Coronary Artery Spasm—1984

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Coronary Artery Spa8m~1984* Tsung o. Cheng, M.D., F:C.C.~t

Coronary artery spasm \ftS virtually unknown not long ago, but the intense, ODgoing interest it bas generated in the past decade bas produced a number of speci6c diagnostic techniques and therapeutic approaches, as well as considerable insight into mechanisms of coronary vascular tone and various coronary syndromes. There is growing evidence that coronary artery spasQlis involvedin unstable angina, stable angina, myocarclial infarction, and sudden death. It is by no

means a benign process and ~ associated with significant morbidity or mortality if misdiagnosed or untreated. It seems clear that what started as a mere clinical curiosity involving a minority of patients with the so-called Prinzmetal's variant angina is snowballing into a ~ajor arena for research, diagnosis, and treatment in the Geld of ischemic coronary artery disease.

artery spasm (CAS), like the click-murmur C ronary syndrome of mitral valve prolapse, represents

agents against CAS, the approach to management of patients with coronary artery disease entered a new era in 19808.

1

another of those medical pendulums that has made several swings in past several decades. Although Osler in 1910 first suggested spasm of a coronary artery was responsible for the acute attack of angina pectoris, his hypothesis was soon discarded, after Blumgart et al" and French and Dock' in early 19405 showed that coronary insufficiency arose chiefly as a result of mechanical obstruction of the coronary artery due to atherosclerosis. Then, in 1959, Prinzmetal and associates" described the entity called variant angina in patients who developed ST-elevation on the ECG during nonexertional angina; since the angina occurred spontaneously, without an increased myocardial oxygen demand, the theory of coronary spasm causing a decreased supply was invoked. However, their theory did not receive much attention, since such spasm had never been actually observed or documented, and since many of their patients had significant atherosclerosis at autopsy. Then, in early 19705, several workers, including this author, e demonstrated by selective coronary arteriography the existence of reversible coronary vasospasm even in the absence of atherosclerosis. It was not until the work of Maserf in the late 19705 that the impact of CAS was really appreciated. With the introduction of calcium slow-channel blockers as a new, definitive, and effective class of therapeutic *From the Division of Cardiology, Department of Medicine, The George ~hington University School of Medicine and Medical Center; Washington, D.C. tProfessor of Memcine. Reprint requut8: Dr. CIaeng, George Wahington University Medical Cm~ 2150 PmnBfllvanitJ Avenue, NWWashjngton, DC 20037

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ATHEROSCLEROTIC INVOLVEMENT OF CORONARY ARrERIES UNDERGOING SPASM

Coronary artery spasm can occur either alone or superimposed on atherosclerosis. The frequency with which spasm occurs in an angiographically normal coronary artery varies among different reported series (Table 1).6,8-12 Four of the five patients reported in this author's initial series in 19738 had normal coronary arteriograms, one of whom at autopsy had normal coronary arteries. In the latest series of this authors experience (unpublished observation), 60 of 80 patients (75 percent) referred for study with the diagnosis ofvariant angina had angiographically normal coronary arteries. In the series reported by Endo and coworkers," 19 of their 35 patients (54 percent) had no coronary artery disease. In all 22 patients reported by Heupler; 11 none had coronary arteriosclerosis. In the series reported by Shubrooks and eo-workers" from the Coronary Care Unit of the Massachusetts General Table I-Incidence o/Corona'l/ ArterrI DiNaBe in PatientI With VtJriGnt Angina Authors

Patients

Yes

No (%)

Cheng et al (1973)' MacAlpin et al (1973)' Shubrooks et al (1975)' Endo et a1 (1975)10 Selzer et al (1976)11 Heupler et al (1980)11 Cheng (1983) (unpublished)

19 20 35 29 22

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Table 2-Syndromea ANocioted With Coronary Artery Sptmn Prinzmetal's variant angina Variant of the variant Angina at rest Unstable angina Effurt angina Acute myocardial infarction Sudden death Monday morning angina in nitroglycerin workers Mitral valve prolapse

A recent study also links variant angina, migraine headache, and Baynauds phenomenon. Miller and coworkers" found that patients with variant angina had an incidence of migraine of 26 percent, compared to 6 percent in the cardiac controls and 10 percent in the normal subjects. Baynauds phenomenon was diagnosed in 24 percent of the study group as opposed to 5 percent and 3 percent in the respective control groups .

