An EAPCI Expert Consensus Document On

CORONARY INTERVENTIONS

EXPERT REVIEW Euro An EAPCI Expert Consensus Document on Ischaemia with Intervention Non-Obstructive Coronary Arteries in Collaboration with 2020;16-online July 2020 publish-ahead-of-print European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group

Vijay Kunadian (UK, Document Chair)1*, Alaide Chieffo (Italy, Document Co-Chair)2, Paolo G. Camici (Italy)3, Colin Berry (UK)4, Javier Escaned (Spain)5, Angela H. E. M. Maas (Netherlands)6, Eva Prescott (Denmark)7, Nicole Karam (France)8, Yolande Appelman (Netherlands)9, Chiara Fraccaro (Italy)10, Gill Louise Buchanan (UK)11, Stephane Manzo-Silberman (France)12, Rasha Al-Lamee (UK)13, Evelyn Regar (Germany)14, Alexandra Lansky (USA, UK)15,16, J. Dawn Abbott (USA)17, Lina Badimon (Spain)18, 19 20 21

Dirk J. Duncker (Netherlands) , Roxana Mehran (USA) , Davide Capodanno (Italy) , Andreas Baumbach (UK, USA)22,23 V. Kunadian and A. Chieffo contributed equally to this document. The authors’ affiliations can be found in the Appendix paragraph. This paper also includes supplementary data published online at: https://eurointervention.pcronline.com/doi/10.4244/EIJY20M07_01

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Ischaemia with non obstrucve coronary arteries (INOCA) Cardiovascular Interventions (EAPCI), appraises the importance of Coronary Microvascular dysfuncon (CMD)/Vasospasc angina (VSA) ischaemia with non-obstructive coronary arteries (INOCA). Angina

pectoris affects approximately 112 million people globally. Up n Step 1: Paent evaluaon si ve to 70% of patients undergoing invasive angiography do not have va Step 2: Non-invasive evaluaon obstructive coronary artery disease, more common in women than aluao Funconal Imaging

ev ±Coronary CT Angiography in men, and a large proportion have INOCA as a cause of their Non-in symptoms. INOCA patients present with a wide spectrum of symp-

n Step 1: Invasive Coronary angiography toms and signs that are often misdiagnosed as non-cardiac leading sive Step 2: FCA guidewire and Adenosine test

to under-diagnosis/investigation and under-treatment. INOCA can va aluao In result from heterogeneous mechanism including coronary vasos- ev Step 3: FCA Vasoreacvity (ACH test) pasm and microvascular dysfunction and is not a benign condition. Compared to asymptomatic individuals, INOCA is associated Epicardial Microvascular Microvascular Vasospasc Angina And Epicardial with increased incidence of cardiovascular events, repeated hospi- Angina Vasospasc Angina tal admissions, as well as impaired quality of life and associated increased health care costs. This consensus document provides INOCA ENDOTYPES a deﬁnition of INOCA and guidance to the community on the diag- Management of INOCA nostic approach and management of INOCA based on existing evi- 1. Lifestyle factors 2. Risk factor management 3. Ananginal medicaons dence from research and best available clinical practice; noting gaps

Visual summary. D in knowledge and potential areas for further investigation. OI: 10.4244/EIJY20M07_01

*Corresponding author: Translational and Clinical Research Institute, Faculty of Medical Sciences, Newcastle University and Cardiothoracic Centre, Freeman Hospital, Newcastle upon Tyne NHS Foundation Trust, M4:146 4th Floor William Leech Building, Newcastle upon Tyne NE2 4HH, United Kingdom. Tel: +44 (0) 191 208 5797. E-mail: [email protected] The article has been co-published with permission in the European Heart Journal and EuroIntervention. All rights reserved. © 2020 the Author(s). These articles are identical except for minor stylistic and spelling differences in keeping with each journal’s style. Either citation can be used when citing this article. This paper underwent review with the European Heart Journal.

RECEIVED ON 03/02/2020 - EDITORIAL DECISION ON 29/05/2020 - ACCEPTED ON 01/06/2020 1

7 - - - - 5,6 Although obstructive 8 Coronary microvascular Coronary 4 Studies carried out in the past two Studies carried 2,3 A large proportion of patients (up to 70%) undergoing to 70%) undergoing (up of patients proportion large A 2 The 2019 ESC guidelines provides guidance on the diagno- on the guidance provides ESC guidelines 2019 The 1 CAD is a frequent and well-acknowledged cause of myocardial CAD is a frequent and well-acknowledged sis and management of patients with chronic coronary syndromes coronary chronic with patients of sis and management (CCS). INOCA endotypes of coronary of demand-supply In the setting of CCS, a mismatch chest cardiac or recurrent to transient lead blood flow may artery cellular due to inadequate ischaemia to myocardial pain related of adenosine-50-triphosphate. availability Introduction heart most common symptom of ischaemic Angina pectoris, the glob- people million 112 approximately disease (IHD), affects ally. dysfunction and epicardial vasospasm, alone or in combination vasospasm, alone or in combination dysfunction and epicardial of mechanisms disease (CAD), are adjunctive with coronary artery these conditions are rarely cor ischaemia. However, myocardial therapy is prescribed rectly diagnosed and, therefore, no tailored As patients continue to a consequence, these for these patients. life, leading recurrent angina with impaired quality of experience unnecessary coronary angiography to repeated hospitalizations, term. short-and long the in outcomes and adverse cardiovascular such as inflammation, systemic inflammatory or auto- inflammatory systemic (Figure 1) such as inflammation, platelet/coagulation arthritis), (lupus, rheumatoid disease immune - myo by as well as abnormalities, metabolic primary disorders, consensus document. this of scope the is beyond bridging, cardial with documented CAD in a patient failure to diagnose epicardial A should promote a subsequent search pathway angina/ischaemia for non-cardiac a search before endotypes INOCA to elucidate causes of chest discomfort is explored. This consensus document provides a definition of ischaemia with of ischaemia This consensus document provides a definition to the (INOCA) and guidance coronary arteries non-obstructive on the diagnostic approach and management community clinical practices. evidence and best current based on existing of INOCA and identify of INOCA definition having a universal In addition, research to improve ing gaps in knowledge will serve to encourage caused Discussion of angina population. for this patient outcomes dilated), (hypertrophic, of cardiomyopathy context by CMD in the per heart, of the diseases infiltrative stenosis, aortic myocarditis, and other possible mechanisms interventions, cutaneous/surgical coronary angiography because of angina and evidence of myo- of and evidence of angina because coronary angiography but arteries coronary obstructive do not have ischaemia cardial ischaemia. have demonstrable decades have highlighted that coronary microvascular dysfunc- that coronary microvascular decades have highlighted vascular dysfunction are additional tion (CMD) and epicardial IHD. of mechanisms pathophysiologic the EAPCI office. The writing task force members have provided provided have force members task The writing office. the EAPCI per be might that relationships forms for all of interest declaration This interest. of of conflicts sources or potential real as ceived and guidance of INOCA document provides a definition consensus approach diagnostic on the and research community to the clinical and best evidence based on existing of INOCA and management areas for further investigation. and identifies practices current - resistance dysfunction enzyme inhibitors enzyme reserve blockade tomographic angiography tomographic coronary angiography bypass surgery disease disease angina C reactive protein C reactive myocardial velocity resistance velocity myocardial infarction flow reserve heart disease coronary arteries with non-obstructive external counterpulsation external Association of Percutaneous Cardiovascular Association of Percutaneous Cardiovascular Documents and Initiatives Committee Documents and Initiatives Society of Cardiology Society Vasomotor Disorders International Study Disorders International Vasomotor trinitrate omen’s Ischaemia Syndrome Evaluation Ischaemia omen’s

European Interventions Scientific W Ischaemic Index of microcirculatory Ischaemia Myocardial Microvascular Positron emission tomography European Invasive functional Fractional Glyceryl Hyperaemic high-sensitive Coronary microvascular Coronary microvascular cardiovascular Coronary Enhanced Coronary artery Coronary artery Chronic coronary syndrome Coronary computed Coronary flow reserve Coronary flow velocity Angiotensin-converting Angiotensin-converting Acetylcholine receptor Angiotensin Adenosine-50-triphosphate blood pressure

HMR This consensus document, a summary of the views of an expert views of an of the summary a consensus document, This Percutaneous of Association European the by organized panel impor the (EAPCI), appraises Interventions Cardiovascular Preamble PET WISE hsCRP IHD IMR INOCA MI MVA SDAIC coronary arteries with non-obstructive of ischaemia tance with collaboration in together is put document This (INOCA). Group on Coronary Working of Cardiology Society European the by COVADIS endorsed and & Microcirculation Pathophysiology The Study) group. Disorders International Vasomotor (Coronary was proposed by the EAPCI consensus document EAPCI INOCA and writing chairs The and its members. Committee Women’s EAPCI by the were selected group task force of this document (EAPCI SDAIC) Committee Documents and Initiatives Scientific force task group writing The Committee. Women’s EAPCI and Committee, Women’s members are represented from the EAPCI and Committee/members, Steering EAPCI SDAIC, COVADIS Group on Coronary Working of Cardiology Society European The formal approval for this Pathophysiology & Microcirculation. of Cardiology Society European by the was provided document by and coordinated Committee Guidelines Practice (ESC) Clinical CMD COVADIS EAPCI ESC FCA FFR GTN CFR CVD EECP ATP CCT CFVR Abbreviations ACEis ARB BP CABG CAD CCS ACH 2 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 3 - 19 (Table 1). (Table

