Prinzmetal's variant angina: Hemodynamic and angiographic observations during pain

Hemodynamic and angiographic data obtained during pain from four patients with Prinzmetal's variant angina are reported. The left ventricular pressure-time index did not increase before or during attacks of angina in three of the four patients; left ventricular systolic performance was impaired during pain in all three. In one of these three patients left ventricular pressure-volume data obtained during angina suggested a reduction in diastolic compliance; in another, pain and S-T segment elevation were present during coronary arterial spasm. The fourth patient had an increase in both arterial blood pressure and heart rate before an attack; in this patient coronary arterial spasm could not be demonstrated during the period of pain and S-T elevation. The data presented suggest that hemodynamic factors that increase the myocardial Oxygen requirements are absent and that coronary arterial spasm is present in some, but not all, patients with variant angina.     

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Two patients complained of chest pain while at rest and during physical activities. However there seemed to be no direct relation between exertional angina and an increasing level of work performed, indicating that these patients had a variable threshold of angina during exercise. In one patient spontaneous chest pain was associated with transient S-T segment changes in precordial leads, and during coronary arteriography the administration of ergonovine induced spasm of the left anterior descending coronary artery. The other patient showed S-T segment elevation in inferior leads during an ergonovine-induced anginal attack and coronary arteriography revealed a spontaneous spasm of the right coronary artery. In both patients repeated exercise tests yielded different results, because the chest pain and S-T segment depression occurred at different work loads with large differences in heart rate-systolic blood pressure product.It is concluded that a variable threshold of angina during exercise is a clinical manifestation in some patients with vasospastic angina and is probably due to the difference in coronary arterial tone at the onset of exercise.     

Prinzmetal's angina during 5-fluorouracil chemotherapy

Variant angina developed during intravenous 5-fluorouracil therapy in a patient without prior history of angina pectoris. Ambulatory electrocardiography demonstrated S-T segment elevation and ventricular ectopy during pain, whereas no symptoms or S-T segment changes occurred during placebo therapy. Prophylaxis with both nifedipine and diltiazem was successful in preventing recurrence. It is believed that 5-fluorouracil induced coronary vasospasm and that this was prevented by prophylactic calcium antagonist therapy. Drug-induced coronary artery spasm may be the cause of 5-fluorouracil-associated chest pain.     

Comparison of coronary arteriographic findings during angina pectoris associated with S-T elevation or depression

Coronary arteriographic findings during an attack of angina pectoris associated with S-T segment elevation and angina associated with S-T depression were compared in 54 patients. Thirty-eight attacks with S-T segment elevation included 2 that were spontaneous, 6 induced by methacholine, 4 by epinephrine with or without propranolol, 9 by arm exercise, 5 by hyperventilation with or without Tris-buffer infusion and 12 by ergonovine maleate. Twenty-nine of the 38 attacks were associated with total occlusion, 8 with subtotal occlusion and 1 with diffuse narrowing of a major coronary artery caused by spasm.Twenty-six attacks with S-T segment depression included 3 induced by methacholine, 13 by arm exercise, 3 by hyperventilation with or without Tris-buffer infusion and 7 by ergonovine maleate. Eight of the 26 attacks were associated with subtotal occlusion and 9 with diffuse narrowing of a major coronary artery caused by spasm; 3 attacks were associated with total occlusion of a major coronary artery well supplied with collateral vessels and 2 with total occlusion of a small coronary branch caused by spasm. Four attacks were associated not with spasm but with fixed subtotal occlusion of a major coronary artery (3 attacks) or total occlusion of a major coronary artery receiving collateral vessels (1 attack).Only 2 of the 31 patients with S-T segment elevation had collateral vessels compared with 8 of the 16 patients with S-T segment depression (p < 0.001). It is concluded that angina pectoris associated with S-T segment elevation usually indicates more severe myocardial ischemia than angina associated with S-T segment depression.     

Exercise-induced cyclic episodes of S-T segment elevation in a patient with variant angina

A unique case of variant angina is described in which cyclic S-T segment elevation was reproducibly induced by exercise. The treadmill test revealed cyclic S-T segment elevation to occur from the first minute onward, recurring with a cycle length of 2 min throughout the exercise while the work load was being increased. Similar cyclic episodes were also induced by the cold pressor test, and the ambulatory electrocardiogram demonstrated spontaneous episodes of S-T segment elevation with a similar cycle length in early mornings. Coronary arteriography revealed a fixed lesion in the mid-portion of right coronary artery with a 90% narrowing associated with coronary spasm leading to subtotal occlusion. The cyclic episodes were abolished by the administration of the calcium antagonist diltiazem. The spontaneous phasic activity of coronary arterial muscle is discussed as a possible cause or mechanism.     