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A Hospital, most of the patients had unstable angina or preinfarction angina, and was a mixed group containing many patients with atherosclerotic coronary obstructive diseases. Thus, it seems apparent that CAS can occur in normal coronary arteries as well as in atherosclerotic vessels. ROLE OF SPASM IN ISCHEMIC CORONARY SYNDROMES While CAS is now clearly established as the cause of Prinzmetals variant angina, "variant of the variant," and angina at rest, there is increasing recognition that CAS may be a significant factor in a broad spectrum of other ischemic coronary syndromes, including classic effort angina, unstable angina, acute myocardial infarction, and sudden death (Iable 2). We reported in 1972 the first instance of acute inferior wall myocardial infarction due to severe spasm of the left circumflex artery," Further support fur the role of CAS in angina and acute myocardial infarction is provided by observations made by Lange and eo-workers" that some munition workers experienced Monday morning angina following withdrawal from chronic industrial nitroglycerin exposure, a few developed acute myocardial infarction, and all had normal or nearly normal coronary arteries at coronary arteriography. Of particular interest is the recent observation that transient Q waves may appear and then disappear in CAS, supporting the concept of the "stunned" myocardium without permanent necrosis. 15

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OrnER CLINICAL SYNDROMES ASSOCIATED WITH CORONARY SPASM

Of interest is the recently reported connection between mitral valve prolapse and CAS.16 One of the most perplexing problems in cardiology is the management of chest pain associated with mitral valve prolapse." Mitral valve prolapse, which may result from coronary artery disease," may also itself be responsible fur CAS. 16 Increased a-adrenergic tone appears to play an important role in both patients with mitral valve prolapse and patients with CAS.19 Therefore, it is not difficult to see the connection between the two.

FIGURE 1. lYPical ECG changes during variant angina

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(A) may occur without angina (8). The same patient later developed advanced degree of heart block (C. top J'Gnel). received a temporary transvenous right ventricular endocardial electrode-pacemaker (C. second J'Gnel) which was removed threedays later (C. third J'Gnel). and subsequently succumbed to ventricular tachycardia and fibrillation (C. bottom J'Gnel). CHEST I 86 I 6 I DECEMBER. 1984

918

At least one of the disorders was present in 24 patients with variant angina, and 11percent of the patients with variant angina had both migraine and Baynauds phenomenon . Emotional stress, which is known to be a factor in Baynauds phenomenon and in migraine, also plays a major role in CAS. Recently, we" analyzed a detailed psychologic profile in 27 middle-aged women with angina and normal coronary arteriograms, and round nine with typical vasospasticangina, the onset ofwhich coincided with sudden worsening of a tense but contained emotional imbalance due to an erupting traumatic experience commonly centered around sexuality. Three of the nine patients had Raynaud's phenomenon, and four had migraine. Our study therefore strongly supports a causal relationship between emotional distress and attacks of CAS and the earlier findings of an increased association among CAS, migraine , and Baynauds phenomenon. CORONARY SPASM, CARDIAC ARRHYTHMIA, AND SUDDEN DEATH

Coronary artery spasm is also given prominent consideration in the cause of sudden death . Serious and often fatal cardiac arrhythmias may occur during an attack ofvariant angina. The association ofadvanced degree heart block with ventricular tachycardia and ventricular fibrillation has been documented in pa-

Coronary Artery Spasm

tients with variant angina" (Fig 1). Other reports noted an incidence of 10 percent of ventricular flbrillation" and 22 percent of cardiac arrest" among patients with variant angina. Although ventricular dysrhythmias have generally been considered the mechanism of sudden death in patients with CAS, recent work from our laboratory round another hitherto unrecognized mechanism, namely: sinus node dysfunctionllu 5 (Fig 2). That three patients were encountered over a relatively short period suggests that it is not an isolated, rare event, but may occur more frequently than commonly recognized. The observation that CAS was the mechanism of sinus node dysfunction in patients with variant angina has direct clinical relevance in two respects . First, just as in other patients with sinus node dysfunction, pacemaker therapy" may be an important consideration in the therapeutic armamentarium of a subset of patients with CAS. Second, use of some drugs used to treat CAS, such as verapamil, should be avoided in the presence of proved or suspected sinus node dysfunction. PATHOGENESIS OF CORONARY ARTERY SPASM