15 Microvascular angina and epicardial angina Microvascular scular 18 spasm Va

n Subsequently, other forms of vasomotor vasomotor of forms other Subsequently, 17 ge brid Ischaemia with non-obstructive coronary arteries coronary non-obstructive with Ischaemia Coronary Myocardial dysfunco microvascular microvascular

a disorders causing chest pain with transient ST-segment depression ST-segment with transient pain chest disorders causing entities inversion were described. Overall, these clinical T-wave or term the under grouped spasm were vessel by epicardial caused been has VSA for criteria diagnostic of standardization A VSA. group (Supplementary previously described by the COVADIS S1). material online, Table EPICARDIAL VASOSPASTIC ANGINA EPICARDIAL VASOSPASTIC of myocar angina (VSA) manifestation is the clinical Vasospastic coronary obstruction epicardial caused by dynamic dial ischaemia described In 1959, Prinzmetal caused by a vasomotor disorder. (transient manifestations electrocardiographic and clinical the to be due to epicardial of a disorder thought elevation) ST-segment spasm. artery coronary Epidemiology AND IN THE GENERAL POPULATION PREVALENCE ACCORDING TO SEX AND AGE do for angina for assessment referred of patients majority The populations not have obstructive coronary arteries. In unselected VSA can co-exist which is associated with worse prognosis. which is associated can co-exist VSA mechanisms may co-exist and contribute to MVA. An updated stand- mechanisms may co-exist and contribute to MVA. angina with presenting patients in MVA for criteria of ardization absence of flow-limit- pectoris or ischaemia-like symptoms in the group by the COVADIS proposed been has CAD ing bolic ta enosis Primary st Coronary me Ischaemi Myocardial abnormality shows 13,14 n Figure 2

12 elets and

ry coagulao

Plat

Inﬂammaon Both vascular dysfunction to emic 15,16 and disease Syst autoimmune inﬂamma Cardiac ischaemia may also be caused may ischaemia Cardiac 2 The most recent ESC guidelines recommend the use of most recent ESC guidelines recommend The 9-11 by vascular dysfunction without obstructive CAD, a condition CAD, a obstructive without dysfunction vascular by blood between mismatch INOCA. In INOCA, the termed recently oxygen demands may be caused by CMD supply and myocardial in the setting coronary artery spasm, typically and/or epicardial coronary atherosclerosis. of non-obstructive MICROVASCULAR ANGINA MICROVASCULAR is the clinical manifestation of myo- Microvascular angina (MVA) myocardial cardial ischaemia caused by CMD. In this clinical entity, ischaemia may result from structural remodelling of the microvasculature (leading to fixed reduced microcirculatory conductance) the coronary arterioles (caus- or vasomotor disorders affecting ing dynamic arteriolar obstruction). the mechanisms of INOCA. Of note, these mechanisms may also obstructive CAD with concomitant in patients cause ischaemia but these cases are and atherosclerosis with outward remodelling by definition. in INOCA not included ischaemia, many stenoses judged as severe on visual assessment, many stenoses judged as severe on visual assessment, ischaemia, of obstructive misclassification Functional flow-limiting. not are severity, occurs in the range of 40-80% stenosis lesions frequently coronary multiple with of patients case in high particularly being lesions. Mechanisms of myocardial ischaemia. Figure 1. Mechanisms of myocardial myocardial fractional flow reserve (FFR) or instantaneous wave- instantaneous (FFR) or reserve flow fractional myocardial to identify patients at high event risk who free ratio will bene- from revascularisation. fit

21 rcon fa rupture e e coronary able plaque Thrombosis Plaque Acut lner ndromes/in Vu sy Many patients with heart a ± heroscleroc diseas heroscleroc At angina Demand coronary artery disease coronary ischaemia ducon in FFR Ischaemia with obstrucve with obstrucve Ischaemia Stable plaque Stable Re on Diagnostic parameters Epicardial Epicardial rc

coronary artery erlap ) fa ) istent SA rs Signs of ischaemia may be present but are not necessary. Signs of ischaemia may be present but are not necessary. sospasm b

Pe va 16 present. Myocardial in Myocardial ntly angina and/or positive stress test have non-obstructive CAD. non-obstructive have stress test and/or positive angina This frequency is higher among women (approximately 50-70%), (approximately women among higher is frequency This registry from to men (30-50%). In a retrospective compared referred with angina 223 patients 11 Denmark including Eastern ries (INOCA te sospasm is freque sospasc angina (V sospasc In Coronary CTA Invasive coronary angiography Impaired coronary flow reserve (cut-off <2.0), invasive or noninvasively determined Coronary microvascular spasm, defined as reproduction of symptoms, ischaemic ECG shifts but no epicardial spasm during acetylcholine testing Abnormal coronary microvascular resistance indices (e.g. IMR ≥25) Effort or rest angina Exertional dyspnoea Presence of reversible defect, abnormality or flow reserve on a functional imaging test al angina va

Va 3,20 nt b nary ar ansie ro Prinzmet These mechanisms can ov Tr a dial blood s or ocar act my

Evidence to Non-obstrucve coronary atherosclerosis ascular angina ascular dysfuncon ascular dysfuncon (CMD) CAD ysiology and contributes

ocardial ischaemia in ocardial and Objective evidence of myocardial ischaemia Absence of obstructive CAD (<50% diameter reduction or FFR >0.80) Evidence of impaired coronary microvascular function Symptoms of myocardial ischaemia my ulaon ﬂow in with subjects risk f nary rc Causes microv

Coro Ischaemia with non obstrucve co with non obstrucve Ischaemia Coronary Microv 3 2 4 1 microci Impairs coronary ph

Criteria failure with preserved ejection fraction would fulfil these criteria: dyspnoea, no obstructive CAD and impaired CFR. For this reason, consider measuringfailure with preserved ejection fraction would fulfil these criteria: dyspnoea, no obstructive CAD and normal <125 pg/mL. end-diastolic pressure (normal ≤10 mmHg) and NT-proBNP LV Definitive microvascular angina is only diagnosed if criterias 1, 2, 3 and 4 are present. CAD: coronary artery disease; CCTA: coronary computed artery disease; CCTA: Definitive microvascular angina is only diagnosed if criterias 1, 2, 3 and 4 are present. CAD: coronary resistance. tomographic angiography; ECG: electrocardiogram; FFR: fractional flow reserve; IMR: index of microcirculatory However, evidence of impaired coronary microvascular function should be present. However, Table 1. Diagnostic criteria for microvascular angina. Table all studies, there is a strong female preponderance for the condi- for the preponderance is a strong female studies, there all study showed that nearly 39% of the US multicentre large A tion. patients selected for coronary angiography because of suspected referred for assessment less than 10% have obstructive CAD. referred for assessment less than 10% have Mechanisms of myocardial ischaemia in INOCA and obstructive coronary artery disease. CAD: coronary artery disease; coronary artery disease. CAD: coronary and obstructive ischaemia in INOCA Figure 2. Mechanisms of myocardial FFR: fractional flow reserve. 4 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 5

------52 However, However, 44,45 are markedly are 40 Most patients with Most patients 40 Interestingly, VSA is VSA Interestingly, 46,47 41 The haemodynamic cor haemodynamic The Previous Asian studies of Previous 51 40 This is typically caused by caused typically is This 49 Under physiological conditions, an conditions, physiological Under 16 A direct consequence of these pathological consequence direct A 50 Two microcirculatory dysfunction endotypes dysfunction endotypes microcirculatory Two Remodelling may occur as a result of cardio Remodelling 16 50 Ischaemia with non-obstructive coronary arteries coronary non-obstructive with Ischaemia European studies have also shown a high prevalence European studies have and Taiwanese populations (19.3%) populations Taiwanese and 39 42,43 16,48 (i) Structural remodelling of the coronary microvasculature is of the coronary microvasculature remodelling (i) Structural (ii) Functional arteriolar dysregulation typically takes place in typically dysregulation arteriolar (ii) Functional more prevalent among men than women. than men among prevalent more populations. In addition, the frequencies of multiple coronary coronary multiple of frequencies the addition, In populations. spasm (≥2 spastic arteries) by provocative (24.3%) testing in Japanese increase in myocardial oxygen consumption generates an upstream upstream an generates consumption oxygen myocardial in increase This is initi vessels. in coronary resistance cascade vasodilatory ated by metabolically triggered vasodilation of distal arterioles, of distal vasodilation triggered by metabolically ated fol- is it and metabolites, certain to sensitive particularly are that of vasodilation (endothelium-dependent) by flow-mediated lowed vessels. as epicardial as well up-stream, located arterioles larger of epicardial vasospasm when systematically tested. vasospasm when systematically of epicardial account for most cases of MVA: structural microcirculatory structural MVA: of cases most for account dysregulation. In other and functional arteriolar remodelling or functional be structural, may dyfsunction words, microvascular both. due to differences in stress protocols and definitions applied, the and definitions applied, in stress protocols due to differences more were patients Female comparable. directly not are studies at vasomotor dysfunction occurring with to acetylcholine sensitive Smoking patients. male with compared doses acetylcholine lower the and hypertension, and diabetes VSA, unlike for risk factor is a is unclear. with dyslipidaemia relationship associated with a decrease in microcirculatory conductance and conductance associated with a decrease in microcirculatory capacity. delivery oxygen impaired Pathophysiology and endotypes ANGINA AND EPICARDIAL CORONARY MICROVASCULAR SPASM ARTERY myocar disease, artery coronary flow-limiting of absence the In dial ischaemia can result from specific pathways of microcircu dial ischaemia dysfunction. latory inward remodelling of coronary arterioles, with an increase in wall in increase an with arterioles, of coronary remodelling inward rar density (capillary capillary to lumen ratio, loss of myocardial efaction) or both. efaction) VSA are between 40 and 70 years of age, and the prevalence tends tends the prevalence 70 years of age, and 40 and are between VSA age of 70 years. the to decrease after changes is a reduction of the vasodilatory range of the coronary of the range vasodilatory of the reduction is a changes blood and oxygen supply to maximal limiting microcirculation, hyper are arterioles remodelled Furthermore, myocardium. the stimuli. vasoconstricting to sensitive patients with non-obstructive CAD have shown that the prevalence CAD have shown with non-obstructive patients with disorders is around 50% in patients of coronary vasomotor angina. higher than those in Caucasians (7.5%). Caucasians in those than higher vascular risk factors, atherosclerosis, left ventricular hypertrophy, hypertrophy, left ventricular vascular risk factors, atherosclerosis, or cardiomyopathies. relates of structural microcirculatory remodelling in response to remodelling microcirculatory of structural relates like adenosine, are vasodilator, a non-endothelium-dependent in flow reserve (CFR) and (ii) an increase (i) a reduced coronary resistance. microcirculatory (hyperaemic) minimal vaso- in which flow-mediated arterioles, size and large medium predominant. is dilation