Exercise-induced coronary spasm with S-T segment depression and normal coronary arteriography

The unique association of both exercise-induced coronary arterial spasm and S-T segment depression with normal findings on selective coronary arterlography is described. The patient had a prior history of typical effort angina that had recently progressed to angina at rest. Despite the change In anginal pattern, the electrocardiogram disclosed S-T segment depression that was consistent with subendocardial Ischemia, during both exercise testing and spontaneous chest pain. Exercise thallium-201 sclntigraphy demonstrated the presence of large perfusion defects of the anterior and septal walls of the left ventricle. Coronary arteriographie findings, in the absence of symptoms, were entirely normal. Severe localized, reversible coronary spasm of the proximal left anterior descending coronary artery was subsequently demonstrated during spontaneous angina, Isometric arm exercise and after the administration of ergonovine maleate. After treatment with isosorblde dlnitrate and nifediplne, the patient had no further chest pain or electrocardiographic changes, and a repeated thallium-201 stress test revealed nomal findings and greatly Improved exercise tolerance.     

Nifedipine in the treatment of unstable angina,coronary spasm and myocardial ischemia

The effects of nifedipine, a potent calcium antagonist, were studied in patients with unstable angina, coronary spasm and myocardial ischemia. Data from two separate groups of patients studied in the cardiac catheterization laboratory indicate that intracoronary injection of nifedipine promptly reversed coronary spasm—whether provoked or spontaneous—in five of six patients. In other patients, direct intracoronary injection of the drug was compared with intravenous administration. After intracoronary injection, local mechanical cardiac action virtually ceased, and the ventricular wall became thinner during systole. Thus, a specific inhibitory action on contractile energy expenditure could be demonstrated in the presence of increased coronary flow. This “oxygen-sparing” effect was tested in a group of 31 patients with symptomatic unstable angina whose pain at rest, with ST-T changes, had not responded to 8 hours of treatment with maximal beta adrenergic blockade, nitrates and bed rest. The addition of 6 × 10 mg of nifedipine rendered 27 of these patients asymptomatic within 1.5 hours. In the four patients who did not respond, coronary arteriography demonstrated severely stenotic lesions. Two of the four patients subsequently responded to intraaortlc balloon pumping and bypass surgery; one patient had a myocardial infarction and one who had a 90 percent reduction in the diameter of the left main coronary artery, died.It is concluded that nifedipine should be added to beta adrenergic blockade therapy if the latter does not appear to be immediately effective. This combination has not been shown to cause any hemodynamlc deterioration, and only a minority of the patients treated sustained a myocardial infarction during the first 3 months of follow-up. The use of nifedipine in unstable angina deserves further clinical evaluation.     

S-T segment elevation and coronary spasm in response to exercise

The prevalence rate of exercise-induced S-T segment elevation of 0.1 mV or greater in symptomatic patients is 3.0 to 6.5 percent in most studies. S-T segment elevation is associated with a more severe degree of myocardial ischemia than depression and frequently implies a high grade coronary stenosis in the vessel that supplies the site of ischemia. Leads V₄ to V₆ and bipolar lead CM₅ have been found to be relatively insensitive in detecting exercise-induced S-T segment elevation.

The pathogenesis of S-T segment elevation is different in three clinical patient subsets reviewed. In patients after infarction, the largest of the three subgroups, exercise-induced S-T segment elevation usually appears in leads with Q waves, is more common after anterior myocardial infarction and implies underlying akinetic or dyskinetic wall motion. Of patients with variant angina, 10 to 30 percent have during exercise S-T segment elevation that is most likely provoked by coronary arterial spasm. The natural history of variant angina is cyclic, and clinical observations and laboratory findings are dependent on particular phases in the disease process and treatment. Finally, 0.2 to 1.7 percent of symptomatic patiënts without infarction or variant angina have exercise-induced S-T segment elevation. Although most of the latter have fixed high grade coronary arterial stenoses at angiography, the exact pathogenetic mechanism of S-T segment shift in this patient group is not yet fully understood.     

