Caitlin Vink

A MULTIMODALITY APPROACH TO UNRAVEL THE PATHOPHYSIOLOGY OF ANOCA

A multimodality approach to unravel the pathophysiology of ANOCA Caitlin E.M. Vink

A Multimodality Approach to Unravel the Pathophysiology of ANOCA Thesis, VU University, Amsterdam, The Netherlands ISBN: 978-94-6522-241-7 Copyright 2025 © Caitlin Vink All rights reserved. No parts of this thesis may be reproduced, stored in a retrieval system or transmitted in any form or by any means without permission of the author. Provided by thesis specialist Ridderprint, ridderprint.nl Printing: Ridderprint Layout and design: Inge Hattuma, persoonlijkproefschrift.nl Financial support for this thesis was provided by ChipSoft, the VU University Amsterdam, and the sponsors of the MICORDIS study

VRIJE UNIVERSITEIT AMULTIMODALITY APPROACH TO UNRAVEL THE PATHOPHYSIOLOGY OF ANOCA ACADEMISCH PROEFSCHRIFT ter verkrijging van de graad Doctor aan de Vrije Universiteit Amsterdam, op gezag van de rector magnificus prof.dr. J.J.G. Geurts, volgens besluit van de decaan van de Faculteit der Geneeskunde in het openbaar te verdedigen op dinsdag 24 juni 2025 om 13.45 uur in de universiteit door Catharina Elisabeth Maria Vink geboren te Gouda

promotoren: dr. E.C. Eringa prof.dr. S.A.J. Chamuleau copromotoren: dr. J.E.A. Appelman dr. T.P. van de Hoef promotiecommissie: prof.dr. J. van der Velden prof.dr.ir. H.M. den Ruijter dr. R.B. van Loon dr. A. van Randen prof.dr. N. van Royen

“Erger je niet, verbaas je slechts” Perry Vink

TABLE OF CONTENTS Introduction 9 Chapter 1. General introduction 9 Part 1. Endotypes of Chronic Coronary Syndrome 19 Chapter 2. Sex differences in prevalence and outcomes of the different endotypes of chronic coronary syndrome in symptomatic patients undergoing invasive coronary angiography: Insights from the global ILIAS invasive coronary physiology registry 21 Atherosclerosis. 2023 Nov;384:117167 Chapter 3. Impact of sex on the assessment of the microvascular resistance reserve 43 Int J Cardiol. 2024 May 1;402:131832 Chapter 4. Meta-analysis and systematic review of coronary vasospasm in ANOCA patients 57 Front Cardiovasc Med. 2023 Mar 13;10:1129159 Part 2. Myocardial blood volume as driver of ANOCA 85 Chapter 5. Reduced Microvascular Blood Volume as a Driver of Coronary Microvascular Disease in Patients With Nonobstructive Coronary Artery Disease: Rationale and Design of the MICORDIS Study 87 Front Cardiovasc Med. 2021 Sep 30;8:730810 Chapter 6. The role of myocardial blood volume in the pathophysiology of angina with non-obstructed coronary arteries: The MICORDIS study 109 Int J Cardiol. 2024 Nov 15;415:132479. Part 3. Quantitative perfusion CMR in ANOCA 141 Chapter 7. Clinical implementation of a fully automated quantitative perfusion cardiovascular magnetic resonance imaging workflow with a simplified dual-bolus contrast administration scheme 143 Sci Rep. 2024 Apr 26;14(1):9665 Chapter 8. Quantitative Perfusion by Cardiac Magnetic Resonance Imaging For Diagnosing Patients with Angina with NonObstructive Coronary Artery Disease 165 Clin Res Cardiol. 2025 Feb 18; epub ahead of print

Part 4. Summary of the thesis, discussion and future perspectives 191 Chapter 9. English Summary 193 Chapter 10. General discussion and future perspectives 199 Chapter 11. Nederlandse samenvatting 211 Appendices 217 List of abbreviations 218 List of publications 220 PhD portfolio 222 Dankwoord 224 About the author 229

1 General introduction

10 Chapter 1 GENERAL INTRODUCTION Ischemic Heart Disease (IHD) is the leading cause of morbidity and mortality worldwide, affecting both men and women. Chronic Coronary Syndrome (CCS) represents a stable yet progressive form of IHD.1 CCS encompasses multiple underlying pathophysiological mechanisms. For decades, clinical cardiology has focused on obstructed coronary artery disease (CAD) as a probable cause of ischemic complaints. However, nearly half of the patients undergoing invasive coronary angiography for suspected CCS do not have obstructed CAD. This condition is called Angina with Non-Obstructed Coronary Arteries (ANOCA). In these cases, angina can arise from changes in vasomotor responses of the coronary circulation including coronary vasospasm and/or alterations in the microcirculation.2 The coronary vascular bed originates at the root of the aorta, where two primary coronary arteries emerge: the right coronary artery (RCA) and the left main coronary artery. The left main coronary artery bifurcates into two major coronary arteries, the left anterior descending (LAD) artery and the left circumflex (LCx) coronary artery. These three large coronary arteries run across the epicardial surface of the heart, branching into various smaller branches, from pre-arterioles, to arterioles and capillaries.3 These small branches (diameter <200 µm) constitute the coronary microcirculation (Figure 1). In a healthy heart, the microcirculation plays an important role in regulating coronary blood flow, supplying oxygen, nutrients and metabolites to the myocardium. Conventional imaging techniques cannot provide adequate visualization and evaluation of the coronary microcirculation. Techniques exist that are capable of for detailed assessment of the coronary microcirculation, however these are not commonly used in clinical practice. Figure 1. Microcirculation Ischemic symptoms occur when oxygen delivery is insufficient to meet oxygen demand in the myocardium. In the microcirculation, oxygen delivery is determined by two parameters,

