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Twelve patients were entered prospectively into a randomized double-blind study comparing the efficacy of nifedipine and isosorbide dinitrate (ISDN) in the treatment of variant angina pectoris due to coronary artery spasm. Using the diary technique, both anginal episodes and nitroglycerin tablets consumed were recorded during the pretrial, no drug period, and both active drug phases. During the baseline pretrial period, an average of 1.1 anginal episodes/day occurred with reduction to 0.28/day during nifedipine treatment and 0.39/day during ISDN treatment. Headache was the major side effect during ISDN treatment, occurring in 9 of 11 (81%) patients; and nonheart failure related pedal edema during nifedipine treatment, occurring in 4 of 12 (33%) patients. Intolerable side effects necessitating cessation of treatment occurred in two patients during nifedipine treatment and in three patients during ISDN treatment. Patients preferred nifedipine over ISDN because of increased efficacy and fewer uncomfortable side effects. We conclude that both nifedipine and ISDN are effective therapy for coronary spasm, but that nifedipine was more effective and was preferred by the majority of patients.

Thromboxane A2 (TxA2), an arachidonic acid metabolite causing vasoconstriction and platelet aggregation, is a putative mediator of coronary-artery vasospasm. To determine whether platelet-released TxA2 causes coronary arterial vasospasm, we measured plasma thromboxane B2 (TxB2, the inactive hydration product of TxA2) in the radial-artery and coronary-sinus blood of seven patients and performed therapeutic trials of antiplatelet agents in nine. Although coronary-sinus TxB2 levels rose from the base line approximately fivefold with spontaneous ischemia, samples drawn early in ischemia showed no rise over base-line values. Although a 150 mg dose of aspirin reduced urinary dinor-TxB2 levels by over 75 per cent, it had no effect on the course of the chronic recurrent form of angina pectoris due to vasospasm ("vasotonic angina"). Similarly, indomethacin had no effect on the frequency or duration of ischemia. TxA2 is unlikely to cause vasotonic angina, but it may be released during coronary vasospasm.

The 24-h ambulatory electrocardiograms of 15 patients with both variant angina and ischaemia-related arrhythmias were analyzed to correlate cardiac pain with the following variables: site, type, duration and magnitude of ECG changes, presence and type of arrhythmias and time of occurrence of ischaemic attacks during the 24-h. Apart from sublingual nitrate therapy, Holter monitoring was performed in the Coronary Care Unit (CCU), in the drug-free state in all patients. During a total of 79 days of monitoring, patients had 1385 ischaemic episodes, of which only 30% were painful. The site of ischaemia did not predict the occurrence of pain. Pain was more frequently associated with ST-segment elevation, longer ischaemic duration, increased time to peak ECG change, and greater ST-segment shift and arrhythmias. When the 259 attacks in association with ventricular arrhythmias were compared to the arrhythmia-free episodes, they were more frequently painful for the same duration and magnitude of ECG ischaemic changes. Furthermore, the complexity of arrhythmias increased the probability of cardiac pain. Most ischaemic episodes occurred at night and a decrease in the frequency of painful episodes (apart from those associated with arrhythmias) was apparent. Thus, in addition to electrocardiographic severity and duration of ischaemia, the presence of ventricular arrhythmias and the time of occurrence seem to influence pain perception during ischaemia.

The coronary hemodynamic effects of ergonovine maleate were examined in 15 patients with a chest pain syndrome not thought to be variant angina. Ergonovine was given intravenously in sequential doses of 0.05, 0.1 and 0.25 mg while measurements were made of systemic hemodynamic variables, coronary sinus blood flow and coronary arteriovenous oxygen difference at intervals during the protocol. Coronary arterial diameters were measured from the 35 mm cineangiogram. Despite an increase in myocardial metabolic demand, as estimated with the heart-rate-blood pressure product, there was no apparent increase in coronary vascular resistance. In addition, there was a significant widening of the coronary arteriovenous oxygen difference in five of the seven patients in whom it could be measured. However, neither chest pain nor ischemic electrocardiographic changes were evoked. Although ergonovine also produced a diminution in epicardial coronary arterial diameters, this effect was not sufficient to explain the absence of appropriate coronary vasodilation. These results suggest that ergonovine may limit the normal vasodilatory response of the arteriolar bed to increases in myocardial metabolic demand.