Refractory Case of Coronary Artery Spasm with Interesting Findings: A Case Report

This is a case of refractory vasospastic angina with unusual electrocardiographic findings and rare coronary angiographic documentation of diffuse spasm of the left coronary system with a baseline of near normal coronary arteries. A 66-year-old man presented with severe vasospastic angina that eventually progressed to non-ST elevation myocardial infarction (NSTEMI). During the episodes of chest pain, the electrocardiogram revealed ST segment depression rather than elevation. Coronary angiography revealed near normal coronary arteries with initial diffuse spasm of the left coronary system. The patient continues to be symptomatic despite treatment with different forms and doses of nitrates and calcium channel blockers. No financial support was needed or provided by any source.     

Exercise-induced angina provoked by aspirin administration in patients with variant angina

The effects of aspirin (4.0 g/day) given orally to eight patients with variant angina were observed. An exercise stress test performed in the morning was positive in two of seven patients during placebo administration, whereas a test performed in the afternoon at the same exercise work load resulted in negative findings. During aspirin administration, the afternoon exercise test repeatedly provoked anginal attacks associated with electrocardiographic changes (S-T segment elevation in five and S-T depression in two). Rate-pressure product at the end of the exercise test during aspirin administration was significantly lower than that during placebo administration (p <0.01). During aspirin administration, the frequency of angina increased markedly, and the attacks occurred not only during the night or early morning but also in the daytime in six of the eight patients. Our observations suggest that aspirin, in this large dose, reduces the capacity for exercise and provokes exercise-induced coronary arterial spasm in patients with variant angina.     

Idiopathic hypertrophic subaortic stenosis: evaluation of anginal symptoms with thallium-201 myocardial imaging.

The evaluation of angina pectoris in patients with idiopathic hypertrophic subaortic stenosis is difficult in those in the age group prone to coronary artery disease. Ten patients with angina pectoris, normal coronary angiograms and idiopathic hypertrophic subaortic stenosis were studied with thallium-201 myocardial imaging performed in conjunction with submaximal treadmill exercise testing. The resting electrocardiogram demonstrated left ventricular hypertrophy with S-T segment abnormalities in seven patients, thereby vitiating the further increase in S-T segment abnormalities that developed in these patients during exercise or in the postexercise period. Of the three patients with a normal resting electrocardiogram, one had significant exercise-induced S-T segment depression. Thallium-201 myocardial imaging revealed no significant perfusion defects in 9 of the 10 patients (90 percent). In one patient with severe left ventricular hypertrophy significant perfusion defects developed after exercise that were not present at rest. Stress thallium-201 myocardial perfusion imaging is a useful noninvasive technique that assists in ruling out the presence of significant coronary artery disease in patients with idiopathic hypertrophic subaortic stenosis.     

S-T segment elevation during exercise: Electrocardiographic and arteriographic correlation in 38 patients

The clinical significance and underlying mechanisms of S-T segment elevation during exercise were evaluated by correlating the exercise-induced S-T elevation with the coronary arteriograms and left ventriculogram in 38 patients. Of these, 37 (97 percent) showed significant coronary artery disease; 71 percent of these had proximal lesions. Of 27 patients with old myocardial infarction manifested in the electrocardiogram at rest, 25 had significant coronary artery disease and a ventricular aneurysm. All 11 patients with no previous myocardial infarction in the electrocardiogram at rest had significant coronary artery disease but only 2 (18 percent) had a ventricular aneurysm. One patient had a ventricular aneurysm without coronary artery disease. The sites of S-T elevation correctly localized the area of ventricular aneurysm of 30 (91 percent) of 33 instances and the area of the compatible diseased vessels in 38 (95 percent) of 40 instances.Our data suggest that (1) S-T elevation during exercise in the absence of a pattern of previous myocardial infarction in the electrocardiogram at rest indicates significant proximal coronary artery disease without ventricular aneurysm, whereas in the presence of such a pattern it is indicative of both ventricular aneurysm and significant proximal coronary artery disease; (2) the sites of S-T elevation accurately identify the location of ventricular aneurysm and the compatible diseased vessels; and (3) ischemia and abnormal wall motion may independently or additively underlie the mechanism for S-T elevation during exercise.     