11 General introduction myocardial blood flow (MBF) and myocardial blood volume (MBV). MBV refers to the total blood content within in the microcirculation including arterioles, capillaries and venules. In healthy individuals, the entire coronary circulation, including the large epicardial coronary arteries, contains about 12mL of blood per 100g of myocardium volume during diastole. The microcirculation contains about 90% of the myocardial blood flow (MBF), and most of the myocardial blood volume (MBV), predominantly within the capillaries.4 MBF and MBV independently regulate oxygen delivery by large and small arteriole, respectively. At rest, approximately half of myocardial capillaries are filled with blood.5 Stress, e.g. an increase in cardiac work, increases oxygen demand in the myocardium, triggering coronary vasodilation and augmenting MBF. Additionally, the fraction of simultaneously perfused capillaries in the myocardium increases, referred to as ‘microvascular recruitment’ (MVR). This regulatory process involves local arteriolar vasodilatation to redirect blood to capillary beds supplying larger areas of the myocardium. As more blood is in direct contact with capillary endothelial cells, tissue oxygenation becomes more efficient, and MBV increases.6, 7 The pathophysiology of ANOCA The typical ANOCA patient is more likely to be female, relatively young and has fewer traditional cardiac risk factors compared to patients with obstructive CAD. Consequently, patients with ANOCA are often classified as ‘low risk’ and discharged without a proper diagnosis or treatment.8 However, similar to patients with obstructive CAD, ANOCA is associated with a reduced quality of life in terms of physical, mental and social wellbeing.9 The pathophysiology of ANOCA is complex and multifactorial, involving abnormal vasomotor responses affecting the entire coronary circulation. These abnormal vasomotor responses involve enhanced vasoconstriction and impaired vasodilation, leading to coronary vasospasm and/or coronary microvascular dysfunction (CMD).10 In 2017, the Coronary Vasomotor Disorders International Study (COVADIS) group established the COVADIS criteria to develop global standards for diagnosing and differentiating between these abnormal vasomotor responses.11, 12 The endothelium plays a crucial role in regulation of the coronary vascular tone by releasing various vasodilators. An important vasodilator in physiological regulation of vascular tone and blood flow is Nitric Oxide (NO). The production of NO in endothelial cells depends on the activity of endothelial nitric oxidase synthase (eNOS), which converts L-arginine into L-citrulline and NO in vascular endothelial cells. In healthy endothelial cells, vasodilator agents such as acetylcholine, histamine or insulin increase intracellular calcium levels (acetylcholine) or phosphorylation of eNOS (insulin), increasing NO production, resulting in subsequent vasodilatation.13, 14 However, vasodilator agents such as acetylcholine and insulin can also have vasoconstriction effects. Insulin can activate the Ras/mitogen-activated protein kinase (MAPK) signaling pathway, resulting in the production of the vasoconstrictor endothelin-1 (ET-1). ET-1 can increase vascular tone, inducing vasoconstriction and counteracting NO-mediated vasodilation.15, 16 In the presence of endothelial dysfunction, acetylcholine directly increases calcium in vascular smooth muscle cells leading to vasoconstriction and vascular spasm. Other contributors 1

12 Chapter 1 to the pathophysiology of ANOCA are thought to be oxidative stress, which induces inflammation through reactive oxygen species (ROS) causing vascular remodeling, or an increased autonomic nerve system, leading to elevated catecholamine levels.17 However, the pathogenesis of ANOCA remains multifactorial and largely unknown. Diagnostic modalities in ANOCA Current diagnostic methods for ANOCA are integrated into the guidelines for evaluating chronic chest pain, primarily focusing on obstructed CAD.2, 18, 19 However, these guidelines often provide limited consideration for further diagnostic testing post-exclusion of obstructed CAD, frequently resulting in a diagnosis of non-cardiac chest pain without completing an invasive evaluation for ANOCA.20 Coronary CTA, a recommended and widely used diagnostic imaging test for obstructed CAD, typically reveals no severe coronary abnormalities in ANOCA. Recent recommendations in current guidelines suggest the use of additional modalities if non-obstructive CAD is diagnosed in symptomatic patients, though these have only been recently incorporated and are not yet widely implemented in clinical practice. Invasive coronary function testing (CFT) evaluated CMD by assessing coronary flow reserve (CFR) and minimal microvascular resistance (MR) using adenosine, as well as vasospasm provocation testing typically using acetylcholine, an endothelium dependent vasodilator, as the provocative agent (Figure 2). In most protocols, acetylcholine is administered manually through intracoronary bolus injections in incremental doses (2, 20, 100, and 200 μg) in the LAD. If no vasospasm occurs in the LAD during assessment, a single dose of 80 μg acetylcholine is administered in the RCA. Vasospasm has been defined as recognizable chest pain and ischemic changes on electrocardiography (ECG), with or without >90% epicardial vasoconstriction on CAG distinguishing epicardial and microvascular spasm. Following occurrence of vasospasm, a re-challenge is performed using the dose that induced vasospasm after intracoronary nitrite administration. This approach allows for assessment of the coexistence of epicardial vasospasm and microvascular vasospasm since microvascular vasospasm is less likely to resolve after nitrate administration. Additionally, it provides insights into the effectiveness on symptoms of nitrate treatment.21, 22. Coronary pressure and flow measurements are taken under resting conditions and during hyperemia induced by 150 μg adenosine, an endotheliumindependent vasodilator.23 CFR is calculated as the ratio of hyperemic average peak flow velocity to basal averaged peak flow velocity. MR, on the other hand, is determined as the ratio of distal coronary pressure to distal coronary flow and during maximal coronary vasodilatation, reflecting structural microvascular alterations. CMD is defined as CFR ≤2,5 and/or a hyperemic microvascular resistance (HMR) >2.5 mmHg/cm/s.11

13 General introduction Figure 2. Currently, all endotypes of ANOCA can only simultaneously be assessed invasively. However, these invasive assessments burden patients with subsequent risks for complications, hospitalization and high costs. Non-invasive methods to detect coronary vasospasm are limited, with proposed tests including the cold pressor and hyperventilation test, but literature on these methods is scare.24 The majority of non-invasive approaches only allow for the assessment of CMD as a possible cause of ANOCA. Myocardial perfusion (i.e. MBF and CFR) can be most accurately and most completely assessed with positron emission tomography (PET) using oxygen-15-labeled water ([15O]H2O-PET). [15O]H2O freely diffuses within the myocardium, is extracted from the arterial blood pool, and is metabolically inert, making [15O]H2O an ideal tracer to quantify MBF in ml/min/g.25-27 However, while [15O]H2O-PET provides excellent information about myocardial perfusion, it only enables noninvasive diagnosis of CMD, offers limited anatomical details, is expensive compared to other imaging modalities and is not widely available. Therefore, in selected centers cardiovascular magnetic resonance (CMR) imaging and transthoracic Doppler echocardiography are available to non-invasively assess CMD, both using adenosine to evaluate coronary flow. Transthoracic Doppler echocardiography enables visualization of the coronary flow in the LAD by measuring pulse-wave Doppler as a flow signal in the mid-distal LAD towards the transducer during diastole.28 Flow measurements are obtained 1

