This editorial refers to 'Gender differences in symptoms of myocardial ischaemia' † , by M.H. Mackay et al., on page 3107 Women with acute coronary syndromes (ACS) or myocardial infarction (MI) still undergo treatment significantly later than men. The reasons for this are unclear, but so-called 'atypical symptoms' in women have been under suspicion. 1 Women are assumed to complain of anginal symptoms that differ from the classical picture of those of men, making diagnosis more difficult and

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... ying effective therapy. This phenomenon is of great relevance for healthcare in women and therefore has been investigated in numerous studies. 2 It has been discussed whether sex or gender is the crucial factor for different presentation-whether differences exist between women and men in the biological mechanisms of pain, i.e. sex, or whether socio-cultural mechanisms, such as lack of awareness of risk or reporting behaviour, mainly contribute to the differences, i.e. gender. Do women have a different form of angina from men, do they interpret pain differently, or do they report it differently? A significant number of studies analysing sex and gender differences in the presentation of MI and angina pectoris agree that women differ from men in their reported symptoms, even though the differences may be small. Most of these studies necessarily had a retrospective design, inquiring of patients after the events concerning the related symptoms. Only studies that focus on a first MI avoid the recall effect-that patients learn from doctors and friends during a first MI which symptoms are to be expected. In such studies, relatively persistent findings are the greater number of symptoms in women and the greater frequency of nausea and pain in the throat or jaws, among others. 3 The large WISE study investigated a broader spectrum of women, 4 covering all women presenting with chest pain in the participating hospitals. The investigators found that chest pain had a lower predictive value for obstructive coronary artery disease (CAD) in women than in men, particularly in younger women, and concluded that this was due to the relatively large prevalence of non-obstructive CAD in the latter cohort. From 10% to 30% of women presenting with ACS, non-ST elevation myocardial infarction (NSTEMI), or STEMI do not exhibit major coronary stenoses at angiography, as compared with 3-15% of men. 5 Women with non-obstructive CAD frequently present with atypical angina; the pain may be more intense and it may persist for ≥30 min. 6 The WISE investigators suggested specific algorithms to detect myocardial ischaemia objectively in these women in addition to coronary angiography, which only detects large vessel obstruction. The WISE investigators suggested techniques to measure myocardial perfusion disturbances that may be due to defects in coronary vasodilatation or to disturbances of the microcirculation, and that occur in the absence of major stenoses of the epicardial arteries, by magnetic resonance imaging (MRI), scintigraphic techniques, or Doppler flow measurements in the coronary arteries after the administration of vasodilating agents. 7 They systematically followed the women with chest pain and evidence of myocardial ischaemia but without obstructive lesions. The follow-up of the affected women was characterized by an increased number of major cardiac events (MACEs), high rates of rehospitalization, and high treatment costs. 8 Thus, non-obstructive CAD may be associated with myocardial ischaemia and has consequences for the clinical outcomes, so that future studies of myocardial ischaemia in women will need to include these cohorts, too. Pain generation in the heart is a complex process (Figure 1 ). It starts with the stimulation of afferent nerve endings in the heart. Nerve growth factor (NGF) is one of the substances involved in cardiac pain sensation. 9 NGF leads to vallinoid receptor activation and stimulation of afferent nerves in the heart. Regarding this first step, it has not yet been established whether vallinoid receptors and NGF are differently expressed in female and male hearts. Both are reduced in diabetic hearts, and this may contribute to the occurrence of silent ischaemia in patients with diabetes. Their manipulation modulates pain sensation in an ischaemic transgenic mouse model. In addition, activation of the RAGE (receptor for advanced glycation end-products) -NF-kB (nuclear factor-kB) axis prevents pain sensation in diabetic hearts. 10 Neuropathy is particularly frequent in diabetic patients, the elderly, and