The predictive value of a strongly positive stress test in patients with minimal symptoms

The ability of a strongly positive stress test to predict left main coronary artery disease in people with suspected coronary artery disease but with minimal or no angina was investigated in 40 such patients. Nine had a history of myocardial infarction but no angina. Thirty-one had mild angina or a history of mild angina. The stress electrocardiograms were analyzed according to criteria known to be associated with left main coronary artery disease in moderately or severely symptomatic patients; (1) early S-T segment changes (stage I or II of exercise), (2) 2 mm or more S-T segment depression, (3) downsloping S-T segments, (4) associated exercise-induced hypotension, (5) prolonged S-T segment changes after the test (≥8 minutes) and (6) anterior and inferior S-T segment depression. The prevalence of left main coronary artery disease was 35 percent and that of any severe coronary artery disease 75 percent. The criterion of anterior and inferior electrocardiographic changes with exercise was most predictive of left main coronary artery disease (P < 0.01 by χ²). Exercise electrocardiography is useful in the prediction of left main or other severe coronary artery disease even when performed in patients who have minimal angina or in those who are asymptomatic after myocardial infarction.     

Altered adrenergic activity in coronary arterial spasm: Insight into mechanism based on study of coronary hemodynamics and the electrocardiogram

To elucidate the pathophysiologic mechanism of coronary arterial spasm, the hypothesis was examined that underlying alterations in sympathetic activity may account for this syndrome in some patients. Observations were directed to alterations in coronary arterial hemodynamics and the electrocardiogram. Spasm of the left anterior descending coronary artery produced a mean increase in coronary vascular resistance of 107 percent (P < 0.05) in four patients in whom coronary sinus blood flow was measured with the thermodilution technique. The alpha adrenergic blocking agent phentolamine, given intravenously, acutely reversed coronary spasm and its clinical manifestations in eight patients and reduced coronary resistance. In four patients, administration of the long-acting oral alpha blocking agent phenoxybenzamine (20 to 80 mg/day) caused disappearance of symptoms during a follow-up period of 3 to 12 months. Transient prolongation of the corrected Q-T interval preceded spontaneous or ergonovine maleate-provoked coronary spasm in 11 patients with variant angina pectoris, whereas no significant change in the Q-T interval followed ergonovine administration in 27 control patients with atypical chest pain who did not have coronary spasm. T wave inversions in the resting electrocardiogram were normalized by isoproterenol infusion in one patient and by long-term phenoxybenzamine treatment in four patients with variant angina pectoris. These Q-T and T wave changes are analogous to those described with unilateral or asymmetric stellate ganglion stimulation in animals.

These observations suggest that alterations in the sympathetic nervous system that are consistent with asymmetric stellate ganglion activity and transient alpha adrenergic receptor stimulation can presage the development of coronary arterial spasm in some patients with variant angina pectoris.     

The influence of early repolarization variant on the exercise electrocardiogram: a correlation with coronary arteriograms

Sixteen adult patients with S-T segment elevation in their resting electrocardiograms characteristic of early repolarization variant (ERV) and chest pain syndromes of possible myocardial ischemia were evaluated with both treadmill exercise electrocardiography and coronary arteriography. Of 14 patients with normal coronary arteriograms, 13 had their resting S-T elevation return (“normalize”) to the isoelectric baseline with physical exercise, while one patient with normal arteriograms and normal left ventricular contractility but moderately elevated left ventricular end-diastolic pressure of unknown etiology developed significant S-T depression with exercise. Two patients with significant coronary atherosclerotic occlusive lesions developed “ischemic” S-T depression during treadmill testing. Symptoms developed during treadmill exercise did not distinguish patients with coronary artery disease from those without. Thus, while ERV at rest may be “normalized” by graded physical exercise in the absence of significant coronary atherosclerosis, the presence of ERV does not prevent the usual electrocardiographic manifestations of exercise-induced myocardial ischemia.     

Sudden death in prinzmetal's angina with coronary spasm documented by angiography: Analysis of three necropsy patients

Clinical and necropsy findings are described in three patients who had angina pectoris at rest, S-T segment elevation on electrocardiography during chest pain, coronary arterial spasm on angiography and sudden death. Although significant “fixed” coronary narrowing (that is, narrowing due to atherosclerotic plaques) was appreciated by angiography in only one of the three patients, necropsy disclosed in all three patients severe fixed coronary narrowings involving particularly the artery in which spasm had been demonstrated during life. Additionally, examination of each 5-mm long segment of the coronary artery that had been spastic during life (two patients) disclosed several focally spastic segments at necropsy, indicating that spasm persisted after death. Although most previously described necropsy patients with Prinzmetal's angina had some fixed coronary narrowing, underlying fixed narrowing may be difficult to identify angiographically as demonstrated by the three patients in this study.     