14 Chapter 1 at rest and during maximal vasodilation, typically using the vasodilators adenosine and dipyridamole. However, due to anatomical variation, the LAD might be difficult to visualize and requires an experienced echocardiographer. Therefore, although in-expensive and widely available this technique is scarlessly used. Compared to other imaging techniques, CMR offers several benefits, such as superior temporal and spatial resolution, accurate assessment of myocardial function and viability, and the ability to do so without exposing patients to ionizing radiation in a time-efficient manner.29 Stress perfusion CMR is an established method for myocardial ischemia detection, using first-pass contrast-imaging to detect perfusion defects. However, visual assessment of stress perfusion is dependent on observer’s expertise, and while fully automated quantitative perfusion (QP) shows promising results for detection of CMD, it requires further investigation before clinical implication. Diagnostic therapies in ANOCA Optimal management and pharmacological treatment of ANOCA is challenging, primarily due to the heterogeneity of underlying mechanisms and the lack of comprehensive evaluation of individual treatments through randomized clinical trials. Currently, management and therapies are based on best clinical practice.30 The CorMicA (Coronary Microvascular Angina) trial is one of the few randomized trials performed in ANOCA, and emphasizes the importance of identifying underlying mechanisms in ANOCA-patients. This identification enables tailored treatment strategies, ultimately reducing angina burden and enhancing quality of life.31 However, inconsistent protocols for invasive CFT and varying definitions of the endotypes of ANOCA have limited our understanding, as the practical approach has only recently been standardized. These limitations highlight the considerable gaps in knowledge that remain, underscoring the necessity for a more precise diagnostic algorithm and emphasizing the importance of identifying individual pathophysiology in ANOCA. OUTLINE OF THE THESIS In this thesis entitled “A multimodality approach to unravel the pathophysiology of ANOCA”, the objective was to provide a better understanding into the pathophysiology of ANOCA, with a particular focus on its distribution across sexes. For this purpose, a variety of studies was performed using both invasive as non-invasive imaging modalities, focusing on symptomatic patients with non-obstructive coronary artery disease. Part 1. Endotypes of Chronic Coronary Syndrome Part one of this thesis is focused on understanding the relationship between sex and various endotypes of chronic coronary syndrome (CCS). In Chapter 2, we explore the relationship between sex and various endotypes of this syndrome. Here, invasive coronary assessment distinguishes between obstructive coronary artery disease and coronary

15 General introduction microvascular dysfunction in both symptomatic men and women. Additionally, this chapter delineates the differences in cardiovascular outcomes among men and women across different endotypes of chronic coronary syndrome. Chapter 3 delves further into the relationship between sexes and invasive coronary function assessment, assessing the vasodilatory capacity of the coronary circulation via the microvascular resistance reserve (MRR). The MRR corrects the vasodilator reserve capacity for the presence of epicardial disease, providing a tool to assess microvascular vasodilator function in the presence of obstructed CAD. Chapter 4 provides a comprehensive review of coronary vasospasm in ANOCA, elaborating on both epicardial and microvascular spasm, as well as its prevalence, clinical characterization, and prognosis in men and women worldwide. Part 2. Myocardial blood volume as driver of ANOCA The second part of this thesis focuses on the role of a reduced MBV as a pathophysiological contributor to the cause of ANOCA. Chapter 5 outlines the background and rationale of the MICORDIS (reduced MIcrovascular blood volume as a driver of CORonary microvascular DISease in ANOCA) study, a prospective randomized clinical study in ANOCA patients compared to healthy controls, investigating this possible pathophysiological phenomenon. In Chapter 6, we demonstrate the results of the MICORDIS-study, evaluating myocardial blood volume through myocardial contrast echocardiography under various physiological stimuli, such as dobutamine-induced stress and hyperinsulinemia induced by the hyperinsulinemic-euglycemic clamp method. Part 3. Quantitative perfusion CMR in ANOCA The last part of this thesis looks into the use of cardiac CMR in ANOCA patients. Chapter 7 presents the validation of an improved and ready-to-implement workflow for quantitative perfusion CMR. This protocol incorporates simplified dual-bolus usage and fully-automated image post-processing, making implementation into clinical practice more accessible. In Chapter 8, this protocol is applied to validate the quantitative perfusion, including visual assessment and absolute quantification of myocardial blood flow (MBF), and deriving myocardial perfusion reserve (MPR), in ANOCA patients from the MICORDIS study, compared to healthy controls. In this thesis, the pathophysiology of ANOCA is explored through a multimodal approach, with a particular focus on sex differences. ANOCA, a condition where ischemic symptoms occur in the absence of obstructive coronary artery disease, is often associated with microvascular abnormalities. Despite its clinical significance, ANOCA is underdiagnosed and poorly understood, particularly in women. This research combines both invasive and non-invasive imaging modalities to enhance the understanding of ANOCA, aiming to improve diagnostic strategies and tailor treatments based on individual pathophysiology. 1

16 Chapter 1 REFERENCE 1. Global, regional, and national age-sex specific all-cause and cause-specific mortality for 240 causes of death, 19902013: a systematic analysis for the Global Burden of Disease Study 2013. Lancet. 2015;385(9963):117-71. 2 Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024. 3. Ogobuiro I, Wehrle CJ, Tuma F. Anatomy, Thorax, Heart Coronary Arteries. StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2024, StatPearls Publishing LLC.; 2024. 4. Duncker DJ, Bache RJ. Regulation of coronary blood flow during exercise. Physiol Rev. 2008;88(3):1009-86. 5 Wei K, Kaul S. The coronary microcirculation in health and disease. Cardiol Clin. 2004;22(2):221-31. 6. Serné EH, RG IJ, Gans RO, Nijveldt R, De Vries G, Evertz R, et al. Direct evidence for insulin-induced capillary recruitment in skin of healthy subjects during physiological hyperinsulinemia. Diabetes. 2002;51(5):1515-22. 7. Fry BC, Roy TK, Secomb TW. Capillary recruitment in a theoretical model for blood flow regulation in heterogeneous microvessel networks. Physiol Rep. 2013;1(3):e00050. 8. Mahendiran T, De Bruyne B. ANOCA and the Endothelium: A Link That Can NO Longer Be Ignored. JACC Cardiovasc Interv. 2024;17(4):488-90.| 9. Gulati M, Khan N, George M, Berry C, Chieffo A, Camici PG, et al. Ischemia with no obstructive coronary artery disease (INOCA): A patient self-report quality of life survey from INOCA international. Int J Cardiol. 2023;371:28-39. 10. Kunadian V, Chieffo A, Camici PG, Berry C, Escaned J, Maas A, et al. An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. Eur Heart J. 2020;41(37):3504-20. 11. Ong P, Camici PG, Beltrame JF, Crea F, Shimokawa H, Sechtem U, et al. International standardization of diagnostic criteria for microvascular angina. Int J Cardiol. 2018;250:16-20. 12. Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J. 2017;38(33):2565-8. 13. Padilla J, Manrique-Acevedo C, MartinezLemus LA. New insights into mechanisms of endothelial insulin resistance in type 2 diabetes. Am J Physiol Heart Circ Physiol. 2022;323(6):H1231-h8. 14. Ahmad A, Dempsey SK, Daneva Z, Azam M, Li N, Li PL, Ritter JK. Role of Nitric Oxide in the Cardiovascular and Renal Systems. Int J Mol Sci. 2018;19(9). 15. Reynolds LJ, Credeur DP, Manrique C, Padilla J, Fadel PJ, Thyfault JP. Obesity, type 2 diabetes, and impaired insulinstimulated blood flow: role of skeletal muscle NO synthase and endothelin-1. J Appl Physiol (1985). 2017;122(1):38-47. 16. Eringa EC, Stehouwer CD, Merlijn T, Westerhof N, Sipkema P. Physiological concentrations of insulin induce endothelin-mediated vasoconstriction during inhibition of NOS or PI3-kinase in skeletal muscle arterioles. Cardiovasc Res. 2002;56(3):464-71.