The exact pathogenetic mechanism for, and etiology of, coronary spasm is not known. However, the revival of CAS as a pathogenetic mechanism of cardiac ischemia has opened new horizons for research, diagnosis, and treatment in the field of coronary artery disease.

c Sinus Node Dysfunction

FIGURE 2. In a patient with coronary vasospastic angina complicated by recurrent syncope, sinus node dysfunction was demonstrated during coronary artery spasm when demand pacing ensued (top). and normal sinus mechanism was present when there was DO coronary spasm (bottom).

Coronary Artery Spasm (Tsung o. Cheng)

- - - Aspirin Dipyr.i.dam:>le ---Ir¥ianethacin SUlfinpyrazone CYCLIC ENOOPER)XIIJE5

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Thrantx:»cane Synthetase (in platelets)

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FIGURE 3. Metabolic pathway of arachidonic acid, synthesis of prostacyclin and thromboxane At, and sites of inhibition by certain antiplatelet drugs.

and controversial. Some investigators have suggested that since aspirin, dipyridamole, indomethacin, and sulfinpyrazone block the conversion of arachidonic acid to cyclic endoperoxides, generation of thromboxane ~ as well as prostacyclin may be inhibited. That these drugs block prostacyclin synthesis may account for the absence of dramatic improvement. As a matter of fact, aspirin" and indomethacin" may sometimes aggravate CAS in variant angina. On the other hand, other investigators have proposed that since prostacyclin is formed in the vascular lining, the coronary arteries with significant atherosclerosis may be incapable of prostacyclin synthesis. Therefore, these agents may block only thromboxane ~ generation, with consequent beneficial effect. Nevertheless, at this time, therapy of CAS with antiplatelet agents has not been conclusively shown to be of benefit. DIAGNOSIS OF CORONARY

The recent discovery of thromboxane .At, a potent vasoconstrictor released by the aggregating platelets, and prostacyclin, a potent vasodilator produced by the vascular endothelial cells, opens a new field of research on the mechanisms that control the local vascular tone. Work on the interrelationship of prostaglandins and platelet function has further helped in understanding involvement of platelets in thrombosis, coronary artery disease, and CAS. The most abundant prostaglandin precursor is arachidonic acid, which is present among the phospholipids of all mammalian cell membranes. Once released from the cell membrane by the action of the activated enzyme phospholipase ~, the arachidonic acid can be metabolized in one of two pathways into oxygenated products by cyclo-oxygenase (also known as prostaglandin synthetase) and thus converted into the stable prostaglandins with two double bonds of the E and F series, as well as into two unstable products with great and contradictory biologic activity: thromboxane .At and prostacyclin (Fig 3). Thromboxane ~ is formed in the presence of thromboxane synthetase, an enzyme found in platelets. Prostacyclin is formed in the presence of prostacyclin synthetase, an enzyme abundantly present in the vascular endothelium. A relative increase in the level of thromboxane ~ or a decrease in the prostacyclin may play an etiologic role in CAS. Indeed, increases in platelet aggregation" and in thromboxane Al~ in coronary sinus blood have both recently been demonstrated during attacks of CAS in variant angina, although there is some question as to whether increased coronary sinus thromboxane ~ production is a cause or a result of vasospastic angina. i9 Antiplatelet agents such as aspirin, dipyridamole, indomethacin, and sulfinpyrazone have inhibitory effects on prostaglandin metabolism and formation of thromboxane ~. However, their role in the management of CAS is unclear

