Journal of the American College of Cardiology Vol. 59, No. 7, 2012 © 2012 by the American College of Cardiology Foundation ISSN 0735-1097/$36.00 Published by Elsevier Inc. doi:10.1016/j.jacc.2011.11.014

Acetylcholine, an endogenous neurotransmitter, is ad- EDITORIAL COMMENT opted to invasively assess the coronary endothelial function. In normal conditions, ACH causes vasodilation by releasing nitric oxide or closely related substances via endothelial Coronary Vasospasm and receptors (3). However, in the presence of endothelial dysfunction, an early marker of coronary atherosclerosis Coronary Atherosclerosis (4–6), ACH induces coronary vasoconstriction via recep- tors localized into the smooth muscle cells (7,8). The degree Do We Have to Choose?* of coronary constriction in response to ACH administration can vary considerably, ranging from mild to complete or Mario Marzilli, MD, Alda Huqi, MD near-complete coronary flow obstruction, as typically ob- Pisa, Italy served in patients with variant angina (9) who present with localized hyper-responsiveness (10). Indeed, as documented from the first angiography studies (11,12), the “state of the art” patient with variant angina was the patient with: 1) rest In this issue of the Journal, Ong et al. (1) sought to angina; 2) normal or near coronary artery tree; and 3) complete or determine the prevalence of coronary spasm in angina near-complete dynamic focal obstruction at provocative test. patients with angiographically normal coronary arteries. Of However, the concept of coronary spasm has evolved 304 patients with stable angina, 144 (47%) had normal since then. The relevance of coronary spasm has been Ͻ coronary arteries or only minimal irregularities ( 20% demonstrated in clinical scenarios other than variant angina diameter reduction) at coronary angiography. Acetylcholine (i.e., stable angina) (13,14), in which involvement of the (ACH) testing was performed in 124 of the 144 patients coronary microcirculation has been suggested as well (15). and provoked coronary spasm in 77 (62%). Thirty-five Moreover, it is now accepted that the degree of spasm can patients (45%) with constrictor response presented with be affected by a number of factors, including resting vaso- Ն epicardial spasm (defined as a 75% diameter reduction motor tone, segmental epicardial coronary artery hyperac- with reproduction of the symptoms of the patient), and 42 tivity, and organic stenosis (16,17). patients (55%) presented with microvascular spasm (defined Ong et al. (1) administered intracoronary ACH in as ischemic electrocardiographic changes with symptom patients with exertional angina. The test was considered reproduction, but no epicardial spasm). Overall two-thirds positive for spasm when either an epicardial coronary flow of patients undergoing the ACH test presented with abnor- reduction of Ն75% at angiography or ischemic electrocar- mal coronary artery vasomotion, a finding that also con- diographic changes occurred during symptom reproduction. firmed the presence of the ischemic syndrome. They excluded per-protocol patients with significant coro- nary atherosclerosis, adhering to the dogma for searching See page 655 coronary artery spasm only in patients with normal and near-normal coronary arteries. The authors are to be congratulated for attempting to Actually, there is no reason to believe that abnormal determine pathophysiological mechanisms underlying coronary vasomotion and endothelial dysfunction are exclu- symptoms and evidence of myocardial ischemia in this sive to coronary vessels with no or minimal atherosclerosis. patient population. Indeed, in the absence of obstructive By limiting investigations to this subset of patients, the coronary artery disease (CAD), management of patients relevance of functional factors in precipitating myocardial with angina represents an unsolved challenge. Such patients ischemia might be underestimated. are often labeled as either patients with “atypical angina” or Coronary spasm, which was initially demonstrated in patients with “false positive results” at noninvasive evalua- patients with normal or near-normal coronary arteries tion. However, long-term follow-up studies suggest that (11,12), frequently occurs at sites of significant atheroscle- patients with angina and ischemia, who do not display rosis, both in acute and chronic settings (18–21). Spasm of obstructive CAD, have increased coronary event rates and atherosclerotic lesions is often associated with myocardial adverse quality of life as compared with those with no ischemia (16,22,23), with coronary vasomotor response evidence of ischemia (2), underscoring the relevance of closely related to plaque burden (24). Moreover, normal or proper identification and treatment. near-normal coronary arteries of patients with focal vaso- spasms show angiographically insignificant atherosclerosis

*Editorials published in the Journal of the American College of Cardiology reflect the (25), suggesting that paradoxical constriction can occur both views of the authors and do not necessarily represent the views of JACC or the during the early as well as advanced stages of disease (26). In American College of Cardiology. addition, the presence of obstructive CAD does not pre- From the Division of Cardiology, Cardio Thoracic Department, University of Pisa, Pisa, Italy. Both authors have reported that they have no relationships relevant to the clude spasm of adjacent, nonobstructive coronary segments contents of this paper to disclose. (27,28), which can actually be responsible for ischemia. 664 Marzilli and Huqi JACC Vol. 59, No. 7, 2012 Coronary Vasospasm and Coronary Atherosclerosis February 14, 2012:663–4

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