- 21,23 27,29 24,25 In the WISE In the 30,31 22 37 compared with western with compared 38 For instance, systematic 32 These seem to affect men and men affect to seem These 36 Similarly, almost two-thirds (62%) almost Similarly, 5 27 Although large studies are lacking, there is studies are lacking, Although large 35 Women have elevated levels of high sensitive levels of elevated have Women 37 After menopause, inflammatory diseases occur more After menopause, inflammatory In a large study with invasive assessment of CMD study in In a large - Age, diabetes, hypertension, and dyslipidaemia were assoc However, these studies should be interpreted in the context However, 21,26 33,34 28 23 Coronary microvascular dysfunction is associated with pro- dysfunction is associated Coronary microvascular The association between traditional cardiovascular risk factors andThe association between traditional cardiovascular Other studies assessing CMD invasively or by positron emis- or by positron Other studies assessing CMD invasively cohort, novel risk variables like those associated with inflamma with associated those like risk variables novel cohort, tion seemed to play a role in CMD. women differently. C reactive protein (hsCRP), protein and a lower monocyte and eosinophil C reactive significant positive association between Beck A count than men. hsCRP symptoms with elevated Depression Inventory cognitive is observed in men, but not in women. level often in women compared to men, which may contribute to sex- to men, which may contribute often in women compared in CMD. differences 1439 men and women with chest pain and no obstructive CAD no obstructive 1439 men and women with chest pain and CFVR in over a period of 19 years, 30% had abnormal included response to adenosine. PREVALENCE OF CORONARY ARTERY SPASM ARTERY OF CORONARY PREVALENCE of angina The Japanese population has a higher prevalence disorders coronary vasomotor to related inflammatory markers in women with INOCA. inflammatory INOCA is not well established. Smoking has been associated with is not well established. Smoking has been INOCA CMD. sion tomography with different cut-offs have found 39-54% have cut-offs with different sion tomography CMD. PREVALENCE OF CORONARY MICROVASCULAR MICROVASCULAR OF CORONARY PREVALENCE DYSFUNCTION in patients with angina and no obstructiveThe prevalence of CMD depends on the methods invasive angiography CAD undergoing 26% of 963 sympto- study, applied. In the iPower and cut-off coronary flow velocitymatic women with no obstructive CAD had transthoracic Dopplerreserve (CFVR) below two when assessed by echo. for coronary angiography between 1998 and 2009, 65% of women of women 2009, 65% 1998 and between angiography for coronary CAD, men had non-obstructive vs. 33% of with an increasing to up reaching sexes, both period in study 10-year the over rate women in 2009. 73% among of women referred for coronary angiography and enrolled in the in the angiography and enrolled referred for coronary of women Women’s sponsored Blood Institute Heart, Lung, and National (WISE), did not have a signi- Evaluation Syndrome Ischaemia CAD with non-obstructive Women stenosis. obstructive ficant CAD. with obstructive were younger than those lupus erythematosus and rheumatoid arthritis are associated with are associated arthritis and rheumatoid lupus erythematosus and angina with patients in encountered frequently CMD and are CMD. that non-invasive estimation of CFVR has several limitations. that non-invasive estimation of CFVR has iated with impaired CMD both in the iPower study and WISE study. and iated with impaired CMD both in the iPower study Other studies have shown that diabetes was uncommon amongOther studies have shown that diabetes was CAD, whilepatients presenting with angina and non-obstructive more prevalent. hypertension and dyslipidaemia were relatively increasing evidence that psychosocial stress is more involved in stress is more involved psychosocial that evidence increasing of IHD manifestations coronary vasomotor disorders and variant CAD. to obstructive compared

- - - - - 69-74 76-78 as well as a higher 68 66 incidence of all-cause death and death of all-cause incidence 74 including increases in mortality, mor mortality, in increases including 5 higher risk of disability, 6,67 In a meta-analysis, In a 75 Vasospastic angina is associated with major adverse events events adverse with major is associated angina Vasospastic 67 It must be noted, the condition is heterogeneous and not all is heterogeneous condition the It must be noted, Importantly, INOCA is associated with a wide variation in clini wide variation is associated with a INOCA Importantly, Should the possibility of non-obstructive causes of ischaemia non-fatal MI in patients with non-obstructive atherosclerosis was was with non-obstructive atherosclerosis non-fatal MI in patients angio- those with in (1.32/100 person-years) than higher much person-years). (0.52/100 vessels epicardial normal graphically by non-invasive imaging techniques ischaemia Proven myocardial with was associated imaging) or nuclear (stress echocardiography compared to of events (1.52/100 person-years) a higher incidence stress testing electro-cardiographic by exercise detected ischaemia 0.56/100 person-years. as CAD have ischaemia with angina and no obstructive patients is docu- when ischaemia a cause of their symptoms. However, prognosis the dysfunction through CMD or endothelial mented have shown a two-to four- Meta-analyses is further impaired. for patients outcome cardiovascular risk of adverse higher fold with CMD diagnosed by positron emission tomography (PET) and a two-fold higher echocardiography Doppler or transthoracic dysfunc- endothelial-dependent epicardial with patients risk in tion. and much more likely to have CMD likely to have more and much symptoms. cause of their as a many may be uncharacteristic, symptoms because In addition, may go undiagnosed. cases of CMD These over time. vary may burden and symptom presentation cal in as non-cardiac classified should not be automatically symptoms have a much higher given the fact that women origin, particularly than men. of INOCA prevalence not be considered by the treating physician, a coronary angio- coronary a physician, treating considered by the be not by incor be followed disease may showing no obstructive gram symptoms, avoidance of further of the patient’s rect interpretation Indeed, treatment. and lack of adequate diagnostic evaluation, coro- showing non-obstructive angiography in INOCA coronary of medi discontinuation inappropriate in result may arteries nary and physician reassurance by the treating paradoxical therapy, cal symp- underlying the refute even may physician the potentially, as many will continue This approach is not patient-centred, toms. repeated to have symptoms that will lead to rehospitalization, treatment. and inappropriate testing diagnostic Short- and long-term prognosis Short- and long-term Angina benign. is far from The prognosis of patients with INOCA CAD with no obstructive of is associated with impaired quality life for patients, incidence of adverse events incidence bidity, and healthcare costs with higher recurrence rates of hospital of rates recurrence higher with costs healthcare and bidity, angiograms. coronary of repeated rates and higher readmissions including sudden cardiac death, acute MI, and syncope which may acute death, sudden cardiac including occur before the diagnosis is established. unfortunately In the WISE study, persistent chest pain, smoking, CAD severity, smoking, CAD severity, chest pain, persistent WISE study, In the independ were significant interval and increased QTc diabetes, as cardiovascular events defined of cardiovascular predictors ent or (MI), congestive heart failure, infarction death, myocardial stroke. - - - - who do Among Some of 55 2,63 53 With the same the With 54 64,65 INOCA, like obstructive CAD, can also pre- CAD, can obstructive INOCA, like 57 The substrate of coronary spasm can be found in found be can spasm coronary of substrate The 58,59 56

These differences in presentation are of particular rele- particular of are presentation in differences These 60-62

It is important to recognize that there is gender variation in It is important to recognize that there is gender variation Epicardial vessel spasm typically has an origin in a hyper-reac vessel spasm typically Epicardial symptoms, women are much less likely to have obstructive CAD vance in young and middle-aged women and also men in young and middle-aged vance such triggering stimuli are smoking, drugs, peaks in blood pres- blood in smoking, drugs, peaks are stimuli such triggering stress, and hyperventilation. sure (BP), cold exposure, emotional aller of context the in also occur vasospasm may coronary Severe to (Kounis syndrome). Coronary segments adjacent gic reactions undergo to prone become also may stents drug-eluting implanted spasm. coronary the haemodynamic correlates of arteriolar dysregulation, observed dysregulation, correlates of arteriolar the haemodynamic vas- (i) a limited are challenge, acetylcholine during intracoronary than 1.5 times resting flow), response to the drug (less odilatory to the no-reflow equivalent flow, in blood (ii) a marked reduction –spasm vessel epicardial without phenomenon, arteri- denoting olar spasm narrowing of of diffuse – and (iii) the development The spasm. coronary tight focal, without vessels epicardial distal the development run along changes frequently above-mentioned changes, electrocardiogram ischaemic and symptoms of anginal of this endotype potential which confirm the ischaemia-generating oestrogen of fluctuating Effects dysfunction. of micro-circulatory have been vasomotion vessel and arteriolar on epicardial levels in as explanations for a higher frequency of symptoms postulated CAD. women without obstructive premenopausal sent with other symptoms such as breathlessness, pain between the weakness, fatigue, extreme nausea, indigestion, blades, shoulder and/or sleep disturbances. vomiting, of both obstructive and non-obstructive manifestation the clinical CAD. abnormal function of both vascular smooth muscle and endothelial function abnormal of coronary vas- primary and non-specific hyper-reactivity A cells. in demonstrated cells has been consistently smooth muscle cular of with variant angina and appears to be a key component patients endothe suggests that evidence Available vessel spasm. epicardial lial dysfunction facilitates the induction of spasm in predisposed the induction dysfunction facilitates lial coronary segments. diac origin, leading to under-investigation and under-treatment and under-treatment to under-investigation diac origin, leading S2). Patients with INOCA (Supplementary material online, Table may present with symptoms similar to angina occurring with CAD. obstructive Clinical presentation present with a wide spectrum of symp- Patients with INOCA as of non-car misdiagnosed are often toms and signs that tive epicardial coronary segment that undergoes maximal con- maximal undergoes that coronary segment epicardial tive stimulus. traction when exposed to a vasoconstrictor In the presence of endothelial dysfunction, dysregulation of the dysregulation dysfunction, of endothelial presence In the - Thus, endothe occurs. cascade upstream vasodilatory described and vasodilation with impaired is associated dysfunction lial arteries and arte- of upstream vasoconstriction even paradoxical which may be demands increase oxygen myocardial rioles when stimuli. to vasoconstrictor hypersensitivity the result of not present with classical anginal symptoms. anginal with classical not present 6 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 7

