Sex-differences in prevalence and outcomes of the different endotypes of chronic coronary syndrome – analysis from the multi-center international ILIAS Registry
Authors: Vink C E M , Hoef T P , Lee J M , Boerhout C K M , Koo B K , Escaned J , Piek J J , Kakuta T , Appelman Y , De Waard G 
Published: October 2022

Abstract

Introduction
Guideline-directed management of chronic coronary syndrome (CCS) remains focused on obstructive causes of angina, and is based on established therapies derived from studies predominantly including men. This occurs despite documented higher mortality from cardiovascular causes in women compared to men, which is hypothesized to be related to a higher prevalence of coronary microvascular dysfunction (CMD) in women. However, data on the relationship between sex, the different endotypes of CCS, and related sex-specific clinical outcomes are limited.

Purpose
This study aimed to investigate the relationship between sex and the different endotypes of CCS, as well as sex-specific clinical outcomes of CCS endotypes.

Method
In patients with stable angina undergoing coronary angiography, the following invasive coronary hemodynamics were characterized: fractional flow reserve (FFR; &lt;0.80 considered abnormal), coronary flow reserve (CFR; &lt;2.0 considered abnormal) and microcirculatory resistance (MR) (hyperemic microvascular resistance; &gt;2.5mmHg/cm/sec or index of microvascular resistance &gt;25 considered abnormal). Patients were stratified into three groups: 1) hemodynamically significant obstructive coronary artery disease (oCAD) (FFR abnormal or a severe coronary stenosis requiring revascularization), 2) no-obstructive coronary artery disease but with CMD (FFR normal, but abnormal CFR and/or MR), or 3) no-obstructive coronary artery disease and no CMD (FFR normal, and normal CFR and MR). We assessed the prevalence of the CCS endotypes across sex, and sex-specific cardiovascular outcomes over a follow-up of 7 years defined as the composite endpoint of death or acute myocardial infarction.

Results
Amongst a total of 1987 included patients, 1435 (72.2%) were men and 552 (27.8%) were women. oCAD occurred in 904 (45.5%) patients, which was significantly more prevalent in men (48.9% (701/1435) of men vs. 36.8% (203/552) of women, p&lt;0.001). In contrast, CMD was significantly more prevalent in women (19.6% (281/1435) of men vs. 24.1% (133/552) of women, p=0.031). Across the population, either oCAD or CMD occurred in 68.4% of men versus 60.9% of women (p=0.002). There were no sex-specific differences in cardiovascular outcomes across CCS entities (Figure 1).

Conclusion
In patients evaluated for CCS who underwent clinically indicated coronary angiography and physiological assessment, men were more likely to have oCAD and women were more likely to be classified as CMD. There were no sex-related differences in the prognosis associated with the individual CCS endotypes. Therefore, pathophysiological changes in the coronary circulation potentially underlying angina pectoris are similarly prevalent in men and women, but the high incidence of CMD in women makes women prone to underdiagnosis if no additional physiological measurements are assessed.

Funding Acknowledgement
Type of funding sources: None.