17 General introduction 17. Swarup S, Patibandla S, Grossman SA. Coronary Artery Vasospasm. StatPearls. Treasure Island (FL): StatPearls Publishing. Copyright © 2024, StatPearls Publishing LLC.; 2024. 18. Virani SS, Newby LK, Arnold SV, Bittner V, Brewer LC, Demeter SH, et al. 2023 AHA/ ACC/ACCP/ASPC/NLA/PCNA Guideline for the Management of Patients With Chronic Coronary Disease: A Report of the American Heart Association/American College of Cardiology Joint Committee on Clinical Practice Guidelines. Circulation. 2023;148(9):e9-e119. 19. Hokimoto S, Kaikita K, Yasuda S, Tsujita K, Ishihara M, Matoba T, et al. JCS/CVIT/ JCC 2023 Guideline Focused Update on Diagnosis and Treatment of Vasospastic Angina (Coronary Spastic Angina) and Coronary Microvascular Dysfunction. Circ J. 2023;87(6):879-936. 20. Samuels BA, Shah SM, Widmer RJ, Kobayashi Y, Miner SES, Taqueti VR, et al. Comprehensive Management of ANOCA, Part 1-Definition, Patient Population, and Diagnosis: JACC State-of-the-Art Review. J Am Coll Cardiol. 2023;82(12):1245-63. 21. Boerhout CKM, Beijk MAM, Damman P, Piek JJ, van de Hoef TP. Practical Approach for Angina and Non-Obstructive Coronary Arteries: A State-of-the-Art Review. Korean Circ J. 2023. 22. Seitz A, Feenstra R, Konst RE, Martínez Pereyra V, Beck S, Beijk M, et al. Acetylcholine Rechallenge: A First Step Toward Tailored Treatment in Patients With Coronary Artery Spasm. JACC Cardiovasc Interv. 2022;15(1):65-75. 23. Reis SE, Holubkov R, Lee JS, Sharaf B, Reichek N, Rogers WJ, et al. Coronary flow velocity response to adenosine characterizes coronary microvascular function in women with chest pain and no obstructive coronary disease. Results from the pilot phase of the Women’s Ischemia Syndrome Evaluation (WISE) study. J Am Coll Cardiol. 1999;33(6):1469-75. 24. Hirano Y, Ozasa Y, Yamamoto T, Uehara H, Yamada S, Nakagawa K, et al. Hyperventilation and cold-pressor stress echocardiography for noninvasive diagnosis of coronary artery spasm. J Am Soc Echocardiogr. 2001;14(6):626-33. 25. Bergmann SR, Fox KA, Rand AL, McElvany KD, Welch MJ, Markham J, Sobel BE. Quantification of regional myocardial blood flow in vivo with H215O. Circulation. 1984;70(4):724-33. 26. Driessen RS, Raijmakers PG, Stuijfzand WJ, Knaapen P. Myocardial perfusion imaging with PET. Int J Cardiovasc Imaging. 2017;33(7):1021-31. 27. Knaapen P, de Haan S, Hoekstra OS, Halbmeijer R, Appelman YE, Groothuis JG, et al. Cardiac PET-CT: advanced hybrid imaging for the detection of coronary artery disease. Neth Heart J. 2010;18(2):90-8. 28. Schroder J, Prescott E. Doppler Echocardiography Assessment of Coronary Microvascular Function in Patients With Angina and No Obstructive Coronary Artery Disease. Front Cardiovasc Med. 2021;8:723542. 29. Patel AR, Salerno M, Kwong RY, Singh A, Heydari B, Kramer CM. Stress Cardiac Magnetic Resonance Myocardial Perfusion Imaging: JACC Review Topic of the Week. Journal of the American College of Cardiology. 2021;78(16):1655-68. 30. Smilowitz NR, Prasad M, Widmer RJ, Toleva O, Quesada O, Sutton NR, et al. Comprehensive Management of ANOCA, Part 2-Program Development, Treatment, and Research Initiatives: JACC Stateof-the-Art Review. J Am Coll Cardiol. 2023;82(12):1264-79. 31. Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, et al. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol. 2018;72(23 Pt A):2841-55. 1

PART 1

Endotypes of chronic coronary syndrome

2 Sex differences in prevalence and outcomes of the different endotypes of chronic coronary syndrome in symptomatic patients undergoing invasive coronary angiography: Insights from the global ILIAS invasive coronary physiology registry Caitlin E.M. Vink, Janneke Woudstra, Joo Myung Lee, Coen K.M. Boerhout, Masahiro Hoshino, Hernan Mejia-Renteria, Seung Hun Lee, Ji-Hyun Jung, Mauro Echavarria-Pinto, Martijn Meuwissen, Hitoshi Matsuo, Maribel Madera-Cambero, Ashkan Eftekhari, Mohamed A. Effat, Tadashi Murai, Koen Marques, Marcel A.M. Beijk, Joon-Hyung Doh, Jan J. Piek, Tim P. van de Hoef, Evald Høj Christiansen, Rupak Banerjee, Chang-Wook Nam, Giampaolo Niccoli, Masafumi Nakayama, Nobuhiro Tanaka, Eun-Seok Shin, Niels van Royen, Steven A.J. Chamuleau, Paul Knaapen,Javier Escaned, Tsunekazu Kakuta, Bon-Kwon Koo, Yolande Appelman*, Guus A. de Waard* *shared last author Atherosclerosis. 2023 Nov;384:117167