------83 84 (Figure 4). The diagnostic criteria diagnostic The Slow-flow points to an 15 15 Overall, most studies demon- studies most Overall, 91 while studies showing a prognostic 92,93 Intracoronary bolus injection of adenosine bolus injection Intracoronary 88 55,84-87 Ischaemia with non-obstructive coronary arteries coronary non-obstructive with Ischaemia or Doppler flow velocity (hyperaemic flow velocity (hyperaemic flow velocity or Doppler 89,90 82 Coronary flow reserve can be calculated using thermodilution Coronary flow reserve can be calculated Diagnostic testing provides information on coronary vascular vascular on coronary information provides testing Diagnostic . Catheter-based measurements of absolute measurements 2. Catheter-based are shown in Table also been have resistance blood flow and microvascular coronary INOCA in evaluation further requires which described previously patients. increase in vascular resistance under resting conditions. in vascular resistance increase ANGIOGRAPHY FUNCTIONAL CORONARY INVASIVE coronary angiography (FCA) Invasive functional is a combina of coro- measurements invasive direct involving technique tory in guidewire diagnostic a with initially function vasomotor nary testing reactivity with pharmacological combination (up to 200 µg) is an alternative option to assess endothelium-inde option to alternative (up to 200 µg) is an pendent vasodilatation. pendent tran- mean divided by hyperaemic time transit (as resting mean time) sit DIAGNOSTIC GUIDEWIRE is per testing using a diagnostic guidewire Coronary function anterior left The angiography. to coronary as an adjunct formed pre-speci as the preferred is usually artery coronary descending mass and myocardial its subtended vessel reflecting target fied arter coronary in other studies Additional dominance. coronary and clini tests are negative ies may be appropriate if the initial should U/kg) (50-70 heparin Intravenous is high. suspicion cal (acti anticoagulation therapeutic to achieve be administered time ~250 s). Diagnostic options include coronary vated clotting sensor guidewire using a pressure–temperature thermodilution Clara, CA, Santa USA) or Vascular, Abbott X™, (PressureWire Volcano or Flowire, Philips XT (ComboWire a Doppler technique con- XT ComboWire The CA, USA). San Diego, Corporation, usual The Eindhoven). (Philips, ComboMap system the to nects is by use of intra hyperaemia approach to inducing steady-state endothelium-inde to achieve venous adenosine (140 µg/kg/min) pendent vasodilation. CORONARY ANGIOGRAPHY CORONARY dur and is preferred (GTN) has a short half-life Glyceryl trinitrate ing coronary angiography. A corrected thrombolysis in myocar thrombolysis corrected A ing coronary angiography. 30 frames/s) at acquired >27 (images count frame infarction dial in the presence of GTN suggests MVA due to impaired resting resting to impaired due in the presence of GTN suggests MVA flow (coronary slow-flow phenomenon). experi- slightly vary according to local may approaches Different and preference. ence divided by resting flow velocity). resting by divided strating the prognostic value of thermodilution-based CFR have strating the prognostic value of thermodilution-based value of 2.0, used a cut-off dysfunction, including a functional disorder, i.e. impaired vasodil- impaired i.e. disorder, functional a including dysfunction, i.e. an increase in structural problem, or vasospasm, and/or atation, MVA, (i) include endotypes Relevant resistance. vascular minimal and chest pain, none, i.e. non-cardiac VSA, (iii) both, (iv) (ii) <50% atherosclerosis, CAD, e.g. diffuse (v) non-flow-limiting may diagnosis clinical A assessment. by visual stenosis severity consensus criteria. expert to according be - - - - first line of test- line first 2 Currently, no technique allows no technique Currently, have given a IIa recommenda given have 2 80,81 Common non-invasive techniques assessing techniques non-invasive Common 13,14,79 21 In the diagnostic pathway for patients assessed for angina rec- assessed for angina In the diagnostic pathway for patients Coronary flow reserve is the ratio of hyperaemic blood flow of hyperaemic Coronary flow reserve is the ratio ommended in the ESC CCS 2019 guideline, the in ommended Diagnosis DETECT ISCHAEMIA METHODS TO NON-INVASIVE coronary microcircu of the abnormalities or structural Functional lation can be responsible for impairment of myocardial perfusion perfusion of myocardial for impairment responsible be can lation coronary epicardial in the absence of large even and ischaemia, stenosis. arteries ischaemia rely on detection of relatively large regional differences differences regional large of relatively rely on detection ischaemia perfu- and/or wall motion in epicardial in left ventricular perfusion emission computed single-photon (i.e. myocardial sion territories These tech- stress tomography or dobutamine echocardiography). the whole left ventri- affects if ischaemia niques are ineffective with CMD. as in patients cle INVASIVE DIAGNOSIS IN THE CATHETERIZATION DIAGNOSIS IN THE CATHETERIZATION INVASIVE LABORATORY 2019 ESC CCS guidelines The ing is non-invasive. In patients with no obstructive CAD ing is non-invasive. In patients with no obstructive on their regional no and/or angiography tomographic computed coronary be may VSA or CMD testing, on functional ischaemia reversible bur significant a with patients in and symptoms of their cause the invasive and non-invasive through testing further of disease, den depend- non-endothelial While should be considered. techniques can acetylcholine ent dysfunction may be assessed non-invasively, Thus, a full diag- during invasive testing. only be administered angio- invasive requires currently assessment for INOCA nostic allow assessment of CFR techniques non-invasive Several graphy. S3). material online, Table (Figure 3, Supplementary tion of endothelium-independent vasodilators such as adenosine, vasodilators of endothelium-independent tion or regadenoson. a direct anatomical visualization of the coronary microcirculation of the visualization anatomical a direct assessment relies on the meas- Therefore, its in vivo in humans. status, such as its functional which reflect of parameters urement blood flow and CFR. myocardial by resting divided stimuli vasoactive various response to in measure of Coronary flow reserve is an integrated blood flow. coronary and the arteries epicardial flow through both the large epi- of the disease obstructive severe once but microcirculation, CFR is a marker of CMD. arteries is ruled out, reduced cardial necessary to calcu- and hyperaemia vasodilatation The maximal through intravenous administra the CFR is usually achieved late tion (‘should be considered’) for guidewire-based measurement of tion (‘should be considered’) for guidewire-based measurement in patients measurements resistance CFR and/or microcirculatory either are that arteries coronary but symptoms, persistent with stenoses with non- moderate or have normal angiographically (ACH) test- acetylcholine disease. Intracoronary flow-limiting considered’ be ‘may recommendation IIb a by is supported ing in whom spasm and for patients to assess coronary microvascular to clarify both endothe- is considered, a IIa recommendation VSA pathobiologi- as well as endothelium-independent lium-dependent of CMD. mechanisms cal Other studies have 98 l

c/norma phy ra ailability es can be v phy s phy ra ormed in any ormed in any ctor ra fa aluaon diog Denot iog local a perf cardiac ischaemia cardiac isk al sequence based on rd G – non-diagnos aluaon r phy mptoms err EC ra hocar aphic angiog ry of sy minaon sive ev ref hoca Ec to t xa Further studies are required to determine the optimal HMR the optimal Further studies are required to determine Ec va sonance Imaging 99 e es omog including ent ev mogr T Re index that would predict CMD. would predict index that suggested that a cut-off of ≥2.5 mmHg/cm/s provides the optimal CMD, for predicting as judged with sensitivity and specificity PET. a Doppler-based index, calculated by dividing intracoronary pres- intracoronary by dividing calculated index, a Doppler-based In a previous study of patients flow velocity. sure by hyperaemic HMR>1.9 [odds coronary arteries, with angina and non-obstructed P=0.007] was an 2.1-114.0), interval confidence (95% 15.6 ratio: predictor of recurrent chest pain. independent Pa trast trast ysical Ischaemic Ischaemic d To ance

Cardiology Cardiology taking - Ph

97 te Funconal imaging ory oler acic Doppler d Step 1: Step re dial Con d incing ongoing his Hist on Emission T re Increased Step 2: Non-in Step y 96 cise T y t high image sitr sis desi Conv equi ansthor r ro ilabilit Myocar Cardiac Magnec Cardiac Po Exer Tr Myocardial Perfusion Imaging Perfusion Myocardial : : ilabilit if va if scle • • • • • • va d d ro onary Compu re re cs sugges or elihood cteris ent GP ±C ra Pa perse and a Cardiologist perse and a ex scularisaon likely y ex va rmaon on athe enally conside ent cha Local Viability assessment also High clinical lik Re erenally conside erenally er Info qualit Local Low clinical likelihood Pa No history of CAD ef ef • • Pr • • • • • Pr • •

27,94,95

Microcirculatory resistance can be calculated by combining pres- by combining can be calculated resistance Microcirculatory mia multiplied by the hyperaemic mean transit time. by the hyperaemic mia multiplied impact of CFR based on Doppler have used a CFR cut-off of 2.5 used a CFR cut-off of CFR based on Doppler have impact or lower. Figure 3. Non-invasive evaluation of INOCA. GP: general practitioner or Doppler- thermodilution- (either sure and flow measurements (IMR) is calculated resistance The index of microvascular based). hyperae coronary pressure at maximal as the product of distal IMR (≥25) is representative of microvascular dysfunction. The hyperaemic myocardial velocity resistance (HMR) index is resistance velocity myocardial The hyperaemic 8 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 9

