As coronary angiography became more widely practiced in the 1960's, it was soon apparent that not all patients with clinical suspicion of coronary artery disease (CAD) had obstruction of epicardial coronary arteries. Several published series, including the National Heart, Lung, and Blood Institute-sponsored Coronary Artery Surgery Study and the Women's Ischemia Syndrome Evaluation (WISE) study, have reported that up to half of patients undergoing coronary angiography are found to have normal or non-obstructed epicardial coronary arteries (1
). In 1967, Likoff et al. (4
) reported 15 women ranging in age from 30 to 53 years with chest pain despite normal coronary angiograms (CPNCA), but with ECG abnormalities at rest (ST segment depression or T wave inversion) that were accentuated by exercise. Despite the ECG changes during exercise, the hemodynamic response--as assessed by pulmonary artery pressure, cardiac output, and oxygen consumption--were reported as normal in the 8 patients in whom these measurements were made. The authors of this article stated that “usual therapy of coronary artery disease was ineffective and unwarranted” in this setting. That same year, Kemp, Elliott and Gorlin (5
) reported a series of 50 patients (62% women) with CPNCA, commenting that as a group, “these patients may frequently have the most severe pain syndromes, often proving refractory to conventional forms of therapy.” Of the 41 patients who underwent metabolic study during isoproterenol stress, 11 demonstrated myocardial lactate production supportive of myocardial ischemia. Four of these 11 patients had ischemic-appearing ECGs during exercise stress; however, 5 additional patients with ischemic-appearing ECGs during exercise stress did not demonstrate myocardial lactate production during isoproterenol infusion. In a 1973 editorial, Kemp noted the heterogeneity of patients included in studies of patients with CPNCA, making it difficult to derive clinical or mechanistic insights about this syndrome (6
). The term “syndrome X” was used in this editorial (based on “group X” in the article under discussion) to denote the uncertainty of chest pain etiology in these patients, a term subsequently used by other investigators, but often with different criteria for its definition.
Twenty-five years ago, our group considered whether impaired coronary microcirculatory dilator responsiveness could limit blood flow response to stress, producing myocardial ischemia and angina, and published our initial findings during the inaugural year of the Journal
). Stephen Epstein and I subsequently proposed “microvascular angina” as a suitable descriptor for this syndrome (8
). Abnormalities in coronary flow and metabolic responses to stress were reported over the years by several groups, findings consistent with a microvascular etiology (by default, based on normal coronary angiograms) for ischemia and symptoms. Others, however, have questioned an ischemic cause for symptoms, even in patients selected for abnormal noninvasive testing such as ischemic appearance of stress ECG, designated by some groups as having “syndrome X.” In 1992, Paolo Camici, Stephen Epstein and I wrote a review article, entitled Pathophysiological Dilemma of Syndrome X
). Despite considerable efforts by many groups since that time, the syndrome remains controversial with regards to pathophysiology, diagnosis and management.
Despite differences of opinion regarding cardiac versus noncardiac mechanisms of chest pain in this population, most groups have reported that patients with CPNCA and structurally normal hearts have a better prognosis with regards to serious cardiac events (myocardial infarction, cardiovascular deat h) compared with CAD patients (10
). Although reassurance helps many patients, most continue to have chest pain resulting in emergency room evaluations, hospitalizations and repeat cardiac catheterizations, with adverse effects on quality of life, employment and health care costs (15