Forty-four cases with myocardial rupture (33 with free wall rupture, 9 with interventricular septal perforation and 2 with papillary muscle rupture), all of which were ascertained by autopsy and/or at surgery, were analyzed. When the following 7 risk factors were actively managed in the acute stage of myocardial infarction, the incidence of myocardial rupture was significantly reduced: a) high blood pressure on admission, b) physical and emotional instability, c) recurrent chest pain, d) aged females, e) no history of angina or myocardial infarction, f) large myocardial infarction on ECG and g) the first 10 days after the attack of myocardial infarction. If cardiogenic shock occurs, surgery should be performed as soon as possible; if not, it should be delayed 3 weeks. The natural history of ischemic heart disease was analyzed in 400 medically-treated patients with significant coronary artery disease. They had been followed up continuously and periodically for more than one year. The prognosis of the patients with 3-vessel disease or left main trunk disease, those with poor left ventricular function (EF less than 30%) and of old age (greater than or equal to 60) and those who had a history of ischemic heart disease was poor. Follow-up study was done in 30 patients with variant angina. They often had life-threatening arrhythmias during attacks (8 ventricular tachycardia or ventricular fibrillation, 8 serious bradyarrhythmia). All patients with variant angina should be treated medically at first, and only patients with organic coronary artery disease and chest pain on effort in spite of the medical treatment should be considered as candidates for AC bypass surgery.

To determine whether calcium-flux blockade with nifedipine blunts coronary vasospasm, four patients with angiographically demonstrable coronary arterial spasm in the absence of significant fixed coronary arterial stenosis were evaluated with coronary arteriography before and after treatment with nifedipine. After initial coronary arteriography, ergonovine was administered in successive doses of 0.05, 0.1 and (when necessary) 0.2 mg intravenously at 3 minute intervals. Three patients had symptomatic high grade focal coronary arterial spasm with electrocardiographic changes, and the fourth exhibited asymptomatic 60 percent constriction of the left anterior descending coronary artery. A maximal ergonovine challenge was repeated 30 minutes later after each patient had been pretreated with a 20 mg sublingual dose of nifedipine. Under these conditions, no patient had chest pain or electrocardiographic changes. Furthermore, neither focal nor diffuse coronary arterial spasm was demonstrable angiographically after the second challenge. Thus, in each case, a single dose of nifedipine precluded the angiographic expression of ergonovine-provoked coronary arterial spasm.

The association of a cardiac disturbance and a subarachnoïd hemorrhage is well known but the cardiac signs seldom look the most important. When studying a case which was very particular because the cardiac signs consisted in a Prinzmetal's variant angina, it finality appears that the Prinzmetal's angina is not so rare as could be thought in such circumstances. Therefore a neurological pathology hidden by a cardiac one has been rarely reported such as it was seen in that case. In the literature, the influence of the parasympathetic and especially the sympathetic nervous system is emphasized as a probable cause of the most frequent cardiac abnormalities. All the authors think the medical cardiac treatment and the surgical treatment of the subarachnoïd hemorrhage have to be done at once.

Angina with "normal coronary arteries" might best be thought of as "angina with coronary dysfunction". It seems likely that this syndrome is due to inadequate regional myocardial perfusion with manifestations similar to those seen when ischemia results from occlusive coronary artery disease. The prognosis of the disorder is favorable, but occasional catastrophic events occur. It appears likely that maldistribution of perfusion results from dynamic changes affecting proximal, and perhaps distal coronary vessels, potentially mediated by vasoactive substances released from platelets precipitating or exacerbating coronary arterial spasm. Clarification of the pathogenesis of the syndrome should permit implementation of more effective therapy and prevention of the rare malignant sequelae of this disorder.

