A renaissance of provocative testing for coronary spasm?

The term variant angina, first used by Prinzmetal et al. (1) in 1959, denotes chest discomfort with classic features of angina but occurring at rest or at night (usually the early morning hours) rather than with exertional or emotional stress. The pain is often associated with ST segment elevation and is relieved by nitroglycerin. A female predominance and frequent association with cigarette smoking, as well as migraine syndromes and Raynaud’s phenomenon, have been recognized. In 1973, spontaneous coronary spasm was documented during coronary angiography in a patient with variant angina (2), confirming the mechanism originally proposed by Prinzmetal et al. (1). Coronary spasm superimposed on minimal-to-mild atherosclerosis is the generally accepted proximate cause of variant angina, but definitive mechanisms have remained elusive. Although chest pain syndromes atypical for angina in the absence of important atherosclerotic obstructions are common, variant angina as described by Prinzmetal et al. (recurrent chest pain at rest with ST elevation) is less common but not rare. The diagnosis is challenging and requires observation of spasm associated with the patient’s typical symptoms and electrocardiographic (ECG) changes. Coronary spasm may of course contribute to other ischemic coronary syndromes, including variable threshhold exertional angina. Ergonovine, an ergot alkaloid used to control postpartum uterine bleeding, was found in 1949 to provoke angina, and was proposed in 1963 as a diagnostic test for coronary disease (3). In early studies, however, patients received very high doses of ergonovine. Severe angina was not uncommon and a reported death in a small series caused the test to be abandoned. Ergonovine testing with very low doses in the catheterization laboratory was utilized frequently in the late 1970s and early 1980s to help identify the mechanism of chest pain when only “insignificant” coronary artery disease (CAD) was found by angiography. Protocols directed cautious administration of increasing doses of intravenous (IV) or intracoronary ergonovine, with angiography several minutes after each dose or whenever chest pain or ECG changes were noted. Ergonovine, which has structural homology to norepinephrine, causes contraction of vascular smooth muscle mediated at least in part by serotonin receptors and stimulates endothelial nitric oxide generation (4). The usual result is mild generalized vasoconstriction (,20% diameter narrowing) in apparently normal coronary arteries (3,5). Strict criteria have been used to define a positive ergonovine angiographic study: near total, and localized spasm, reproducing the patient’s typical symptoms or associated ST segment shifts. Using these criteria, positive ergonovine studies have been reported in 20% to 40% of patients with clinically suspected variant angina (6). The test was generally believed to be low risk, although cases of intractable spasm requiring intracoronary nitroglycerin have been reported (7,8). When ergonovine was used in .1,000 consecutive patients by Bertrand et al. (6), there were also four cases of ventricular fibrillation with successful resuscitation. Two forms of ergonovine (ergonovine maleate and methylergonovine) have been used in the angiographic laboratory with very similar, if not identical, responses. Only methylergonovine is currently available in the U.S. In this issue of the Journal, Song et al. (9) follow up on their earlier proposal for a noninvasive test for coronary