Inappropriate coronary vasoconstriction in patients with coronary artery disease: A role for nifedipine?

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.     

Blockade of central nervous system GABAergic tone causes sympathetic-mediated increases in coronary vascular resistance in cats

Picrotoxin, an antagonist of gamma-aminobutyric acid, produces an increase in coronary vascular resistance, S-T segment elevation, and ventricular arrhythmias after an intravenous injection of 2 mg/kg in chloralose-anesthetized cats. To determine whether these responses were due to blockade of central nervous system GABAergic mechanisms leading to an increase in sympathetic outflow to the coronary vasculature, several types of experiments were performed. First, picrotoxin was injected directly into the brain in a dose of 600 micrograms while coronary blood flow and S-T segment changes were monitored. Central nervous system administration of this agent resulted in a significant increase in coronary vascular resistance, S-T segment elevation, and arrhythmias. Second, animals were pretreated with the gamma-aminobutyric acid receptor agonist drug, muscimol, prior to central administration of picrotoxin. Pretreatment prevented the usual increase in coronary vascular resistance, S-T segment elevation, and arrhythmias. Third, animals were subjected to acute bilateral cardiac sympathetic denervation prior to picrotoxin administration. Denervation attenuated the picrotoxin-induced increase in coronary vascular resistance (mean = 11.6 +/- 2.1% vs. 26.1 +/- 7.1%, P less than 0.05) and elevation in S-T segment (mean = 0.09 +/- 0.03 mV vs. 0.29 +/- 0.04 mV, P less than 0.05), and prevented arrhythmias. Pretreatment with the alpha-receptor blocking agent, phentolamine, produced even more pronounced antagonistic effects. These results suggest that blockade of central nervous system GABAergic tone leads to enhanced sympathetic outflow to the coronary vasculature, resulting in an increase in coronary vascular resistance of sufficient intensity to cause S-T segment elevation and arrhythmias.     

Exercise electrocardiography: recognition of the ischemic response, false positive and negative patterns

The ischemic electrocardiographic response is characterized by S-T segment depression in the left ventricular leads. When this response is elicited by exercise and is accompanied by anginal discomfort, it constitutes powerful diagnostic evidence of the presence of coronary arterial obstructive disease. The amount of exercise required to elicit the response is closely related to the extent of the obstruction. S-T segment elevation provoked by exercise rarely occurs with proximal severe stenosis in the left anterior descending coronary artery or in leads exploring the region of healed myocardial infarcts. Depression of the J point may be an ischemic manifestation reversible by administration of nitroglycerin.The ischemic electrocardiographic response may be obscured by conduction defects as in bundle branch block and healed myocardial infarcts. False positive ischemic responses may be encountered in patients taking digitalis glycosides or potassium-depleting drugs, or in patients with hyperadrenergic states, pectus excavatum or short P-R Intervals.     

Syndrome of symptomatic coronary arterial spasm with nearly normal coronary arteriograms

The clinical manifestations of symptomatic coronary arterial spasm were analyzed in 30 patients whose coronary arteriograms demonstrated no fixed severe obstructions. The study group consisted of 14 men and 16 women (average age, 47 years). Angina at rest was invariable and it was usually typical in quality, location, duration and response to nitroglycerin. Exertional angina occurred in 23 percent and syncope with angina in 33 percent. Spontaneous remission of angina for at least 1 month occurred in 57 percent of patients. Prinzmetal's variant angina occurred in 77 percent of patients and only S-T segment depression or T wave changes during angina occurred in 23 percent. Major arrhythmias during ischemia developed in 47 percent. Exercise tests were positive in 24 percent. Myocardial infarction, probably due to coronary spasm, occurred in 7 percent of patients. Isosorbide dinitrate and propranolol were effective therapy in only 39 percent and 6 percent of patients, respectively. Nifedipine, a calcium flux antagonist, was effective in 80 percent of patients.Patients with normal coronary arteriograms who have clinical features suggestive of coronary arterial spasm should be considered for further investigation, including long-term electrocardiographic monitoring and provocative testing for spasm.