------12,113 110,111 110,111 The 100-102 which influ- on the grounds 2 (Supplementary mate- (Supplementary A pragmatic approach pragmatic A 55,84-87,103-108 109 mol/L, respectively mol/L, –4 There is a strong need for well-designed clini There is a strong need for well-designed 112 shows the steps in the invasive evalu- Figure 4 shows the steps in the invasive

Ischaemia with non-obstructive coronary arteries coronary non-obstructive with Ischaemia 15,55 , and 10 –5 or a non-hyperaemic pressure ratio ≤0.89. 100 , 10 –6 are suggested though some institutions might prefer Figure 4 are suggested though some institutions Flow-limiting obstructive CAD may be assessed using FFR FFR assessed using may be CAD obstructive Flow-limiting ation of INOCA. Based on current practice, Steps 1, 2, 3 as shown as 3 2, 1, Steps practice, current on INOCA. Based of ation in of INOCA. Further studies Steps 1, 3, 2 in the invasive evaluation evalu of invasive the best sequence to determine warranted are and risks of The complications ation in the diagnosis of INOCA. described. previously well coronary procedures are invasive for FCA according to whichever protocol works best in individ protocol whichever to according for FCA ual centres might be implemented. A standard approach involves approach standard A be implemented. might centres ual approximat at concentrations infusion of acetylcholine sequential ing 10 binary thresholds of continuous data should be viewed within viewed should be data of continuous thresholds binary IMR, and FFR Coronary flow reserve, of the patient. the context the diagnostic range of their across have prognostic significance deter to possible is it evaluation invasive this Thus, in values. mine endothelium-independent CMD (CFR, IMR); endothelium- CMD endothelium-independent mine ACH) and vasospastic response to CMD (microvascular dependent as an assess- ACH) as well artery response to response (epicardial of low-grade stenoses (FFR). ment FUNCTIONAL CORONARY INVASIVE PHARMACOLOGICAL ANGIOGRAPHY is by testing for vasoreactivity approach The most established infusion of acetylcholine, intracoronary The potential risk of the invasive assessment should be weighed The potential risk of the invasive assessment against the benefit of the diagnosis for the patient, acknowledging on based management whether studied been not has it so far that prog- influence may diagnostics by invasive gathered information (CorMicA) has found a benefit in nosis while only one pilot trial terms of symptoms. Management of INOCA multidisciplinary a with patient-centred be should Management stud- Unfortunately, care approach might be helpful to the patient. in and heterogeneous CMD are small ies on therapy to improve is no evidence-based there currently and and methodology design of CMD. treatment which is the ratio of mean distal coronary pressure to mean aor mean to coronary pressure distal of mean ratio is the which tic pressure at maximal hyperaemia – abnormal FFR is defined FFR abnormal – hyperaemia pressure at maximal tic as ≤0.80 ences coronary vascular tone via muscarinic receptors on endothe- on receptors muscarinic via tone vascular coronary ences use of intracoronary The cells. smooth muscle and vascular lial recommended is VSA and for the diagnosis of MVA acetylcholine practice guidelines by the 2019 ESC CCS clinical safety and efficacy. of its demonstrated cal trials to guide future research and clinical recommendations. and clinical research to guide future trials cal of INOCA. for the management Figure 5 provides an algorithm LIFESTYLE FACTORS due to the frequent pres- In all patients with established INOCA ence of coronary atherosclerosis and endothelial dysfunction, . A clinical diagnosis to rule-in or rule-out clinical A S4). rial online, Table estab- to according made is vasospasm to due VSA and/or MVA lished criteria. b b Diagnostic criteria FFR >0.8 CFR ≥2.0 IMR <25 HMR <1.9 No or <90% diameter reduction No angina No ischaemic ECG changes FFR >0.8 CFR <2.0 IMR ≥25 No or <90% diameter reduction +angina +ischaemic ECG changes FFR >0.8 CFR ≥2.0 IMR <25 HMR <1.9 ≥90% diameter reduction +angina +ischaemic ECG changes FFR >0.8 CFR <2.0 IMR ≥25 HMR ≥1.9 No or <90% or ≥90% diameter reduction +angina +ischaemic ECG changes FFR >0.8 CFR ≥2.0 IMR <25 HMR <1.9 No or <90% diameter reduction No angina No ischaemic ECG changes HMR ≥1.9 Vasoreactivity (acetylcholine test) Vasoreactivity Diagnostic guidewire and adenosine test Vasoreactivity (acetylcholine test) Vasoreactivity test Diagnostic guidewire and Adenosine (acetylcholine test) Vasoreactivity Diagnostic guidewire and Adenosine test (acetylcholine test) Vasoreactivity (acetylcholine test) Vasoreactivity logy - Pathophysio Diffuse coronary artery atherosclerosis CMD and Adenosine test Diagnostic guidewire Epicardial spasm Both CMD and epicardial spasm None Diagnostic guidewire and Adenosine test IMR and HMR values shown in table as alternative measures of b c a INOCA endotypes angina angina microvascular and vasospastic angina chest pain limiting CAD 1 Microvascular 2 Vasospastic 3 Both 4 Non-cardiac 5 Non-flow- Non endothelial dependent microvascular angina may be diagnosed non-invasively by <50% stenosis severity by visual assessment microcirculatory resistance (based on thermodilution or Doppler: respectively). the methods described. a c CAD: coronary artery disease; CFR: coronary flow reserve; FFR: fractional flow reserve; HMR: hyperaemic myocardial velocity resistance; IMR: index of microvascular resistance. Table 2. INOCA endotypes diagnostic criteria. diagnostic endotypes 2. INOCA Table * te er dial 50 - 80% Modera s ge + ischaemic ECG No or < 90% or ducon ) Microvascular Microvascular sospasc Angina And Epicar t 2. + angina 3. chan ≥ 90% diamet re 1. Va 0 test

EDP esen ovascular Dysfuncon Dysfuncon ovascular Pr LV And negative non-invasive or invasive testing for TYPES a IMR ≥ 25 FFR > 0.8 CFR < 2. s y & The ability of specific diets, such as anti-inflamma- ph er 59,114 nary Micr ra Angina e and Adenosine test e and Adenosine No angina No ischaemic No or <90% No or <90% ducon 3. ECG change 2. diamet re 1. tory, vegan, or Mediterranean, to improve symptomatic coronary symptomatic coronary vegan, or Mediterranean, to improve tory, obesity should be vascular dysfunction is unknown. However, addressed. Coping with stress, the chronic and recurrent nature of symptoms may need extra attention, as they may have an important impact on working abilities in this often relatively young patient group. CAD. Microvascular Microvascular Coro INOCA ENDO Mild < 50% FFR + CFR + IMR* c guidewir es s

n soreacvity (Acetylcholine t er Va sospasc Angina vascular vascular Epicardial Epicardial duco esen Va ro 1. ≥ 90% diamet re 2. + angina 3. + ischaemic ECG chang Pr IMR < 25 FFR > 0.8 CFR ≥ 2.0 n Step 1: Coronary angiog 1: Coronary Step Step 3: Step Step 2: Diagno Step nary Mic s ro Dysfunco er 0% pain Normal Combo wire is an alternative option to measure FFR, CFR and IMR. is an alternative option to measure Combo wire No Co b ducon Non cardiac 1.No or <90% diamet re 2.No angina 3.No ischaemic ECG change

tailored counselling on lifestyle factors is warranted to address address to warranted is factors lifestyle on counselling tailored risk factors, reduce symptoms and improve quality of life and prognosis. Behavioural interventions can be supported by nurse practitioners, experts in nutrition, psychologists, exercise physio- Adequate lifestyle support therapists, sports medicine, and so on. is comparable to other cardiovascular disease (CVD) prevention guidelines and preventive strategies in patients with stable Invasive evaluation of INOCA. CFR: coronary flow reserve; FCA: functional coronary angiography; FFR: fractional flow reserve; flow reserve; angiography; FFR: fractional FCA: functional coronary flow reserve; Figure 4. Invasive evaluation of INOCA. CFR: coronary left ventricular end-diastolic pressure. LVEDP: resistance; IMR: index of microvascular epicardial ischaemia. epicardial 10 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 11

