positron tomography. With the use of radionuclide ventriculography, Rozanski et a1.18g found that a high proportion of patients with coronary artery disease exhibit left ventricular dysfunction and silent ischemia when subjected to mental stress in the form of mental arithmetic, a Stroop color color word test, and especially a personally relevant speaking task. Similar findings were described by LaVeau et al.,“’ using an ambulatory radionuelide method for assessing left ventricular function. Reduction in ejection fraction during mental stress was limited to patients with coronary artery disease who also demonstrated an abnormal ejection fraction response to physical exercise. In addition to stimulation of the adrenergic system, platelet dysfunction with increased aggregability was found in human subjects during mental stress and/or adrenaline infusion.lgl Most recently, lg2 the same result, was described in concert with sympathoadrenal discharge induced by emotional stress in patients with coronary artery disease. Coronary vasospasm and cocaine abuse. Over the

woman of nitro-

past decade, recreational abuse of cocaine was implicated in the pathogenesis of myocardial ischemia and infarction,1g3-‘g7 arrhythmia,1g8-200 and dilated cardiomyopathy. 901,202 Ischemia production by vasoconstricting or thrombogenic actions of this drug may be responsible for all its harmful clinical effects. In most reported cases of myocardial infarction, coronary angiography performed later was normal. When coronary angiography was performed at an early stage, a thrombus could be found.20” Coronary spasm was documented in a few caseqZo4, 205even though an ergonovine provocation test tended to be negative. A generally held belief that cocaine directly enhances the sensitivity to norepinephrine in the nerve terminalszo6, 2oi was challenged by the finding of a direct effect on increasing calcium flux across the cell membrane of vascular smooth muscles.208, 2og Cocaine seems to ignite the spasm-thrombosis interaction independently from the endothelium. Experimentally, vasospasm can be inhibited by pretreatment with diltiazem.210 Lange et a1.211 evaluated the effects of cocaine on coronary vasoreactivity in human subjects. Despite an only mild reduction of the diameter of epicardial arteries, a more significant increase in coronary vascular resistance was found, indicating vasoconstriction of the intramural coronary vessels. The impact of the widespread cocaine abuse on cardiovascular and general health is probably not fully recognized at present. More basic and epidemiologic investigations are needed to clarify the extent of this self-inflicted damage. Unusual sites of ischemia producing spasm. Vasospasm has been reported to occur in unusual locations

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of the coronary circulation and in saphenous vein and internal mammary artery (IMA) conduits to coronary arteries. The incidence of spasm of the IMA at its natural location or when it functions as a coronary conduit is not determined. Several reports and many anecdotal observations tend to suggest that postoperative spasm of IMA conduits is not rare.212-214 Frequent postoperative use of nitroglycerin infusions prophylactically or after the earliest electrocardiographic signs of ischemia may have been responsible for the infrequency of this complication. Another possible reason is the apparent low vulnerability of the IMA to spasmogenic as well as vasodilative stimuli.215 This may be the result of a greater endothelium-dependent relaxation capacity of the IMA in comparison with that of venous grafts.216 Early postoperative217T 21s or late21g spasm of saphenous vein grafts has also been reported and implicated in the pathogenesis of vein graft occlusion. The true incidence of this phenomenon is not clear, but is undoubtedly influenced by judicious use of vasodilators in the perioperative period. Spasm has been reported in the left anterior descending coronary artery at the site of a myocardial bridge. 220 The authors proposed this mechanism as an explanation of some cases with bridge-induced ischemia. Vasospasm of the left main coronary arteryW221 or multivessel spasm118>222 may understandably result in more serious consequences in view of the large myocardial area affected. Microvascular ischemia (Syndrome X). The name syndrome X is being gradually replaced by microvascular angina. This change indicates that more insight and knowledge about this mysterious entity are replacing ignorance. There are major differences between this syndrome and variant angina. Pain unlike that of variant angina is typically exertional, lasts longer, and is associated with ST segment depression. Extramural coronary arteries are normal and are not necessarily vulnerable to vasoconstrictive stimuli. The main abnormality seems to be localized in the microvascular coronary circulation not visualized by coronary angiography. Recent evidence has indicated that changes of vascular tone may occur in distal coronary arteries, the intramural circulation, and collateral vessels.223s224Responsiveness of the microcirculation has been difficult to assess accurately. In many patients with ischemia and no coronary atherosclerosis or large artery spasm, hemodynamic and metabolic studies tend to suggest an abnormal response at the level of the small coronary vessels. This evidence225-227 includes (1) inadequate coronary flow and vasodilator response; (2) failure of coronary vessels to dilate normally in response to potent vasodi-

