36 Chapter 2 using acetylcholine reactivity testing.16 Coronary vasospasm is highly prevalent in patients with non-obstructive CAD as assessed by intracoronary acetylcholine provocation testing and is more prevalent in women compared to men.26 Non-cardiac chest pain such as pulmonary or gastrointestinal disorders are another explanation for the non-diagnostic coronary angiograms in our study.27 Limitations The results from the present study should be interpreted with several limitations in mind. First, this is an observational study consisting of multiple prospective registries from different expert centers across the world. Hence, inherent heterogeneity in the study protocols may have influenced the study and its findings. However, conversely, our study cohort represents a large collection of multiethnic CCS patients from multiple centers and thus significant external validation and generalizability to our findings. Second, medication use was not registered in all patients and medication changes after ICA were not considered as part of our analysis. Since it is recognized that women are more likely to be underdiagnosed and undertreated in CCS, medication could be a confounder on the effect of sex differences and prognosis after ICA.7 Third, the ILIAS-registry did not contain information on the character of anginal symptoms. This could be important, since it has been described that women and patients with CMD frequently present their symptoms differently to men and patients with obstructive CAD.7, 28 Fourth, clinical endpoints relevant to chronic coronary syndrome, such as hospitalization and reduced angina-burden, were not available. Lastly, this study might have oversimplified the complexity of vasomotor pathophysiology by using cut-off values derived from continuous variables to stratify into the different endotypes. However, this approach adheres to contemporary clinical and scientific practice. Conclusion In this large global registry of symptomatic CCS patients referred for coronary angiography, we observed a clinically relevant sex difference in the prevalence of CCSendotypes between women and men using invasive physiological testing. While women had a higher prevalence of CMD, men had a higher prevalence of significant obstructive CAD. Men had a worse 5-year TVF rate compared to women, likely attributable to the observed higher prevalence of obstructive CAD. In summary, because CMD was present in 29% of women and 23% of men (and is associated with a worse prognosis compared to patients with physiologically normal coronary arteries), our findings underscore the class IIB recommendation from the ESC/EAPCI guidelines16 to perform guidewire based CFR-measurements once obstructive CAD is ruled out in CCS patients referred to the catheterization laboratory.
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