122 Table 3. Table r ss ke re st te ra Coping with Diabetes mellitus ACEi have been demonstrated to 124 sospasc angina sospasc In patients with evidence of either epi- of either with evidence In patients 84,126 Va Calcium channel bloc Nicorandil 59,123 In the CorMicA trial, a stratification based trial, a stratification In the CorMicA 116 1. 2. Long-acng nit 3. Ischaemia with non-obstructive coronary arteries coronary non-obstructive with Ischaemia A Smoking cessaon t and in women with CMD with improved CFR and improved CMD with with in women and 125 s emen t ctor ns and fa medical therapy was used, taking into account the measurements into account was used, taking therapy medical angina improve was shown to approach and the coronary testing at CAD with no obstructive at of life in patients control and quality 6 months and at 1 year. angina frequency. improve hyperaemic myocardial blood flow in hypertensive MVA blood flow in hypertensive MVA myocardial improve hyperaemic patients, cardial or microvascular spasm following acetylcholine testing, spasm following acetylcholine cardial or microvascular should be considered as first-line therapy. antagonists calcium it may be needed to give unusual VSA with severe In patients daily), (2×200 mg diltiazem antagonist high dosages of calcium with of hydropyridine (such as diltiazem) or even a combination (such as amlodipine), blockers calcium dihydropyridine and reduced CFR and/or increased IMR (that Inpatients with MVA channel calcium beta-blockers, remodelling) arteriolar reflect may ACEi are used. blockers, and The efficacy of short-acting nitrates may vary and often needs to may vary nitrates short-acting of The efficacy poorly ineffective, be repeated. Long-acting nitrates are frequently due with MVA patients symptoms in and may aggravate tolerated effect. to a stealing anti-ischaemic treatment often achieves disappointing results. disappointing achieves often treatment anti-ischaemic medicaon emen yle sta - - - EI/ARB st ctor manag fe Dyslipidaemia AC ht manag fa ig 1. Li We Consider 3. Ananginal 2. Risk r ke Statins are bene- Management of INOC Management ACEi/angioten and 116 ercise 59,108,117,118 Ex r angina 119-121 ke andil ovascular imetazidine Betabloc Tr Micr Hypertension Nutrion 6. 1. 2. Calcium channel bloc 3. Nicor 4. Ranolazine 5. Ivabradine Best choice of (combined) BP medications depends medications BP (combined) of choice Best 115 ficial in patients with non-obstructive CAD, and their anti-inflam in patients with non-obstructive ficial with in those patients also be effective may properties matory reduced CFR and vascular spasm. ANTIANGINAL MEDICATION is INOCA with patients in symptoms of anginal Treatment group represent a heterogeneous as the patients challenging pharmacological Standard lacking. are trials randomized and lar changes and to reduce the frequency and intensity of anginal intensity and frequency the to reduce changes and lar symptoms. RISK FACTOR MANAGEMENT RISK FACTOR CVD dyslipidaemia, risk factors hypertension, The traditional of coro- to the pathology contribute may all smoking, and diabetes and vasospastic dysfunction and structural nary microvascular objective therapeutic The main of the circulation. remodelling of microvascu is to prevent progression of strict control of BP Management of INOCA. ACEI: angiotensin-converting enzyme inhibitor; ARB: angiotensin receptor blocker. ARB: angiotensin receptor ACEI: angiotensin-converting enzyme inhibitor; Figure 5. Management of INOCA. on the predominant mechanism of anginal symptoms, e.g. vasos- e.g. symptoms, anginal of mechanism predominant the on enzyme angiotensin-converting The use of pastic and/or MVA. CFR in CMD (ACEis) improves inhibitors sin receptor blockade (ARB) can be easily combined with both blockade (ARB) can be easily combined sin receptor antagonists and beta-blockers. calcium

108,117,118

Therefore we 112

Mechanisms of effect Mechanisms In about 25% of patients, symptoms 2 Myocardial oxygen consumptionMyocardial Myocardial oxygen consumption Workload coronary spasmSpontaneous and inducible Oxygen demand Spontaneous and inducible coronary spasm Oxygen demand Myocardial oxygen consumption Workload ascular smooth muscle relaxationascular smooth ascular smooth muscle relaxation maintaining cellular homeostasis ↓ Potassium channel activator with coronary Increases cell tolerance to ischaemia by Improve CFR ↓ May improve small vessel remodelling Improve coronary endothelial function Pleiotropic effects including reduced vascular ↓ properties Antioxidant V ↓ perfusion reserve index Improves microvascular to ischaemia by Increases cell tolerance maintaining cellular homeostasis Improve CFR ↓ remodelling May improve small vessel ↓ relaxationvia vascular smooth muscle ↓ ↓ via large epicardial vasodilation ↓ Potassium channel activator with coronary microvascular dilatory effect V microvascular dilatory effect inﬂammation in patients with MVA and reduced CFR in patients with MVA

– – – – – – – – – – – – – – – – – – – – – – – 135 The use of low-dose tricyclic antidepressants, such as imipra- 134 are refractory to these treatment options. Enhanced external counterpulsation might be used as an adjunctive treatment for INOCA only in CCS patients who are refractory to both traditional antianginal drugs (beta blockers, calcium channel blockers, nitrates, etc.) as well as more novel interventions such as ranolazine, trimetazidine, and ivabradine. Rho kinase inhibitors reduce contractility in the vascular wall and are currently under investigation for reducing coronary vasoreactivity. recommend antianginals as currently stipulated in the updated 2019 ESC CCS guidelines which provides a stepwise strategy for antian- guidelines also recommend trimetazi- The CCS ginal drug therapy. dine as a second-line drug in patients with CCS whose symptoms or who are intolerant to, other are not adequately controlled by, medicines for angina pectoris. mine, may be helpful to reduce the intensity of symptoms. However, it should be noted that there is currently no evidence-based However, and aggravated nociception. medication for INOCA

- 132,133 Some 130,131 In patients 129 First-line ther 128 Treatment 127 ACE inhibitors (Ramipril 2.5-10 mg), ARBs Calcium channel blockers (Amlodipine 10 mg daily) blockers (Amlodipine Calcium channel Calcium channel blockers (Amlodipine 10 mg or Verapamil 240 mg SR (Amlodipine 10 mg or Verapamil Calcium channel blockers daily or 120-360 mg single or divided doses)or Diltiazem 90 mg twice 240 mg SR or Verapamil Calcium channel blockers (Amlodipine 10 mg single or divided doses)or Diltiazem 90 mg twice daily or 120-360 mg Beta-blockers (Nebivolol 2.5-10 mg daily) (Nebivolol 2.5-10 mg Beta-blockers twice daily or 500 mg-1 g twice daily in theRanolazine (375-750 mg USA) 2.5 -10 mg), ARBsACE inhibitors (Ramipril Nitrates (Isosorbide mononitrate XL 30 mg) Nicorandil (10-20 mg twice daily) Nicorandil (10-20 mg twice daily) (35 mg twice daily) Trimetazidine Statins (Rosuvastatin 10-20 mg) Trimetazidine (35 mg twice daily) Trimetazidine

Diagnosis The use of nicorandil, a combinatorial vasodilator agent acting In perimenopausal women without obstructive CAD, a com- women without obstructive In perimenopausal ACE: angiotensin-converting enzyme; ARB: angiotensin receptor blocker; CFR: coronary ﬂow reserve; MVA: microvascular angina; VSA: vasospastic receptor blocker; CFR: coronary ﬂow reserve; MVA: ACE: angiotensin-converting enzyme; ARB: angiotensin angina VSA + Both MVA VSA MVA Table 3. Medical therapy in the management of INOCA. in the management therapy 3. Medical Table patients with persistent anginal symptoms may benefit from the use of ivabradine, which decreases heart rate both at rest and during its However, left ventricular contractility. exercise without affecting is poorly investigated and still controversial. in MVA efficacy via nitrate and potassium channel activation, may be an effective via nitrate and potassium channel activation, may be an effective are often reported. alternative although side effects bined regimen of a low-dose alpha beta-blocker or selective beta- or selective bined regimen of a low-dose alpha beta-blocker (diltiazem) antagonist calcium and bisoprolol) (nebivolol, blocker in reducing anginal symptoms, as the loss can be highly effective with a fast rise dysfunction autonomic of oestrogens often induces during exercise. in heart rate with MVA mixed beneficial results of ranolazine have been pub- with MVA lished, demonstrating benefit in patients with low CFR. apy can also be combined with the use of ranolazine, an anti-anginal and ventricular compli- myocyte relaxation improves agent which ance by decreasing sodium and calcium overload. 12 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 13 )

) t eries (INOCA es ovascular c angina (VSA ) phy 3. Ananginal medicaons hy Micr sospasc Angina And Epicardial And Epicardial est ra ap Va sospas A luaon Va t CH t va

angiog YPES luaon OT sive e va anagemen e va onary m ovascular Angina ment of INOC ent ctor soreacvity (A Funconal Imaging ge Micr fa Pa oronary oronary CT Angiogr Va sive Cor scular dysfuncon (CMD)/ scular dysfuncon INOCA END ±C va va Mana 2. Risk Step 2: Non-in Step Step 1: Step

Ischaemia with non-obstructive coronary arteries coronary non-obstructive with Ischaemia n aluao ev s ep 2: FCA guidewire and Adenosine t ep 3: FCA