22 Chapter 2 ABSTRACT Background and aims The management of chronic coronary syndrome (CCS) is informed by studies predominantly including men. This study investigated the relationship between patients sex and different endotypes of CCS, including sex-specific clinical outcomes. Methods In patients with CCS undergoing coronary angiography, invasive Fractional Flow Reserve (FFR) and Coronary Flow Reserve (CFR) were measured. Patients were stratified into groups: 1) obstructive coronary artery disease (oCAD) (FFR≤0.80, no revascularization), 2) undergoing revascularization, 3) non-obstructive coronary artery disease with coronary microvascular dysfunction (CMD) (FFR>0.80, CFR≤2.5), and 4) non-obstructive coronary artery disease without CMD (FFR>0.80 and CFR>2.5). Results 1836 patients (2335 vessels) were included, comprising 1359 (74.0%) men and 477 (26.0%) women. oCAD was present in 14.1% and was significantly less prevalent in women than in men (10.3% vs 15.5%, respectively p < 0.01). Revascularization was present in 30.9% and was similarly prevalent in women and men (28.2% vs. 31.9%, respectively p = 0.13). CMD was present in 24.2% and was significantly more prevalent in women than men (28.6% vs 22.6%, respectively p < 0.01). Normal invasive measurements were found in 564 patients (33.0% women vs 30.0% men, p = 0.23). Male sex was associated with an increased risk of target vessel failure compared to women (HR.1.89, 95% CI 1.12–3.18, p = 0.018), regardless of CCS-endotype. Conclusions Sex differences exist in the prevalence and outcomes of different endotypes of CCS in symptomatic patients undergoing invasive coronary angiography. In particular, oCAD (and subsequent revascularization) were more prevalent in men. Conversely, CMD was more prevalent in women. Overall, men experienced a worse cardiovascular outcome compared to women, independent of any specific CCS endotype.

23 Sex Differences in Chronic Coronary Syndrome: Data from the ILIAS Physiology Registry Graphical Abstract. Prevalence of endotypes of CCS per sex on per-patient level, with the highest prevalence of normal coronary arteries in women and the highest prevalence of revascularization in men. No significant differences were found on target vessel failure outcome. oCAD: obstructive coronary artery disease; FFR: fractional flow reserve; CMD: coronary microvascular dysfunction; CFR: coronary flow reserve, Revasc: revascularization-group; HR: hazard ratio; CI: confidence-interval 2

24 Chapter 2 INTRODUCTION Chronic coronary syndrome (CCS) remains the leading cause of death worldwide in both men and women.1-3 CCS has multiple underlying pathophysiological mechanisms and clinical presentations. Classically, CCS has most frequently been associated with the presence of obstructive epicardial coronary artery disease (oCAD). However, more recently, there is an increasing understanding of the role of coronary microvascular dysfunction (CMD) in the pathophysiology, symptomatology and adverse clinical outcome of patients with CCS. To date, the invasive diagnosis of CCS has focused mainly on the detection of oCAD, which is known to be more prevalent in men than women 4, 5 irrespective of the presence of typical angina symptoms or positive non-invasive ischemia testing.5, 6 Despite this, there exists an apparent clinical outcome paradox, with women more frequently experiencing cardiovascular death in CCS compared to men.7 One hypothesis to explain this differential outcome between the sexes in CCS may be that there is a higher prevalence of CMD, and thus adverse cardiovascular outcome,8 in women as compared to men.7-9 However, data supporting this rationale is currently lacking, owing to previous studies reporting on sex differences in the prevalence of CMD being small and in highly selected patient groups. Accordingly, in order to adequately inform on the prevalence of CMD in symptomatic patients with CCS presenting to the catheterization laboratory, we investigated the relationship between patient sex and the different endotypes of CCS, as well as their association with long-term clinical outcomes in the large multicenter ILIAS registry. PATIENTS AND METHODS Study population The ILIAS registry is a multi-center, global registry of patients with accompanying comprehensive invasive epicardial and microvascular physiological assessment and associated clinical outcomes. The registry consists of prospectively gathered from 20 expert medical institutes in the Netherlands, Korea, Japan, Denmark, Spain, Italy and the United States of America. Patients were enrolled into the ILIAS registry if they underwent clinically indicated coronary angiography and comprehensive invasive physiological assessment of at least one native coronary artery. Patients with hemodynamic instability, significant valvular pathology, prior coronary artery bypass graft surgery, as well as culpritvessels of acute coronary syndromes were excluded.

25 Sex Differences in Chronic Coronary Syndrome: Data from the ILIAS Physiology Registry Individual patient data were collected and anonymously stored in a fully compliant cloudbased clinical data platform (Castor EDC, Amsterdam, The Netherlands). The ILIAS registry was registered at ClinicalTrials.gov (NCT04485234). For the present study, the following inclusion criteria were applied: i) Invasive coronary angiogram performed to evaluate CCS, ii) both invasive Fractional Flow Reserve (FFR) and Coronary Flow Reserve (CFR) physiological indices were measured, and iii) individual patient outcome data were available. Invasive coronary assessment Invasive coronary assessment was performed according to standard techniques. Invasive physiologic measurements were performed using either separate pressure- (PressureWire, RADI medical – now Abbott Vascular, St Paul, MN, USA) and Doppler velocity sensorequipped coronary guidewires (FloWire, Endosonics – now Philips-Volcano, San Diego, CA, USA), a dual pressure- and Doppler flow velocity-equipped guidewire (ComboWire, Volcano Corp. – now Philips-Volcano, San Diego, CA, USA), or a temperature-sensitive pressure sensor-equipped guidewire (PressureWire, St Jude Medical-now Abbott Vascular, St. Paul, MN, USA). Prior to physiological assessment, intracoronary nitroglycerine (100 or 200 μg) was administered in all cases. Baseline (bAPV) and hyperemic average peak flow velocities (hAPV) were obtained from Doppler velocity measurements. The inverse of the average basal (bTmn) and hyperemic mean transit times (hTmn) was derived from resting and hyperemic thermodilution curves as described previously.10 Hyperemia was induced according to local standards by intravenous infusion of adenosine (140 μg/kg per min) or adenosine-triphosphate (ATP 150 μg/kg per min) through a peripheral or central vein, intracoronary bolus injection of adenosine (20-200mcg), or intracoronary bolus injection of nicorandil (3 mg). FFR was calculated as the ratio between mean hyperemic distal coronary pressure and mean hyperemic aortic pressure, and FFR≤0.80 was considered abnormal.11 CFR was calculated as the ratio between hyperemic and baseline coronary flow, and CFR≤2.5 was considered abnormal.12 Microvascular resistance (MR) was calculated as the ratio of distal coronary flow and distal coronary pressure during hyperemia. For MR, the hyperemic microvascular resistance index (HMR) was derived from Doppler velocity measurements and the index of microcirculatory resistance (IMR) was derived from thermodilution measurements. HMR≥2.5 13 and IMR≥25 were considered abnormal.14 Clinical follow-up To ascertain the occurrence of target vessel failure (TVF), clinical follow-up was obtained either at outpatient clinic visits or by telephone contact. TVF was a composite vessel-level endpoint, consisting of cardiac death, acute myocardial infarction not clearly attributable to a nontarget vessel, and clinically driven revascularization of the target vessel by means 2