ARTERY

SPASM

The diagnosis ofCAS is clinically important not only because it may playa role in the pathogenesis ofseveral well-known coronary syndromes, but also because specific treatment with various drugs, including the recently introduced calcium slow-channel blockers, is now available. The diagnosis is usually obvious if typical ECG changes in the form of ST-segment elevations over the site corresponding to the coronary artery in spasm are observed during an attack (Fig lA). Unfortunately, some of these patients may have no angina during the period of ST-segment elevation (Fig lB)-"variant angina without angina"6-and, thus, unless continuous 12-lead ECGs are obtained, the diagnosis may often be missed. Many patients with variant angina have infrequent attacks, and consequently ambulatory Holter monitoring is a low-yield procedure. The only certain means of diagnosing coronary artery spasm are, ofcourse, by coronary arteriography. However, angiographic observations ofcoronary spasm during routine studies in the cardiac catheterization laboratories are rare, and usually made by chance except when contrast injections are performed during an episode of variant angina. The incidence of coronary spasm observed during routine angiographic studies is low; because of: (1) the frequent occurrence of"benign" catheter-induced spasm, especially of the right coronary artery; (2) the common practice of premedicating patients with atropine, which tends to mask coronary spasm." (3) the routine use of nitroglycerine for repeated left ventriculography preceding coronary arteriography; (4) delay in exchanging a preformed coronary catheter when the coronary artery in spasm is not the one for which the catheter is designed; (5) concern over repeated injections of the spastic coronary arteries during angina with alarming ECG - changes and reflex reaction of prompt nitroglycerine CHEST I 88 161 DECEMBER, 1984

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FIGURE 4. Induction of right coronary artery spasm, angina and ST-segment elevation in II and III by ergonovine maleate (Ergotrate) and subsequent resolution following sublingual nitroglycerin administration in a patient with variant angina.

administration; (6) the relatively small statistical chance of occurrence at angiography of transient coronary spasm in a sedated patient, unless one is patient enough to wait for its spontaneous occurrence or it is induced. Therefore, what is usually indicated to establish a diagnosis is provocative testing. In the United States the most commonly used agent is ergonovine maleate (Ergotrate)." The latter is an ergot alkaloid and a smooth muscle constrictor. It should be emphasized that ergonovine maleate (Ergotrate), a lysergic acid and amine alkaloid, rather than ergotamine tartrate (Gynergen), which is an amino acid alkaloid, is to be used in provocative testing because of less tendency for endothelial damage and excessive uterine contraction

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with the former than with the latter 34 Several protocols of ergonovine testing have been proposed; common to all reported protocols is coronary arteriography and evaluation of baseline left ventricular hemodynamic function prior to ergonovine administration, intravenous (IV) administration of ergonovine in incremental doses (0.05, 0.10, 0.20, 0.30, and in some cases 0.40 mg) with continuous hemodynamic and ECG monitoring, and standby freshly prepared nitroglycerin solution for IV or intracoronary administration for prompt reversal of induced CAS. For an ergonovine test to be positive, all of the followingthree criteria-typical angina, a focalcoronary artery spasm of greater than 40 percent, and ST-segment elevations (Fig 4)-must be met, as esophageal spasm may result

5. Atrial-pacing-induced ST-segment elevation and angina in a patient with variant angina. Coronary Artery Spurn (Tsung

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from ergonovine stimulation and produce pain indistinguishable from angina." It is therefore obvious that ergonovine testing should only be done in a coronary arteriographic laboratory, although in some centers ergonovine testing has been performed in a coronary care unit for patients whose coronary anatomy is known from a recently performed coronary arteriogram . Contraindications are the same whether or not coronary arteriography is done and include multiple critical organic stenoses, severe left ventricular dysfunction or heart failure, recent myocardial infarction, recent prolonged myocardial ischemic pain, significant hypertension, uncontrolled ventricular arrhythmias, cerebrovascular disease, and pregnancy. While other provocative tests have been proposed, such as methylcholine injection, cold pressor test , atrial pacing' (Fig 5), and exercise" (Fig 6), ergonovine testing remains the most sensitive and specific method for diagnosis of CAS35 and is safeprovided there is strict adherence to the above-outlined protocol. 36 ROLE OF CALCIUM IN CORONARY SPASM

It is now clear that the human epicardial coronary artery is not just a passive conduit through which blood flows but a highly reactive vessel in constant motion with cyclicalperiods ofcontraction and relaxation. This phenomenon of vasomotion is most probably a part of the normal process of autoregulation and is a calciummediated event." Coronary artery spasm can be regarded as a strong contraction of smooth muscle induced by an increase in intracellular calcium ions. Such increases in intracellular calcium ions occur in response to stimulation of the artery with an agonist, such as o-adrenergtc stimulation with norepinephrine.

