Women, ‘non-specific’ chest pain, and normal or near-normal coronary angiograms are not synonymous with favourable outcomeThe opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology.

The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. The opinions expressed in this article are not necessarily those of the Editors of the European Heart Journal or of the European Society of Cardiology. One of the more troubling findings from gender-based studies is the observation that only half of women who have chest pain suggesting ischaemia present stenotic coronary lesions (>50% lumen diameter narrowing), whereas the remainder show non-obstructive or apparently normal arteries at angiography.1 Women with chest pain and non-obstructive coronary artery disease (CAD) constitute a great source of consternation to practicing physicians. Among these patients, there are an unknown number who can be shown to be suffering from cardiac pain presumed to be ischaemic. Most of these women complain of chest pain and disability for years, and the morbidity is considerable.1 New findings demonstrate that some of these patients may be at an increased risk of myocardial infarction and cardiac death.1 Advanced coronary atheroma can be present despite a normal or near-normal coronary lumen,2 and may provide a link between seemingly normal coronary arteries and increased risk of future cardiac events. Chest pain is the most common symptom of CAD prompting subjects to seek attention from physicians. Women are more likely to have non-specific chest pain symptoms than men, which may contribute to missed diagnoses of coronary heart disease and increased risk of acute events.3 Patients with atypical symptoms profile have approximately twice the delay before hospital admission, are less likely to receive therapy, and suffer higher mortality rates. Research on symptoms and their relationship with outcome has mainly focused on women with obstructive CAD.4 Johnson et al.5 look at women with non-obstructive CAD and demonstrate that different symptoms' profiles are associated with different long-term outcomes. The authors evaluated 412 patients without obstructive CAD. Two hundred and sixty-one women with significant CAD served as controls. Of these 412 patients without obstructive CAD, 189 continued to experience episodes of chest pain for more than 1 year, whereas the remaining 223 had a complete resolution of symptoms after discharge. Coronary events occurring after 1 year were recorded for a follow-up length of 4–5 years. Noteworthy, the rate of most serious outcomes was unexpectedly high in this supposedly low-risk population. The combined endpoint of death, myocardial infarction, stroke, and heart failure was almost twice as high in women with persistent chest pain (14.4 vs. 8.5%). These findings do not fit with the notion that normal or near-normal coronary angiography implies benign prognosis and prompt renewed debate about the proper strategy for public health efforts targeting early atherosclerosis. Clinicians often use the quality of pain to assess the likelihood of significant CAD and the risk of adverse outcome. The classic definition for ‘typical’ angina is ‘retrosternal chest discomfort (may radiate to neck, jaw, epigastrium, or arms) with a characteristic quality (squeezing, pressure-like, heavy) and duration (usually 2–20 min), worsened by physical exertion or emotional stress, and relieved by rest or nitroglycerin’.6 Interestingly, the great majority (∼70%) of women in the study of Johnson et al.5 had an atypical quality of symptoms either if they showed insignificant or significant CAD. What are the primary implications of this finding? First, although many studies have well documented that patients are more likely to experience subsequent coronary events if they present with typical symptoms, as Milner et al.4 show, it is recommended that clinicians not exclude adverse outcomes based only on the quality of the symptoms. Second, these data do not suggest that all women with diagnosis of non-specific chest pain require admission to the hospital if they have recurrence of the symptoms. Conversely, it reinforces the idea that diagnosis of significant CAD would be missed in most of these patients if clinicians rely on the credence that symptoms fit with classic angina. Annually, there are more than 5 000 000 visits to the US emergency departments for the evaluation of chest pain and related symptoms. Nearly 50% of such patients are women. Many of these patients (∼1 400 000) are admitted to hospitals with diagnosis of unstable angina and myocardial infarction without ST-segment elevation. Patterns of rest pain with or without ECG changes and/or release of marker of myocardial injury seem to identify very high-risk patients in this population. Despite a substantial improvement in care, patients still have a considerably high incidence of short and long-term adverse outcomes. The risk continues to increase for at least 3–4 years after an episode of unstable syndromes.7 Death may range from 1.2 to 8.7% at 3 years follow-up. Recent work has shown that patients requiring hospital admission for suspected unstable angina but with a discharge diagnosis of non-specific chest pain were at substantially increased risk of subsequent coronary events.8 Approximately 9% of patients without diagnostic ECG and elevation of markers of myocardial cell damage died or sustained non-fatal myocardial infarction in the subsequent 2.5 years. Taken together, these studies suggest that an acute coronary event marks a patient for a high long-term risk of recurrence. Patients with unstable angina are at higher risk than patients with stable effort-related angina, whatever is the quality of symptoms. Information from coronary angiography would not significantly alter this paradigm. Angiography cannot predict patients likely to undergo further plaque rupture.9 In the article by Johnson et al.,5 the entry point of the condition under consideration is the recurrence of ‘chronic chest pain symptoms’ as evaluated at 1-year follow-up. The proportion of patients undergoing angiography was large for those patients classified as ‘non-obstructive’ (61% of the study population) and those classified as ‘atypical chest pain’ (67% of the study population), suggesting that the investigators purposely pursued an extensive evaluation in this subset of low-risk patients, despite their clinical classification. Further studies are needed to define meaningful clinical subsets of non-obstructive CAD patients, in which preventive therapy may be planned appropriately. These minor caveats aside, the most important finding by Johnson et al.5 is that even ‘non-specific’ chest pain persisting for long-time is a prognostic marker in patients with normal or near-normal angiography, and perhaps in the general population.10 The whole concept of women having heart disease is relatively new, dating to 15 or 20 years ago. The fact that there are still physicians who seem to treat women differently than men is, therefore, not surprising, but it is certainly disturbing. Despite the equivalent risk profiles, women are much more likely to be classified as lower risk. Consequently, women are less likely than men to get preventive recommendations from their doctors. The unequivocal home message from this study is that women, ‘non-specific’ chest pain, and normal or near-normal angiograms, are not synonymous with favourable outcome. Misinformation about these features may keep women far from getting appropriate cardiac care. Women, on their own, or physicians are reassured by the results of angiography and may have difficulties recognizing symptoms as being cardiac in origin. They simply think that atherosclerosis is a common disorder and that women are the wrong gender to be having a heart attack. Misconception of symptoms and outcomes in non-obstructive CAD may help explaining some of the widely reported sex-differences in treatment patterns. Women and men share a common illness, namely CAD. In the past several years, medical research has traditionally focused on the prevalent male anatomy (obstructive coronary disease) and male experience of symptoms as ‘typical’, with all others (female) considered ‘atypical’. Obstructive coronary disease as ‘standard’ has resulted in biases in cardiac research, with the exclusion or under-representation of women in many clinical studies. Recent evidence demonstrates that non-obstructive CAD is prevalent in women. A review of some major reports on this issue, beginning in the 1990s, shows that many studies omit men entirely, yet non-obstructive CAD could be present also in male cardiac patients. Middle-aged post-menopausal women are now the model subjects in most studies on non-obstructive coronary disease. The expected consequence is the assumption that whatever are the findings for the ‘female standard’, the results would also hold true for men. Female gender still remains a protective risk factor against coronary atherosclerosis. Research on non-obstructive coronary disease should also include men. Otherwise, there is a contradiction in the logic. Women (and men) with chest pain symptoms and normal or near-normal coronary arteries at angiography are at risk of future coronary events. Further research is needed to accurately establish the most appropriate diagnostic and therapeutic strategies in this population. The number of patients that must be enrolled in these studies is great as relatively low-risk patients are included. Development of large-scale collaborative clinical trials and registries is recommended. Conflict of interest: none declared.