26 Chapter 2 of CABG or PCI. All patient-reported adverse events were verified by evaluating hospital records or contacting the treating general practitioner or cardiologist. Definition of different endotypes of CCS Patients were classified into different endotype groups of CCS based upon i) their dichotomized FFR and CFR values, and ii) whether revascularization was performed. First, the undergoing revascularization group (‘Revasc.’ group) consisted of those vessels where revascularization was performed, regardless of the accompanying pre-PCI physiology values. Second, the hemodynamically significant obstructive CAD group (‘oCAD’ group) consisted of those vessels where FFR was ≤0.80, but no revascularization was performed. Third, the non-obstructive coronary artery disease with coronary microvascular dysfunction group (‘CMD’ group) consisted of those vessels where FFR was >0.80 and CFR was ≤2.5. Fourth, the non-obstructive coronary artery disease without CMD group (‘Normal’) group consisted of vessels where FFR was >0.80 and CFR was >2.5.15 Statistical analyses Descriptive data were analyzed on a per-patient basis for clinical characteristics, and on a per-vessel basis for all other calculations. Independence was assumed for vessellevel analyses. Normality of the distribution was tested with the Shapiro-Wilk statistic. Continuous variables are presented as mean ± SD or median [first quartile – third quartile], and were compared using the Student t-test or Mann–Whitney U test depending on whether data was distributed normally. Categorical variables were presented as number (%) and were compared using Pearson’s chi-square test. For the vessel level analyses, robust linear and logistic regressions with Huber-White robust standard errors were used to adjust for clustering of vessels within patients, where appropriate. Event rates over time were presented using the Kaplan-Meier method. To compare the risk of the occurrence of adverse events between groups, multivariable (marginal) Cox proportional hazard regression was used to calculate adjusted hazard ratios (HR) and 95% confidence interval (CI). All clinical characteristics were considered as co-variates in univariate Cox regression analysis, where variable significantly associated with TVF (p for inclusion <0.1) were used to adjust for confounding. Statistical analysis was performed using Stata version 14.1 (StataCorp, College Station, Texas). A p-value <0.05 was considered statistically significant. RESULTS Patient population Of the 2322 patients included in the ILIAS Registry, 1836 patients (2335 vessels) fulfilled study inclusion- and exclusion criteria. The study population included 477 women (26.0%), with a mean age of 65.7 ± 10.2 years, and 1359 men (74.0%) with a mean age of 63.3 ± 10.2 years (p < 0.01). Full baseline characteristics are presented in Table 1.

27 Sex Differences in Chronic Coronary Syndrome: Data from the ILIAS Physiology Registry A statistically significant difference was found in left ventricular ejection fraction between women and men (63.6 ± 8.0% vs. 60.1 ± 9.6%, p < 0.01). Furthermore, women less often smoked tobacco compared to men (16.1% vs. 24.2%, p < 0.01), less often had diabetes mellitus (24.2% vs. 29.6%, p = 0.02), prior myocardial infarction (13.2% vs. 23.2%, p < 0.01) or prior percutaneous coronary intervention (PCI) (18.4% vs. 32.0%, p < 0.01). Conversely, women more often had a positive family history of cardiovascular disease compared to men (38.6% vs. 30.1%, p < 0.01) (Table 1). Angiographic and physiological characteristics are also summarized in Table 1. The left anterior descending coronary artery (LAD) (59.4%) was most frequently examined. With regards to coronary flow assessment, 1373 vessels (58.8%) were evaluated with coronary thermodilution, and 962 vessels (41.2%) with Doppler flow velocity. Table 1. Baseline characteristics Total Women Men p-value Total number of patients n = 1836 n = 477 (26.0) n = 1359 (74.0) Demographics Age, yrs 63.9 ±10.3 65.7 ±10.2 63.3 ±10.2 <0.01 Ejection fraction, % 60.9 ±9.4 63.6 ±8.0 60.1 ±9.6 <0.01 Coronary risk factors Hypertension, % 1099 (60.1) 293 (61.6) 806 (59.6) 0.45 Hyperlipidemia, % 1234 (67.4) 318 (66.8) 916 (67.6) 0.77 Positive family history, % 560 (32.4) 175 (38.6) 385 (30.1) <0.01 Current smoking, % 399 (22.1) 76 (16.1) 323 (24.2) <0.01 Diabetes mellitus, % 516 (28.2) 115 (24.2) 401 (29.6) 0.023 Prior myocardial infarction, % 378 (20.6) 63 (13.2) 315 (23.2) <0.01 Prior coronary intervention, % 473 (28.2) 83 (18.4) 390 (32.0) <0.01 Medication at hospital admission Beta-blocker, % 839 (50.2) 223 (49.5) 616 (50.5) 0.69 Nitrates, % 617 (37.8) 161 (38.2) 456 (37.7) 0.86 Calcium antagonist, % 699 (41.8) 183 (40.5) 516 (42.3) 0.51 ACE-inhibitors, % 748 (44.7) 180 (39.8) 568 (46.5) 0.014 Aspirin, % 1403 (83.9) 377 (84.6) 1026 (84.0) 0.83 Total number of vessels n = 2335 n = 596 (25.5) n = 1739 (74.5) Measurement technique 0.27 Doppler flow velocity, % 962 (41.2) 257 (43.1) 705 (40.5) Thermodilution, % 1373 (58.8) 339 (56.9) 1034 (59.5) Hyperemic stimulus <0.01 Intravenous adenosine, % 528 (22.6) 103 (17.3) 425 (24.4) Intravenous ATP, % 347 (14.9) 80 (13.4) 267 (15.4) 2