The calcium ion acts as the excitiltion signal for the muscle cells ofthe artery to couple and contract. When the cells are stimulated to contract by any of the neurohormonal substances that have this ability, an influx of calcium takes place. Calcium, upon entering the cell through voltage-dependent channels, first binds to calmodulin, a calcium-binding protein in smooth muscle, and the calcium-calmodulin complex activates the enzyme myosin-kinase that catalyzes the transfer of phosphate to myosin. In this form, myosin can interact with actin to produce muscle contraction and arteriolar constriction. Additional reeeptor-operated Ca + + channels can be recruited as a consequence of activation of a-adrenergic receptors in the sal" colemma. CALCIUM-CHANNEL BLOCKER THERAPY

From the above description-greatly simplified-it seems obvious that there are several points at which the excitation-contraction coupling by calcium can be interrupted or inhibited. Calcium fluxes can be cut off at the surface ofthe cell membrane; within the calcium ..slow" channel or channels in this membrane; between the membrane and the sarcoplasmic reticulum, or in such a wayas to prevent release or uptake ofcalcium by the sarcoplasmic reticulum; or, finally, by preventing the binding of calcium to the regulatory proteins. This, basically, is what the various calcium-channel blockers do. Calcium-ehannel blockers offer a whole new approach to the therapy of CAS. They are a giant step forward in 19805 in management of vasospastic angina, in the analogous to the introduction of ~ -blockers treatment of classic exertional angina in the 1960s. In the United States three calcium-ehannel blockers CHEST I 88 I 6 I DECEMBER. 1884

123

are available: nifedipine, verapamil, and diltiazem. Although they are grouped under the general heading of calcium-channel blockers, each drug has a different chemical structure-s-nifedipine, a dihydropyridine derivative; verapamil, a papaverine derivative; diltiazem, a benzothiazepine derivative-and its own specific pharmacologic and pharmacokinetic mechanisms of action and adverse reactions and, therefore, its specific clinical indications and contraindications. However, all three are very effective against CAS. Nifedipine is effective against CAS in usual dosage of 30 to 120 mg/day in divided doses every six hours. Its principal side effect is pedal edema due to peripheral vasodilation. It has no effect on the conduction system and can be given safely with ~-blockers and nitrates. Verapamil is a very effective agent for CAS, especially if there is coexistent supraventricular tachyarrhythmia. The standard dosage is 80 to 480 mg/day in divided doses every six to eight hours. Side effects include constipation, muscle cramps, rash, nausea, and vomiting. It can be given along with nitrates, or; With caution, ~-blockers, but should not be given to patients with conduction disturbances, sinus node dysfunction, or congestive heart failure. Diltiazem is also effective against CAS, and, at its usual dosage of 240 to 360 mg/day in divided doses every six hours, is practically devoid of any adverse reactions. It can be given safely with ~-biockers or nitrates, but is contraindicated in AV conduction disease and severe left ventricular failure. The effectiveness of calcium-ehannel blockers in treating CAS has now changed the diagnostic approach to patients with Prinzmetals variant angina. In some centers, the therapeutic response to a calcium-channel blocker is frequently used as an alternative to establishing a diagnosis by ergonovine test. As a matter of fact, with effective calcium-channel blocker therapy, the ergonovine test often becomes negative (Fig 7). USE OF P-BLOCKERS IN CORONARY SPASM

Patients who have CAS without significant coronary atherosclerosis generally respond exceedingly well to calcium-channel blocker therapy. Those who have CAS superimposed on fixed atherosclerotic coronary disease may occasionally require the addition of pblockers to reduce myocardial oxygen demand. Betablockers alone are not effective agents for the treatment of CAS, and in fact may exacerbate clinical symptoms by increasing a-adrenergic activity. However; if nitrates and/or ca1cium-channel blockers are used simultaneously, p-blockers, especially propranolol because of its antiplatelet effects, may be administered with impunity. RELATION OF CORONARY SPASM TO CORONARY ATHEROSCLEROSIS