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myocardial

ischemia

17 13

lators (dipyridamole); (3) augmented response of these vessels to vasoconstrictors (ergonovine); (4) increased myocardial oxygen extraction; (5) increased lactate production as a result of inadequate consumption in response to increased metabolic demands. A detrimental effect on left ventricular function has not been uniformly detected. While left ventricular end-diastolic pressure was found to inappropriately increase in response to atria1 pacing,228 left ventricular function, as assessed by ambulatory pulmonary artery pressure, was not found to be changed.22g The cause or causes underlying abnormal small vessel response are unsettled. Potential explanations include inappropriate sympathetic stimulation, circulating vasoconstrictor substance, release of endothelin or other endothelial constricting factors, or primary abnormalities of smooth muscle function. New experimental evidence230 suggests that microvascular function may be “stunned” after reversible ischemia, with prolonged impairment of vasodilator responsiveness. Whether this phenomenon may play a role in the larger spectrum of microvascular ischemia is unclear at present. This syndrome may represent coronary manifestations of a more generalized smooth muscle disorder. Impaired vasodilator response was also found in the peripheral circulation (forearm) of these patients, correlating well with impaired coronary response.231 In addition, there is a high prevalence of associated esophageal motility disorders. In many of these, pain may be directly related to esophageal spasm following exertion reflux,232 or may represent an abnormal visceral nociceptive reaction. Whether other phenomena such as premature beats or increased loading during exercise may also incite angina-like pain in these supersensitive patients remains unclear. On the other hand, it is becoming evident that a subset of patients with microvascular ischemia suffers from manifest or hidden psychological abnormalities, including evidence of panic or anxiety disorder.233-235 The link between psychological stress and vasoconstriction of small coronary arteries may include sympathetic discharge, stress-induced platelet dysfunction,‘“ll 236and the neurotransmitter neuropeptide Y .38 Recent examination of the site of increased coronary resistance and the mechanism. of pain in syndrome X has revealed new insights and propositions. There is general agreement that the abnormality resides in prearteriolar vessels. Epstein and Cannon237 suggested that flow is impeded in the small intramuscular prearteriolar vessels, prior to branching of the subepicardial vessels. Maseri et a1.238 expanded this concept by distinguishing between conductive

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Fig. 5. A, Profound repolarization abnormality chest pain in a S-year-old woman with syndrome ately elevated. 6, Improved ST and T changes on was normal. Recurrent angina responded well to

suggestive of subendocardial infarction during severe X. Creatinine phosphokinase MB fraction was moderthP following day. Two days later coronary angiography treatment with nifedipine.

vessels that offer only negligible resistance and resistive vessels, which by changing their tone regulate myocardial perfusion by maintaining the desired level of pressure at the origin of arteriolar vessels. Metabolic regulation of this function is probably mediated by endothelium-derived vasodynamic substances. Defective release of endothelium-derived relaxation factor23g or increased reactivity to endothelin or neuropeptide Y33 may overpower the capacity of metabolic regulation.2”8 Transmural myocardial steal phenomenon may occur as a result of localized pharmacologic (dipyridamole) or metabolic arteriolar dilation, which tends in turn to aggravate

ischemia. On the other hand, the inconsistent relationship between pain and the severity of both ischemia and myocardial dysfunction in syndrome X suggests a relatively independent mechanism of pain induction. Indeed, chest pain in this syndrome may occur in the absence of any demonstrable myocardial ischemia. The recent proposition of Maseri et a1.,23s based on earlier workZ40 that adenosine released by a compensatory mechanism may be the mediator for pain, seems to explain much of the discrepancy. This release may occur in amounts sufficient to induce pain as a response to patchy localized prearteriolar vasoconstriction not sufficient by itself to cause de-

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monstrable ischemia or measurable alteration in myocardial function. Aminophylline, an adenosine antagonist unlike calcium channel antagonists or nitrates, is capable of producing a consistent lessening of pain in syndrome X.241 The prognosis of microvascular angina is believed to be good in general. Occasionally myocardial necrosis may occur in the form of subendocardial infarction (Fig. 5). Repetitive ischemic myocardial damage may result in depressed left ventricular function and intraventricular conduction abnormalities with the full clinical picture of dilated cardiomyopathy.242 Principles of the management of vasotonic myocardial ischemia. Coronary vasoconstriction alone is not a