dial

Step 1: In Step St St

ve si va Non-in ctor

sospasc

Angina Coronary Micro

n aluao ev Epicar

sive va In estyle Ischaemia with non obstrucve coronary art non obstrucve coronary Ischaemia with 1. Lif Visual summary. - - as well 21,136 4 and Visual summary Table and To date, there are no disease-modifying therapies spe- there are no disease-modifying date, To Angina pectoris is the most common symptom of ischaemic heart disease affecting many millions of people globally. of ischaemic heart disease affecting many millions of people globally. Angina pectoris is the most common symptom angiography because of angina and evidence of myocardial ischaemia do not haveA large proportion of patients undergoing coronary ischaemia. This entity is defined as INOCA (Ischaemia with Non-Obstructiveobstructive coronary arteries but have demonstrable Coronary Arteries). (50-70%) than among men (30–50%) undergoing coronary angiography for angina.INOCA is found more frequently among women or in combination with CAD, is a mechanism of myocardial ischaemia and symptomsCoronary microvascular dysfunction (CMD), alone in INOCA. with comparable incidence of adverse events as well as impaired quality of life asINOCA is not a benign condition and associated obstructive CAD. no tailored therapy is prescribed for these patients whose symptoms are often dismissedINOCA is often not diagnosed and, therefore, or downplayed. MRI, and SPECT are available to detect ischaemia in INOCA. MCE, PET, Multiple non-invasive techniques including TTDE, and interventional diagnostic procedure consisting of a diagnostic guidewire, pressureInvasive strategies, using coronary angiography should be implemented to laboratory, and flow measurements, and pharmacological coronary reactivity testing in the catheterization differentiate be tween vasospastic angina, microvascular angina and non-cardiac pain. in these patients is warranted. ThisA stratified approach to the management of INOCA to address the short and long-term prognosis guidelines and use ofincludes tailored counselling on lifestyle factors, risk factor management as per CVD prevention pharmacotherapy to alleviate ischaemia and symptoms. NCT03417388) is testing if all INOCA patients should be treated with A current large randomized, controlled strategy trial (WARRIOR ACEI and statins. therapy should be administered and, ifFor patients experiencing vasospastic angina, calcium channel blockers, followed by nitrate still symptomatic, the use of nicorandil should be considered. coronary flow reserve and/or highFor patients in whom a diagnosis of microvascular angina has been established based on abnormal should be considered,microcirculatory resistance (suggesting microvascular remodelling), an initial therapy with beta-blockers ranolazine and EECP can be considered.followed by use of calcium channel blockers. When symptoms continue, use of nicorandil, spasm, an initial therapy withFor patients in whom the diagnosis of microvascular angina is based on the presence of microvascular be considered.calcium channel blockers should be considered, followed by use of ranolazine and EECP can may be helpful to reduce the intensity ofThe use of low-dose tricyclic antidepressants, such as imipramine and xanthine derivatives, symptoms. understanding and to developGiven the lack of in-depth knowledge, further research is urgently needed to increase our mechanistic innovative tailored therapies in order to better manage this serious condition. 137 1 2 3 4 5 6 7 8 9 10 11 12 13 14 15 ACE: angiotensin-converting enzyme inhibitor; CAD: coronary artery disease; CFR: coronary flow reserve; CVD: cardiovascular disease; EECP: enhancedACE: angiotensin-converting enzyme inhibitor; CAD: coronary artery disease; CFR: coronary flow reserve; positron emission tomography; imaging; PET: external counter pul.sation; MCE: myocardial contract echocardiography; MRI: magnetic resonance single-photon emission computed tomog.raphy; TTDE: trans thoracic Doppler echocardiography. SPECT: Table 4. Key messages. Table cific to INOCA. The Women’s IschemiA Trial to Reduce Events to Reduce Trial IschemiA Women’s The INOCA. to cific enroll Artery Disease is currently in Non-ObstRuctIve CORonary pro- NCT03417388) in a multicentre, ing subjects (WARRIOR: to evaluate evaluation, outcome randomized blinded spective, (IMT) and usual care ACEI/ARB therapy and statin intensive symptomatic in events cardiovascular adverse (UC) on major Zibotentan With The Precision Medicine women with INOCA. Gaps in knowledge and future studies and future in knowledge Gaps shown in key messages are The - often correctly diag is not that INOCA 6. It is evident Figure prescribed is therapy no tailored consequence, as a that, nosed and positive’. as ‘false dismissed often are who for these patients recur experience to continue will these patients Consequently, hospi- to repeated leading of life, quality rent angina with poor angiography, coronary unnecessary and talizations as poor clinical outcome. There is an urgent need of large stud- large of need urgent is an There outcome. as poor clinical 5 and ies designed to address this problem as shown in Tables help (NCT03477890) is ongoing and will trial The CorCTCA 6. when of INOCA significance and clinical clarify the prevalence - on coronary computed tomography angio standard care is based graphy.

s ve etween om ha d. eb is another te at ympt D, an this serious n ds rr re sng te ﬀe di manage r d to e te ischaemia an eacvity be te

to as INOCA. ocardial ischemia . nd prognosis is wa ocardial ischaemia do not ga allevia apies coronaryr condion o

eded f my yt in INOCA. eo ther pain. ell-bein alone or in combinaon with CA alone or in combinaon ave gently ne should be implemen mw enty is defined mechanisms of my ischaemia IDP) innov This h is ur ct sospasm, Pharmacological e( rc te va f pharmacotherap esea o de T develop eo rr st To Us Epicardial pon MRI, PE furthe eo T Appendix. Authors' affiliations of Faculty Institute, Research and Clinical Translational 1. University and Cardiothoracic Newcastle Sciences, Medical NHS Foundation Tyne Centre, Freeman Hospital, Newcastle upon Leech Building, Newcastle upon William M4:146 4th Floor Trust, Tyne NE2 4HH, UK; 2. IRCCS San Raffaele Scientific Institute, Hospital, San Raffaele and University Salute Vita 3. Italy; Milan, Milan, Italy; 4. British Heart Foundation Glasgow Cardiovascular Sciences, and Medical of Cardiovascular Institute Centre, Research San Carlos Clinico Hospital 5. UK; Glasgow, of Glasgow, University Madrid, Spain; 6. Department IDISSC, University, Complutense the Nijmegen, Center, Radboud University Medical of Cardiology, University Bispebjerg Netherlands; 7. Department of Cardiology, Georges Hospital 8. European Denmark; Copenhagen, Hospital, Paris University and Paris Pompidou (Cardiology Department), (INSERMU970), Paris, France; Center Research Cardiovascular UMC, Location Amsterdam Cardiology, of Department 9. Amsterdam, the Netherlands; Center, Medical VU University and Science Vascular and Thoracic Cardiac, of Department 10. approach and the management of INOCA based on the existing based on the of INOCA the management and approach Future prospec- current practice. and the best available evidence address a num- to research is required ongoing well-designed tive of and management ber of unanswered questions in the diagnosis these patients. ess the short and long-ter as SPEC ocardial s e demonstrable ischaemia. nt chniques ar av enonal diagnosc procedur f my te me angiography because of angina and evidenc because of angina angiography rv th re te mo bu management TTDE, MCE, of INOCA to addr T, or nd in ct ET fa ya arteries ow measu in INOCA. sospasc angina, microvascular angina and non-cardiac risk understanding he lack of in-depth knowledge, dfl asive funconal va is a mechanis nt oms ors, D, ct undergoing coronary Give fa he management ympt Non-inv ssure an ssure ot re ds prevenon guidelines prevenon ht ,p -style 53 fe our mechanisc obstrucve coronary approac per CVD using coronary angiograph guidewire ischaemia an increase gies fied oporon of paents in combinaon with CA in combinaon To te ra ra ounselling on li A st dc Diagnosc A large pr

asive st ailore

T Inv CMD alone or

:K INOCA EY MESS EY ES AG patientsA systematic approach to diagnose and treat these car. should be implemented by clinicians and interventional diologists dealing with these patients. as well asNational and international scientiﬁc societies, to supportthe pharmaceutical and biomedical industries future research to address the incomplete understanding of the lack of targeted pharmacological the pathophysiology, treat.ment, and the evidence-based management of patients with INOCA. Creating awareness of this condition through campaigns and media to ensure timely provision of care to these patients. INOCA should be recognized as a clinically important entityINOCA should be recognized as a clinically important in daily clinical practice.

2 3 4 1 Table 5. Recommendations. Table - INOCA, a major health problem, is associated with under-diag This consensus docu- prognosis. and poor nosis, under-treatment cardiologist ment provides the treating clinician/interventional diagnostic/investigational guidance regarding the recommended Conclusions in Microvascular Angina (PRIZE) trial holds future promise holds future Angina (PRIZE) trial in Microvascular is an Zibotentan NCT04097314). Identifier: (ClinicalTrials.gov may provide benefit that antagonist receptor A oral, endothelin response of in vasoconstrictor by opposing the reported increase to endothelin. coronary microvessels Figure 6. Key messages. 14 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 15 Future research Ischaemia with non-obstructive coronary arteries coronary non-obstructive with Ischaemia COVADIS Steering Committee: C. Noel Bairey Merz (USA); John Merz Bairey Noel C. Committee: Steering COVADIS (IT); Filippo (AU); Colin Berry (UK); Paolo Camici Beltrame Crea (IT); Juan Carlos Kaski (UK); Peter Ong Pepine (DE); Carl (JP). Dr Phyo Shimokawa (DE); Hiroaki (US); Udo Sechtem Newcastle Cardiology in Fellow Clinical Academic NIHR Khaing PhD Fellow BHF Clinical Sidik, Dr Novalia UK and University, to the Figures UK for their contribution University of Glasgow, was consensus document The EAPCI INOCA in this document. Acknowledgements Transplant Department, A.O.U. ‘Policlinico-Vittorio Emanuele’, A.O.U. ‘Policlinico-Vittorio Department, Transplant for Cardiovascular 22. Centre Italy; Catania, University of Catania, Queen Institute, Research Harvey William Devices, and Medicine Mary University of London and Barts Heart Centre, London, UK; USA. New Haven, CT, School of Medicine, University Yale 23. population in different countries. population in with the diagnosis of microvascular dysfunction Improved tools to facilitate means. invasive and non-invasive studies with the newest techniques aimed atNon-invasive diagnostic of cardiac ischaemia, including endothelialidentifying alternate origins or coronary microvascular dysfunction. dysfunction, coronary vasospasm, usingdiagnostic evaluation during coronary angiography Prospective studies on testing (ACh). techniques and intracoronary drug novel catheter-based as well as the occurrence of major adverse cardiacclass and quality of life events at clinical follow-up. new evaluating existing (statin ACEi/ARB) and Large randomized studies kinase inhibitors. receptor antagonist and Rho medications such as ETa its diagnosis and treatment. educative campaigns toImmediate action points should include launching pathophysiology of INOCA,generate awareness regarding the causes and of patients with anginalemphasizing that the diagnosis and management and treatment of flow-limitingsymptoms should go beyond the identification stenoses. regarding INOCA byEducation should address therapeutic nihilism beneficial effect that objectivedisseminating available evidence regarding the tailored treatment has on qualitydocumentation of the cause of chest pain and of life of these patients. of the variousCost effectiveness study to evaluate the cost effectiveness INOCA. diagnostic approaches in the management of dietary and stress reducingStudies on lifestyle interventions, in particular programmes. microvascular pathology inStudies evaluating the association of INOCA with other vascular beds for example the brain. pregnancy-related with HFpEF, Studies evaluating INOCA and its association conditions. Gaps in knowledge Few studies evaluating the pathophysiology of INOCA. evaluating the pathophysiology Few studies evaluate microvascularFew diagnostic tools to the pathophysiology of INOCA. Mechanistic studies to understand dysfunction. techniques to diagnoseFew studies using non-invasive INOCA. diagnose INOCA. Few invasive studies to tailored therapy in INOCA.Few studies evaluating the angina to evaluate the impact of a tailored therapy on Prospective studies of anginal symptoms in patients with INOCA Treatment represent ais challenging as the patients lacking. heterogeneous group and randomized trials are INOCA.Lack of awareness among clinicians regarding and of Surveys to evaluate the awareness of cardiologists/clinicians of INOCA Lack of studies evaluating the cost effective diagnostic approaches in INOCA. TheFew studies on lifestyle interventions in INOCA. ability of specific diets, such as anti-inflammatory, vegan, or Mediterranean, to improve symptomatic coronary vascular dysfunction is unknown. ofFew studies to clarify the clinical significance micro-vascular dysfunction in non-cardiac organs. history ofPrevalence of INOCA among women with prior studied. pregnancy-related conditions is insufficiently Lack of large studies on the prevalence of INOCA. studies on the prevalence Lack of large the general as well as surveys in registries Prospective national/international 2 3 4 5 6 7 8 9 1 10 11 12 All these actions should be promoted by national and international scientific societies, as well as the pharma and biomedical industries, in the firmAll these actions should be promoted by national unmet need in clinical practice, a virtuous cycle of progress in science and technology will bebelief that, once INOCA is acknowledged as a major and prog.nosis of these patients. ACEi: angiotensin-converting enzyme inhibitor; Ach: acetycholine;initiated, ultimately improving the quality of life ARB: angiotensin receptor blocker; HFpEF: heart failure with preserved ejection fraction. Table 6 Future research to address INOCA to address research 6 Future Table Public Health, Padova, Italy; 11. North Cumbria Integrated North Cumbria 11. Italy; Padova, Health, Public Department Cumbria, UK; 12. Trust, Care NHS Foundation Paris, Hospital Paris University, Lariboisie`re of Cardiology, College Imperial Heart and Lung Institute, 13. National France; London, London, UK; 14. Ludwig-Maximilians-University, Yale Medicine, Munich, Germany; 15. Section of Cardiovascular Bart’s USA; 16. CT, New Haven, Medicine, of School University Heart Centre, St Warren and Institute Cardiovascular UK; 17. Lifespan London, Bartholomew’s Hospital, West USA; RI, Providence, Brown University, of School Medical Alpert Smithfield, i Creu Santa la de Program-ICCC, IR-Hospital 18. Cardiovascular Barcelona, Spain; 19. Erasmus MC, University Sant Pau, CiberCV, 20. Zena Netherlands; the Rotterdam, Rotterdam, Center Medical Sinai Mount Institute, Cardiovascular Wiener A. and Michael and CardioThoracic-Vascular USA; 21. NY, York, New Hospital,