There have been reports that in animals fed high-

cholesterol diets, calcium-blockers can alter the natural course of atherosclerotic disease." Ginsburg" followed up patients taking diltiazem for over two years and found that the number of cardiovascular events such as heart attack, sudden death, and angina decreased markedly. Thus, calcium-ehannel blockers may actually alter the course of the disease process as well as relieve symptoms. This observation assumes a new significance in light of recent report that prolonged CAS may actually lead to coronary atherosclerosis." Marzilli and associates" recently described a patient whose spontaneously occurring coronary arterial spasm eight months later progressed to fixed arteriosclerotic narrowing that required coronary artery bypass surgery. Thus, two distinctive mechanisms are currently postulated to be involved in the pathogenesis of ischemic coronary heart disease: (1) fixed organic obstruction by progressive atherosclerosis of the coro-

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7. During cardiac catheterization (fi"" panel) the patient , spontaneously developed angina and ST-elevatfon in leads 2 and 3 with reciprocal ST-depression in lead 1 due to right coronary artery spasm (aecond panel), accompanied by sinus bradycardia (third panel) and ventricular tachycardia (fourth panel),unrelieved by two sublingual O.4-mg nitroglycerin tablets (fifth panel), but promptly relieved by chewing 10 mg of nifedipine (arth panel). Thereafter; intravenous ergonovine maleate in incremental doses up to 0.6 mg failed to provoke coronary artery spasm, angina, or ECG changes (seventh ptJnel). The time of each event is indicated in left: upper comer of each panel. FICURE

nary arteries, and (2) dynamic functional obstruction by transient coronary vasospasm. Heretofore, these two mechanisms have been thought to be unrelated. Now it has been well shown that not only can fixed atherosclerotic narrowing often bea nidus for superimposed coronary vasospasm, but also that coronary spasm itself can lead to later development of fixed atherosclerotic coronary obstructions. CONCLUSION

The revival of coronary artery spasm as a pathogenetic mechanism of cardiac ischemia is opening new horizons fur research, diagnosis, and treatment in the field of ischemic heart disease, The clinical manifestations of ischemic heart disease appear to result from a variable combination of fixed organic stenoses and transient functional changes in the coronary lumen resulting from vasoconstriction and intravascular obstruction by blood elements. Variant angina represents only one aspect of a continuous spectrum of vasospastic myocardial ischemia. At one end of the spectrum is a normal coronary artery which is so susceptible to vasoconstrictive stimuli that spasm can be elicited by a host of stimuli, even of relatively low intensity; this hypersensitivity is efficiently reduced by nitrates and calcium-ehannel blockers, At the other end of the spectrum is advanced coronary atherosclerosis which may be so severe as to require coronary bypass surgery for effective myocardial revascularization. Between these two extremes, various combinations of the two exist. The triggering stimuli responsible for the local vascular hypersensitivity are' likely to be different in different patients, and even in the same patient during different episodes. Their nature remains to be elucidated. REFERENCES

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30 Miwa K, Kambara H, KawaiC. Effect of aspirin in large doses on attacks of variant angina. Am Heart J 1983; 105:351-55 31 Cheng TO. Angina aggravator. Mod Medicine 1983; 51:234 32 Cheng TO. Against routine use of atropine during coronary CHEST I 88 I 8 I DECEMBER, 1884

I2S

arteriography. Cathet Cardiovasc Diagn 1981; 7:459

33 Cheng roo Ergotrate in coronary artery spasm. Circulation 1976; 53:585-86 34 Cheng

roo

Ergonovine in coronary vs esophageal spasm. Ann

Surg 1984; 199:123

35 Walen D D, Szlachcic J, Bonan R, Miller D D, Dauwe It: Theroux ~ Comparative sensitivity of exercise, cold pressor and ergonovine testing in provoking attacks of variant angina in

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patients with active disease. Circulation 1983; 67:310-15 36 Cheng roo Irreversible coronary occlusion and ergonovine, Circulation 1982; 65:640 37 Ginsburg R. CoronarY artery spasm: clinical experience and implications. Hosp Pract 1983; 18:165-76 8, 1iivella MG, Palumbo C, Maseri A. 38 Marzilli M, ~ldstein Some clinical considerations regarding the relation of coronary vasospasm to coronary atherosclerosis: a hypothetical pathogenesis. Am J Cardioll980; 45:882-86