Differences in the various protocols and whether investigators were reporting the concentration in the syringe or the estimated concentration in the coronary artery led to some confusion as to the dose of acetylcholine between studies. The initial selective infusion catheter method used a steady-state maximum concentration of acetylcholine in a coronary artery of≈ 10–6 mol/L. The manually delivered methods usually report a dose of≤ 100 μg given over 20 seconds through a diagnostic catheter, which, if mixed in a 5-mL syringe, 23 amounts to≈ 10–5 mol/L in the coronary artery. This is important, because a high enough concentration may overcome the endothelial response to cause direct vasoconstriction, even in angiographically normal arteries. 24, 25

In general, the vasoconstriction in patients without variant angina was much less and was more diffuse than that observed in patients with true coronary spasm and variant angina. However, in the presence of mild stenoses or disease, a modest vasoconstrictor response reflecting endothelial dysfunction could contribute to myocardial ischemia. 26 In reality, vasoconstriction causing angina is probably part of a spectrum with some murky overlap. The Japanese Coronary Spasm Association27 and several classic studies5, 6, 18, 24 define coronary spasm as a> 90% stenosis or occlusion with acetylcholine or ergonovine. Variant angina requires this definition of spasm plus chest pain with ST elevation. Vasoconstriction without the clinical syndrome or with lesser and more diffuse degrees of constriction arguably indicate endothelial dysfunction and, if this occurs with angina, could be called vasospastic angina. 18