28 Chapter 2 Table 1. Baseline characteristics (continued) Total Women Men p-value Total number of patients n = 1836 n = 477 (26.0) n = 1359 (74.0) Intracoronary nicorandil, % 687 (29.4) 187 (31.4) 500 (28.8) Intracoronary adenosine, % 773 (33.1) 226 (37.9) 547 (31.5) Examined vessel 0.017 LAD, % 1378 (59.4) 381 (64.4) 997 (57.7) LCX, % 424 (18.3) 95 (16.1) 329 (19.0) RCA, % 518 (22.3) 116 (19.6) 402 (23.3) Hemodynamic parameters FFR, [IQR] 0.82 [0.76-0.91] 0.83 [0.78-0.92] 0.82 [0.76-0.90] <0.01 CFR, [IQR] 2.63 [1.8-3.2] 2.50 [1.8-3.0] 2.68 [1.8-3.3] <0.01 HMR, mmHg/cm/s, [IQR] 2.27 [1.62-2.75] 2.36 [1.71-2.73] 2.24 [1.58-2.76] 0.18 IMR, U, [IQR] 20.7 [12.6-24.1] 20.5 [12.4-24.0] 20.7 [12.6-24.1] 0.66 Reduced FFR (<0.80), % 851 (36.5) 184 (30.9) 667 (38.4) <0.01 Reduced CFR (≤2.5), % 1213 (52.0) 331 (55.6) 882 (50.8) 0.04 Increased MR, % 563 (28.1) 148 (28.2) 415 (28.0) 0.94 Increased HMR (>2.5), % 321 (13.7) 91 (15.3) 230 (13.2) 0.39 Increased IMR (>25), % 240 (10.3) 56 (9.4) 184 (10.6) 0.63 Data presented as n(%), mean ±standard deviation or median [1st quartile – 3rd quartile] Abbreviations: yrs: years; ACE: Angiotensin-Converting Enzyme; ATP: adenosine triphosphate; LAD: left anterior descending coronary artery; LCX: left circumflex coronary artery; RCA: right coronary artery; FFR: Fractional flow reserve; CFR: coronary flow reserve; HMR: hyperemic microvascular resistance index; IMR: index of microcirculatory resistance; IQR: interquartile range Despite equivalent mean angiographic diameter stenoses between the sexes (women: 49.4% vs. men: 52.1%, p = 1.00), FFR across the studied vessels was significantly higher for women vs. men (FFR 0.83 [0.78–0.92] vs. 0.82 [0.76–0.90], p < 0.01). Consequently, men more often demonstrated a hemodynamically significant FFR (≤0.80) compared to women (30.9% vs. 38.4%, p < 0.01). CFR was significantly lower for women vs. men (CFR 2.50 [1.8–3.0] vs. 2.68 [1.8–3.3], p < 0.01), and consequently, the prevalence of an abnormal CFR (≤2.5) was higher in women compared to men (55.6% vs. 50.8%, respectively p = 0.04). MR was equivalent between women and men, irrespective of either HMR or IMR methods of resistance quantification. Endotypes of CCS by sex The graphical abstract shows the patient-level prevalence of CCS endotypes. Within the study population, obstructive CAD occurred in 826 patients (45%) with 959 vessels (41%). Revascularization was performed in 567 patient (30.9%), and rates did not differ between women and men (28.1% vs. 31.9%, respectively p = 0.13). oCAD without revascularization occurred in 259 patients (4.1%). oCAD was more frequently observed in men compared

29 Sex Differences in Chronic Coronary Syndrome: Data from the ILIAS Physiology Registry to women (15.5% 10.3% respectively, p < 0.01). Women were more likely to have CMD compared to men (28.5% vs. 22.6% respectively, p < 0.01). Lastly, there was a similar occurrence of normal invasive physiologic measurements in both women and men (32.9% vs. 30.0% respectively, p = 0.23). Patient characteristics stratified according to CCS endotype are shown in Table 2. Table 2. Baseline characteristics per CCS-endotype oCAD Revasc CMD Normal Total number of patients n = 259 (14.1) n = 567 (30.9) n = 443 (24.2) n = 564 (30.8) Total number of vessels n = 308 (13.2) n = 651 (27.9) n = 586 (25.1) n = 787 (33.8) Demographics Men, % 210 (81.1) 433 (76.4) 307 (69.3) 407 (72.2) Age, yrs 62.6 ±10.5 64.2 ±10.3 65.4 ±10.0 63.0 ±10.2 Ejection fraction, % 61.3 ±9.4 60.5 ±9.5 60.5 ±10.1 61.4 ±8.6 Coronary risk factors Hypertension, % 155 (59.9) 345 (61.2) 269 (60.9) 329 (58.3) Hyperlipidemia, % 193 (74.2) 392 (69.4) 289 (65.1) 361 (64.0) Positive family history, % 95 (38.3) 165 (31.2) 137 (33.4) 166 (30.3) Current smoking, % 60 (23.5) 140 (25.0) 79 (18.0) 121 (21.8) Diabetes mellitus, % 77 (29.6) 180 (31.8) 115 (25.9) 144 (25.6) Prior myocardial infarction, % 54 (20.8) 146 (25.8) 85 (19.1) 93 (16.5) Prior coronary intervention, % 70 (29.3) 149 (29.6) 109 (28.1) 145 (26.7) Medication at hospital admission Beta-blocker, % 122 (50.8) 294 (58.7) 185 (47.7) 240 (44.2) Nitrates, % 106 (45.3) 182 (38.1) 140 (36.3) 192 (35.8) Calcium antagonist, % 102 (42.5) 215 (42.7) 164 (42.2) 219 (40.3) ACE-inhibitors, % 113 (47.1) 239 (47.6) 173 (44.5) 223 (41.0) Aspirin, % 208 (87.4) 453 (90.1) 308 (79.2) 436 (80.2) Data presented as n(%) or mean ±standard deviation. Abbreviations: yrs: years; ACE: Angiotensin-Converting Enzyme 2

30 Chapter 2 Figure 1 shows the prevalence of CCS endotypes per sex, on a per-vessel level. The analysis on a per-vessel level demonstrated consistent results with the per-patient level analysis. Supplementary Table 1 shows the CCS endotypes according to sex for CFR≤2.0 (the CFR threshold recommended by the recent European Society of Cardiology consensus document).16 Analyses according to both CFR≤2.0 and CFR≤2.5 yielded similar and consistent results. Figure 1. Prevalence of endotypes of CCS per sex on vessel-level, with the highest prevalence of normal coronary arteries in women and the highest prevalence of revascularization in men Abbreviations: TVF: Target Vessel Failure; oCAD: obstructive coronary artery disease; CMD: Coronary microvascular dysfunction; Revasc: Revascularization-group Long-term clinical outcomes determined by sex and CCS endotypes During a 5-year follow-up period, one or more TVF events occurred in 146 vessels (8.0%). Overall, the incidence of TVF events was relatively low across all CCS endotypes. Figure 2A depicts the per-vessel Kaplan-Meier time to event curves for TVF, stratified by sex. Sex, age, diabetes mellitus, positive family history, previous myocardial infarction, use of beta-blockers, use of nitrates, and the method used to measure coronary flow were all associated with 5-year TVF. After adjustment for these potential cofounders, patient sex remained an independent predictor of TVF, where men had a higher risk for TVF than women (HR.1.89, 95% CI 1.12–3.18, p = 0.018). Likewise, men had a trend towards a shorter mean survival time (14.6 years, 95% CI 13.9–15.3) compared to women (15.4 years, 95% CI 14.4–16.3).