frequent cause of ischemia but rather contributes to a variable extent to its production, dependent on the severity and the nature of associated organic disease. Focal coronary vasospasm is the primary mechanism of transmural ischemia in Prinzmetal’s variant angina, especially in patients with normal or only mildly stenosed coronary arteries. Segmental vasoconstriction, on the other hand, is implicated in the interaction of aggregating platelets, spasm, and clotting. This mechanism appears to be responsible for unstable myocardial ischemia and acute myocardial infarction. Generalized vasoconstriction of smaller intramural vessels is believed to be the dominant mechanism in microvascular ischemia, also called “syndrome X.” Furthermore, a degree of vasoconstriction probably involving collateral circulation may also play a role in the pathogenesis of stable myocardial ischemia. The management of these different forms of ischemia should therefore be tailored to the proportional significance of individual factors involved in the pathogenesis. The following trends seem to have been established after more than a decade of intensive investigation of the phenomenon of coronary vasoconstriction: (1) Individual predisposition is a potent determinant of the intensity of vasoconstriction and therefore of the location on the ischemic spectrum. (2) Angina1 pain and ischemia are not one and the same. While they can coexist and correlate with each other, each one can occur despite the apparent absence of the other. (3) There is undeniable interaction between coronary vasoconstriction and mental or psychological stress. (4) For unclear reasons, vasotonic ischemia seems to be more predominant in females and in certain populations. (5) For the diagnosis of vasoconstriction, provocative tests may not be necessary in most cases. Under normal cardiac output, normal oxygen saturation and carrying capacity, and a normal oxyhemoglobin dissociation curve, vasoconstriction is the predominant

Vasotonic myocardial &hernia

17 15

cause of reduced supply ischemia. A therapeutic trial with coronary spasmolytic agents seems to be warranted whenever coronary arteriograms are normal in a patient with unmistakable evidence of myocardial ischemia. (6) P-Blockers are not effective in ischemia predominantly because of reduced supply. On the contrary, by permitting unopposed ol-adrenergic activity, these drugs can have a detrimental effect.243 (7) Most tested calcium antagonists appear to be highly and almost equally effective in reducing ischemic episodes of Prinzmetal’s variant angina.244 More vasoselective agents (nifedipine, nicardipine) are probably more suitable for predominant vasospasm, while agents with more potent myocardial depressive action are suitable for ischemia of mixed etiology and that, associated with left ventricular hypertrophy. (8) Calcium antagonists are not as uniformly effective in prearteriolar vasoconstriction (syndrome X).245 Tachycardia-associated coronary vasoconstriction may paradoxically follow treatment with nifedipine in this syndrome.246 (9) Nitrates still play a major supportive role in vasospastic ischemia. Their major action in reducing myocardial demand tends to complement the action of calcium antagonists. (10) Neither coronary angioplasty nor coronary bypass surgery should be considered as the primary treatment of choice for predominantly vasotonic myocardial ischemia. This form of ischemia should not, on the other hand, be considered as a contraindication for the two treatment modalities if symptoms and objective evidence of ischemia persist despite adequate medical treatment of vasospasm. (11) Magnesium may be an important element in maintaining the arterial capability to dilate. Magnesium deficiency was detected in patients with Prinzmetal’s angina. I40 In addition, pretreatment with magnesium infusion was found to suppress angina1 attacks induced by hyperventilation in patients with Prinzmetal’s variant angina.247 Calcium antagonists in the treatment of vasotonic ischemia. The widespread use of calcium antagonists

may be responsible for masking vasospasm in many patients with a predisposition for vasotonic ischemia. These drugs are considered highly effective, with significant differences between individual agents. Nifedipine was found to be quite effective in Prinzmetal’s angina. 248-251In most patients treated, the response was uniformly satisfactory with sustained long-term benefits. Sublingual application of the drug may be helpful in aborting attacks of vasospastic angina. 252 Caution should be exercised, however, in mixed (two-component) angina, where nifedipine may produce a paradoxical vasoconstrictor effect.253 Diltiatem was also found to be effective in a ran-

17

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domized double-blind cross-over study.“‘“, 255 Beneficial action was sustained in long-term therapy.“:“’ Verapamil proved in clinical trials to be effective for short- and long-term therapy.‘57, 258 Newer agents such as nicardipine and nisoldipine also seem to have potent coronary spasmolytic actions.“5g Long-term prognosis in vasotonic angina. Many studies involving large numbers of patients with myocardial ischemia due primarily to coronary vasoconstriction have dealt with the long-term prognosis.‘60265The extent and severity of associated organic coronary artery disease was uniformly found to represent a major determinant of outcome. The risk of cardiac death or acute myocardial infarction reaches its peak in the early phase after onset of symptoms, correlating therefore with the level of disease activity. In most studies, the overall prognosis was felt to be good and it improves further with the use of calcium antagonists.2”5 Coronary artery bypass surgery is indicated in the presence of severe multivessel disease, but may be associated with a high rate of perioperative infarction if performed in the early phase of heightened disease activity. Continued uninterrupted medical therapy with calcium antagonists appears to be the backbone of effective management of most syndromes of vasotonic myocardial &hernia. The author gratefully acknowledges the assistance of student volunteers, Stella Tam and Matt Beaulieu, who aided in the gathering of the extensive reference material, as well as Beth Saltzman, from St. Mary’s Hospital and Medical Center library, who assisted with verification of the reference listings.

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