75 Meta-analysis and systematic review of coronary vasospasm in ANOCA patients spasm can be unmasked. This is not daily practice and also was not performed in the included studies in this review.4 CAS and ethnicity Our review observed differences in prevalence of epicardial spasm between Asian and Western World population. Previously multiple hypothesis for this observed difference in prevalence have been described. First, environmental and genetic factors may play a pivotal role. For example, it has been proposed in literature that the coronary arteries of Japanese CAS patients have an increased coronary artery basal tone compared to Caucasian patients, that may be related to an increased hyperreactivity in reaction to provocation test stimuli.33 Second, underestimation of the prevalence of CAS in Western World countries is suggested due to the fact that spasm provocation testing is performed more routinely only since recently.34 In the 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes the spasm provocation test has been recommended as a diagnostic tool in ANOCA patients, also in the recently published EAPCI expert consensus document concerning invasive coronary function testing.3, 36 Third, in Asian countries an injection speed of 20–30 s is most commonly used, which is higher compared to Western World countries and as described previously the occurrence of CAS increases with higher injection speed.4, 32 Forth, in line with our analysis, an increased incidence of diabetes mellitus in Asian populations is frequently described and it has been suggested that diabetes mellitus plays a role in the development of CAS due to the fact that it is associated with endothelial dysfunction and subsequent CAS.36 CAS and sex differences While the majority of ANOCA patients are women, we found that epicardial spam occurred more often in men. Previous research using intracoronary ultrasound has shown that the presence of subtle atherosclerotic infiltration is associated with CAS in ANOCA.37 In men, coronary atherosclerosis is more prevalent at a younger age compared to women and might explain the higher prevalence of epicardial spasm in men.38 Smoking, which is more common in men is a well-known risk factor for CAS, due to inactivation of nitric oxide.32 Furthermore, it is known that, in women cardiovascular risk, including epicardial spasm, increases after menopause.39 Possibly a part of the included women is still protected by their premenopausal state. Unfortunately information regarding menopausal state was lacking. In line with our analysis, previous studies also reported a greater burden of coronary microvascular dysfunction, including microvascular spasm, among women.14 The underlying cause is not defined yet, but lower myocardial mass, smaller body size and more tortuous coronary arteries with thinner walls are suggested to play a role.40 Prognosis The prevalence of cardiac mortality and MI seems comparable low between ANOCA patients with and without epicardial spasm. However, both groups have an impaired prognosis compared to the normal population, most likely due to the fact that a part of 4
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