A case is reported of the variant form of Prinzmetal angina, occurring two months after effort angina, in which the electrocardiogram revealed a Q wave in V2 in addition to ST segment elevation in precordial leads all of which disappeared in a few minutes. Several hours later, the ECG changes were suggestive of antero-septal infarction. However, four days later an R wave was present in lead V2, and 12 days after the acute episode, the tracing became entirely normal. Cinecoronary angiography revealed severe obstruction of the anterior descending artery, and a moderate obstruction of the left circumflex artery. The possibilities of spasm and/or coronary thrombosis, of spontaneous recanalization and of reperfusion due to thrombolysis are discussed, in addition to interpreting the abnormal Q waves as presumably due to severe myocardial ischemia resulting from acute coronary insufficiency. The present case exemplifies the concept that the syndromes of acute coronary heart disease cannot always be precisely differentiated, since they often overlap and are difficult to identify.

The effects of intravenous magnesium on exercise-induced angina were examined in 15 patients with variant angina and in 13 patients with stable effort angina and were compared with those of placebo. Symptom-limited bicycle exercise and thallium-201 myocardial scintigraphy were performed after intravenous administration of 0.27 mmol/kg body weight of magnesium sulfate and after placebo on different days. In all patients, serum magnesium levels after administration of magnesium sulfate were about twofold higher than levels after placebo. Exercise-induced angina associated with transient ST segment elevation occurred in 11 patients with variant angina receiving placebo and in only 2 of these patients receiving magnesium (p less than 0.005). On the other hand, exercise-induced angina was not suppressed by magnesium in any patient with stable effort angina. In these patients there was no significant difference in exercise duration after administration of placebo versus after administration of magnesium. The size of the perfusion defect as measured by thallium-201 scintigraphy was significantly less in patients with variant angina receiving magnesium than that in those receiving placebo (p less than 0.001), whereas it was not significantly different in patients with stable effort angina receiving placebo versus magnesium. In conclusion, exercise-induced angina is suppressed by intravenous magnesium in patients with variant angina but not in patients with stable effort angina. This beneficial effect of magnesium in patients with variant angina is most likely due to improvement of regional myocardial blood flow by suppression of coronary artery spasm.

Coronary arterial vasoconstriction, well recognized in Prinzmetal's variant angina, may participate in the pathogenesis of classic angina as well. Several recent studies in patients with obstructive coronary artery disease suggest that apparently spontaneous reductions in coronary blood flow can result in myocardial ischemia and even infarction. Evidence supporting the alpha adrenergic nervous system as a cause of such coronary vasoconstriction is reviewed, particularly the results of provocative testing with the cold pressor stimulus. Upon exposure of the skin to cold, patients with coronary artery disease demonstrate an inappropriate coronary vasoconstrictor response, often sufficient to produce angina. Normal patients, by contrast, show no change in coronary vascular resistance. In patients with a diseases coronary circulation, inappropriate vasoconstriction further restricts myocardial perfusion and appears to be little affected by beta adrenergic blocking agents or nitrates in the usual dosages. Nifedipine has proved effective in preventing coronary arterial spasm in patients with Prinzmetal's angina. Studies currently in progress suggest that it is also effective in blocking inappropriate coronary vasoconstriction in patients with typical angina. Nifedipine may thus be a useful addition to the treatment of ischemic heart disease.