31 Sex Differences in Chronic Coronary Syndrome: Data from the ILIAS Physiology Registry Figure 2. Cumulative TVF-event rate per sex in overall population on per-vessel level Kaplan Meier-curve of total population per sex and per CCS-endotype (A) Kaplan Meier-curves of CCS per sex (B) Kaplan Meier-curves of CCS per endotype, excluding the revascularization-group Abbreviations: TVF; Target Vessel Failure, CCS; Chronic Coronary Syndrome; HR: Hazard-Ratio; CI: Confidence-Interval; CMD: Coronary microvascular dysfunction; oCAD: obstructive oronary artery disease Figure 2B depicts the per-vessel Kaplan-Meier time to event curves for TVF, stratified by CCS endotype (excluding the revascularization group). A significant difference in 5-year TVF rates was observed across CCS endotypes (log rank p for trend < 0.01], which was higher than the TVF risk observed in vessels with CMD [HR 1.9, 95% CI 1.28–2.89, p < 0.01 vs. OCAD]. CMD was, however, associated with increased TVF compared with physiologically normal coronary arteries (HR 2.58, 95% CI 1.62–4.44, p < 0.01 for CMD vs. normal). Correspondingly, mean survival time was 11.5 years (95% CI 10.5–12.5) for the 2

32 Chapter 2 oCAD group, 14.1 years (95% CI 13.0–15.1) for the revascularization group and 15.6 years (95% CI 14.5–16.6) for the normal coronary artery group. Figure 3 depicts Kaplan-Meier time to event curves for TVF, stratified by sex according to the following CCS endotypes. Figure 3A compares oCAD vs. revascularization. Figure 3B depicts CMD, and Figure 3C depicts normal coronary arteries. A difference in 5-year TVF rate was found between sexes in the normal coronary artery group, with a higher risk for TVF in women compared to men (HR 4.5, 95% CI 1.07–19.3, p = 0.041). No sex difference was found in 5-year TVF rate in the other endotypes. However, men who underwent revascularization had a significant lower risk for TVF compared to men with obstructive CAD who did not undergo revascularization (HR 0.60, 95% CI 0.38–0.93, p = 0.022). Conversely, this difference in risk for TVF was not found in women who underwent revascularization compared to women with obstructive CAD whom did not undergo revascularization (HR 0.88, 95% CI 0.41–1.89, p = 0.74). Results were consistent when the CFR cutoff value of 2.0 was used instead of the CFR cut-off value of 2.5 (Supplementary Figures 1 through 3).

33 Sex Differences in Chronic Coronary Syndrome: Data from the ILIAS Physiology Registry Figure 3. Cumulative TVF-event rate per sex (A) Kaplan Meier-curves of oCAD per sex (B) Kaplan Meier-curves of CMD per sex (C) Kaplan Meier-curves of normal coronary arteries per sex Abbreviations: HR: Hazard-Ratio; CI: Confidence-Interval; oCAD: obstructive coronary artery disease; CMD: Coronary microvascular dysfunction; Revasc: Revascularization-group 2

34 Chapter 2 DISCUSSION The present study describes the sex-specific prevalence and clinical outcome of the different endotypes of symptomatic CCS patients referred for clinically indicated invasive coronary angiography in a large global patient cohort. The endotypes of CCS were comprehensively characterized by combined assessment of intracoronary pressure and flow to distinguish obstructive CAD, CMD and physiological normal endotype groups (Figure 4). The main study findings were as follows: In patients referred for invasive coronary angiography for the evaluation of CCS: 1) oCAD was significantly less prevalent and CMD was significantly more prevalent in women compared to men; 2) long-term cardiovascular outcomes (defined as TVF) were sequentially worst for patients with obstructive CAD, followed by patients with CMD. Conversely, patients with physiologically normal coronary arteries had the best long-term cardiovascular outcomes; 3) men experienced a worse 5-year TVF rate compared to women; 4) no sex-specific differences in prognosis was observed in the obstructive CAD, revascularization and CMD groups; and, 5) in the presence of oCAD (FFR≤0.80), men who underwent revascularization had lower risk of TVF at 5 years than men in whom revascularization was not performed. Conversely, this impact of revascularization was not identified in women. Invasive coronary physiological assessment in men and women Earlier studies have shown that women experience angina differently, have less extensive atherosclerosis and suffer from obstructive CAD less frequently compared to men.17-18 Yet, the prevalence of the distinct CCS endotypes across sexes encountered in catheterization laboratory in daily clinical practice is poorly understood. In the present large study, obstructive CAD was indeed less prevalent in women compared to men presenting with stable angina (15.5%, 210/1359 vs. 10.3%, 49/477). Additionally, we found a trend towards less revascularization in women compared to men (28.2%, 134/477 vs. 31.9%, 433/1359) suggesting an excess of obstructive CAD in men referred to the catheterization laboratory for suspected stable ischemic heart disease. This observation of the presence of exertional angina in the absence of obstructive CAD has been suggested by the Women’s Ischemia Syndrome Evaluation (WISE) study as being potentially related to a higher prevalence of CMD in women compared to men.5,19 However, the WISE-study is limited in its scope owing to its inclusion of only women. Accordingly, our study addresses this limitation by the inclusion of a multiethnic cohort of both men and women across multiple centers. Within this wider, clinically-representative, patient population, CMD was indeed significantly more prevalent in women compared to men (28.5% vs. 22.6%). Our findings are also consistent with a recent meta-analysis by Meliva et al.20, which similarly demonstrated a high pooled prevalence of CMD in ANOCA patients 41% (95% CI: 36–47%), with CMD being more prevalent in women compared to men

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