Ergonovine maleate (Ergotrate) was given to 57 patients undergoing coronary arteriography for investigation of angina occurring at rest or without provocation when routine study showed normal arteries or insufficient occlusive disease to explain their symptoms. This provocative test induced coronary arterial spasm in 13 patients, 10 of whom had definite Prinzmetal's angina. The spasm was easily reversed with sublingually administered nitroglycerin. The spasm was occlusive or nearly occlusive in nine patients, and there was associated reproduction of the chest pain and S-T elevation similar to the spontaneous episodes. One patient with Prinzmetal's angina had S-T depression rather than elevation in association with the chest pain. The other three patients without Prinzmetal's angina had focal narrowing without coronary occlusion, reproduction of the chest pain or electrocardiographic changes. Of the 44 patients who did not demonstrate coronary spasm in response to ergonovine, 29 had normal coronary arteries and 15 had various degrees of atherosclerotic occlusive disease. We conclude that cautious administration of ergonovine maleate during coronary arteriography can be safely used to elicit coronary spasm in some patients who have insufficient fixed occlusive disease to explain their symptoms.

Exercise tests were performed in 14 patients with untreated variant angina with frequent spontaneous attacks and in 15 patients after treatment abolished the attacks. (1) Anginal attacks associated with ST elevation were induced by exercise in 79% of untreated patients. By contrast, ST elevation was not observed in treated patients and ST depression was induced in 53% of the cases. (2) Exercise-induced ST elevation in untreated patients was shown in the same leads as the spontaneous attacks. (3) Exercise-induced ST elevation appeared initially during the recovery phase after exercise in 36% of untreated patients. Exercise-induced ST depression appeared during or immediately after exercise. (4) The reproducibility of exercise-induced ST elevation was low with repeated tests at different stages, but exercise-induced ST depression was consistently observed. (5) The exercise-induced ST depression and lack of ST changes in treated patients were highly suggestive of the presence and absence of organic coronary artery disease, respectively. However, the exercise-induced ST elevation in untreated patients did not differentiate between the presence or absence of organic stenosis of the coronary arteries. The results of exercise tests vary with the stage of variant angina. It is suggested that a coronary arterial spasm is a trigger mechanism for exercise-induced angina in cases of variant angina with frequent spontaneous attacks.

The term coronary artery spasm should not be used interchangeably with the specific clinical syndrome "variant angina" since it does occur in other acute and chronic ischemic heart disease syndromes. The term coronary artery spasm should not be applied to patients with ischemic heart disease unless there is clinical, angiographic, and physiologic evidence of its presence. The diagnosis of coronary artery spasm is confirmed by angiography, i.e. change in caliber of the coronary arteries plus evidence of ischemia. Probable diagnosis is in patients who have the syndrome of variant angina, i.e. rest angina associated with ST segment elevation on the electrocardiogram. One can be highly suspicious that the spasm is at work in patients who have rest angina, especially those with unstable angina. One can be suspicious of patients who have variable effort angina or walk-through angina. Coronary artery spasm is a possibility in patients with an acute myocardial infarction or acute re-infarction and is also possible that sudden death in patients with normal coronary arteries can be related to coronary artery spasm. Coronary artery spasm is the usual cause of myocardial ischemia in patients with rest angina without effort angina. This has also commonly been documented in patients with rest and effort angina. There are isolated reports suggesting that patients with effort angina pectoris also develop coronary artery spasm. Coronary artery spasm has been documented to occur in association with acute myocardial infarction. Whether coronary artery spasm is the cause or the result of myocardial infarction has not been determined at this time. However, the recent combined use of intracoronary nitroglycerin and intracoronary streptokinase in patients with acute myocardial infarction has shown reversal of totally obstructed arteries and suggests the relationship between coronary artery disease, coronary artery spasm, and in situ coronary thrombosis. The incidence of sudden death in patients with documented coronary artery spasm is unknown. But, since complete heart block and/or ventricular tachycardia occur during episodes of coronary artery spasm, it is not unreasonable to assume that some patients have died as a result of these rhythm disturbances. The prognosis of patients with coronary artery spasm seems to depend on the presence or absence of severe coronary atherosclerosis, i.e. those with severe disease have a worse prognosis. Current therapy of patients with coronary artery spasm involves the use of nitrates and calcium antagonists.(ABSTRACT TRUNCATED AT 400 WORDS)

To examine whether intracoronary injections of acetylcholine induce coronary artery spasm in patients with vasospastic angina, incremental doses (20, 30 and 50 micrograms) were injected directly into the coronary arteries in 12 patients with variant angina (Group A: rest angina with electrocardiographic ST-segment elevation during attacks), 19 with vasospastic angina (Group B: rest angina and/or effort angina with variable threshold in the treadmill exercise stress test), 11 with organic coronary artery stenosis but without angina (Group C), and 14 without coronary artery disease (Group D). A temporary cardiac pacemaker was positioned in the right ventricle. Coronary artery spasm was defined as severe vasoconstriction (greater than or equal to 90% of reduction in the luminal diameter) with chest pain and/or ischemic changes in the electrocardiogram. Intracoronary injection of acetylcholine induced spasm of at least one coronary artery in all 12 patients (100%) of Group A, in 18 (95%) of Group B, in two (18%) of Group C, and in two (14%) of Group D. Thus, the sensitivity of this method for inducing coronary spasm was 100% in group A, 95% in Group B, and 97% in Group A plus Group B. The specificity for inducing spasm was 86% in Group D, and 84% in Group C and Group D. When acetylcholine was injected separately into the left and right coronary arteries, spasm of both the coronary arteries was observed in two (40%) of Group A, in five (33%) of Group B, and none (0%) of Group C and Group D. Acetylcholine (20 micrograms) induced coronary spasm in 10 (83%) of Group A and only in nine (47%) of Group B.(ABSTRACT TRUNCATED AT 250 WORDS)

Vigorous hyperventilation was induced for five minutes immediately after a five-minute infusion of 100 ml of Tris-buffer (pH 10) in nine patients with Prinzmetal's variant angina. In eight of the patients, chest pain with ischemic changes in the electrocardiogram occurred during this procedure or within five minutes after it ended. Coronary arterial spasm appeared after the procedure and disappeared after the administration of nitroglycerin in all four patients in whom coronary cinearteriography was performed. This was evident both before and after the procedure and after sublingual administration of nitroglycerin (0.6 mg). The oral administration of 90 mg of diltiazem, a calcium antagonistic drug, two hours before, completely suppressed the attack induced by the procedure in all of the five patients who received this drug. We conclude that hyperventilation plus Tris-buffer infusion induces coronary arterial spasm and anginal attack in patients with Prinzmetal's variant angina and that diltiazem suppresses these reactions.

Six patients who had documented coronary spasm and no coronary artery with organic obstruction greater than 50% developed angina and ST-segment elevation on exercise testing. Oral verapamil, 160-480 mg/day, prevented exercise-induced ischemia in all patients and increased maximal work capacity from 611+/- 250 kpm to 808 +/- 160 kpm (p less than 0.02). In two patients, a relationship between the prevention of exercise-provoked ischemia and the plasma concentration of verapamil was demonstrated, and in one of these, the relationship had a diurnal pattern. Patients with variant angina may develop coronary spasm on effort and often respond to verapamil.

Spasm of a large coronary artery occurs most often from midnight to early morning and least often in the afternoon, due to the circadian variation of the tone of the large coronary artery in most patients with variant angina. Alpha adrenergic stimulation induces coronary spasm most easily in the early morning and least easily in the afternoon. Coronary spasm is due to strong contraction of coronary vascular smooth muscle cells which is triggered by an increase of intracellular calcium ions; hyperventilation plus TRIS-buffer infusion induces coronary spasm by decreasing hydrogen ions which antagonize the action of calcium ions. Administration of nitroglycerin promptly relieves the acute attack of coronary spasm, and calcium antagonists such as diltiazem, nifedipine and verapamil, which block the entry of calcium ions into coronary vascular smooth muscle cells and dilate large coronary arteries, prevent the occurrence of coronary spasm.

A patient with a pheochromocytoma presented with profound hypertension and the clinical syndrome of coronary artery spasm after the initiation of beta blockade therapy. It is postulated that intense unopposed alpha receptor stimulation can precipitate coronary artery spasm in susceptible persons with this tumor.