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and national life expectancy, all-cause mortality, and cause-specific mortality and cause-specific mortality all-cause mortality, and national life expectancy, analysis for the Global for 249 causes of death, 1980-2015: a systematic Burden of Disease Study 2015. Lancet. 2016;388:1459-1544. 2. S, Simonsen L, Galatius KW, Hansen T, Hermann T, Dominguez H, Sehestedt disease and prognosis in Prescott E. Prediction of obstructive coronary artery 2019;40:1426-1435. patients with suspected stable angina. Eur Heart J. 4. no with pectoris angina Stable E. H, Prescott Kelbaek E, Jorgensen JK, Madsen major risks of increased with associated obstructive coronary artery disease is adverse cardiovascular events. Eur Heart J. 2012;33:734-744. 6. depression, low physi- highly prevalent and associated with long-term anxiety, cal functioning, and quality of life in stable angina pectoris. Clin Res Cardiol. WS. Weintraub Morrone D, Patel MR, A, AN, Guarini G, Huqi DeMaria Obstructive coronary atherosclerosis and ischemic heart disease: an elusive link! 8. diagnostic advances and therapeutic need. Heart. 2018;104:284-292. 9. Juni P, WF, Fearon P, Tonino M, Pijls N, Vanderheyden J, A, Bartunek Milkas versus hemodynamics to predict the natural history Angiography De Bruyne B. of coronary stenoses: fractional flow reserve versus angiography in multivessel 2018;137:1475-1485. Circulation. evaluation 2 substudy. References 1. Agewall S, Dickstein K, T, Deaton C, Cuisset Prescott E, Storey RF, Gilard M, Hasdai D, Hatala R, Escaned J, Gersh BJ, Svitil P, T, Edvardsen Achenbach S, Bax JJ, ESC M, Valgimigli Muneretto C, Masip J, Mahfoud F, for the diagnosis and man- Scientific Document Group. 2019 ESC Guidelines for the diagnosis and Force Task agement of chronic coronary syndromes: the the European Society of management of chronic coronary syndromes of Cardiology (ESC). Eur Heart J. 2020:41:407-477. 3. 2007;356:830-840. 5. 2013;102:571-581. 7. reports grants from Abbott Laboratories, grants from AstraZeneca, AstraZeneca, from grants Laboratories, Abbott grants from reports Israel Deaconess, grants grants from Beth Bayer, grants from grants from DSI, Behring, grants grants from CSL from BMS, grants Pharmaceuticals, Novartis from grants Medtronic, from other Laboratories, Abbott from personal fees from OrbusNeich, The Abiomed, other from other from Abbott Laboratories, from per fees from Boston Scientific, personal Company, Medicines sonal fees from Medscape/WebMD, personal fees from Siemens from fees personal Medscape/WebMD, fees from sonal fees from PLx Opco Inc/dba PLx Medical Solutions, personal Regeneron from other and support non-financial Inc, Pharma other from Sciences, personal fees from Roivant Pharmaceuticals, Corp, personal fees from Sanofi, Spectranetics/Philips/Volcano Affairs), (Janssen Scientific Medtelligence personal fees from Bristol from other Affairs, Janssen Scientific from fees personal Research Partners, other Watermark Myers other from Squibb, the sub- outside from Claret Medical, other from Elixir Medical, Andreas work. Davide Capodanno has nothing to disclose. mitted has nothing to disclose. Baumbach -

Conflict of interest Conflict Amgen, from other Bayer, from other reports Kunadian Vijay Astra Zeneca, other from Daiichi from Abbott, other other from is sup- Kunadian Vijay work; and Sankyo, outside the submitted Astra Zeneca (funder research grant from ported by an external Kunadian is also sup- Vijay number ISSBRIL0303). reference Research for Health Institute National by the ported/funded Newcastle at based Centre Research Biomedical Newcastle The University. and Newcastle Trust Hospitals NHS Foundation not necessarily author(s) and those of the views expressed are Vijay of Health. Department NIHR or the NHS, the of the those Foundation Clinical Kunadian also supported by the British Heart Foundation Heart British the for CS/15/7/31679 Grant Study SEgmeNt elevatIOn myocaRdial older patients with non-ST Alaide Trial. infarction Randomised TreAtment Interventional fees from personal Abiomed, from fees reports personal Chieffo fees from Cardinal Abbott, personal personal fees from Biosensor, work. submitted the outside fees from Magenta, personal Health, during the fees from Servier, reports personal Paolo G. Camici Colin Berry reports grants, non-financial conduct of the study. grants, non-financial Vascular, Abbott support and other from support from non-financial AstraZeneca, support and other from from support Boehringer Ingelheim, grants and non-financial from HeartFlow, support and other GSK, grants, non-financial from Opsens, grants, non-finan- support and other non-financial support from non-financial Novartis, from other and support cial work; and Colin Berry outside the submitted Siemens Healthcare, Foundation Heart British support from the research acknowledges and Medical (PG/17/ 2532884; FS/17/26/32744; RE/18/6134217) reports per Escaned (MR/S005714/1). Javier Council Research proposed by the EAPCI Women’s Committee and its members. members. and its Committee Women’s EAPCI by the proposed Diebold from the ESC/EAPCI and Marion Torre la Marielle de of co-ordination in the support and help valuable for their office committee. the writing Abbott, personal fees from Philips, outside the sonal fees from Angela H.E.M. Maas has nothing to disclose. work. submitted has nothing to disclose. Nicole Karam has nothing Eva Prescott has nothing to disclose. Chiara Appelman Yolande to disclose. reports Gill Louise Buchanan to disclose. has nothing Fraccaro fees personal and grants Bayer, from fees personal and grants grants and personal fees from Daichii-Sanyo, grants from Pfizer, Manzo- work. Stephane submitted the outside Menarini, from reports other Al-Lamee Rasha disclose. to has nothing Silberman submitted the outside Menarini, from other Volcano, Philips from Lansky Alexandra to dis-close. has nothing Regar work. Evelyn disclose. to nothing has Abbott J. Dawn disclose. to nothing has other from Sanofi, AstraZeneca, Lina Badimon reports grants from Astra-Zeneca, other from A-Biotics, other from Lilly, grants from other from other from Research Forum on Beer and Lyfestyle, outside from Pfizer, other and Lyfestyle, Forum on Beer Research Dutch from grants work. Dirk J. Duncker reports submitted the work. Roxana Mehran outside the submitted Heart Foundation, 16 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 EuroIntervention 2020;16-online publish-ahead-of-print July 2020 17

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2020;13:33-45. Interv. Cardiovasc 127. dysfunction. Pharmacological approaches to coronary microvascular 2014;144:283-302. Pharmacol Ther. 125. Options Cardiovasc Curr Treat microvascular coronary dysfunction. and angina Med. 2010;12:355-364. 128. Watkins S, Eteiba H, Shaukat A, Lindsay M, Robertson K, Hood S, McGeoch R, M, Robertson K, Hood S, McGeoch R, A, Lindsay S, Eteiba H, Shaukat Watkins D, Rush C, Sattar N, Corcoran D, Collison E, McCartney P, Yii McDade R, outcomes of angina RM, Oldroyd KG, Berry C. 1-Year Touyz A, McConnachie invasive coronary function testing (CorMicA). management guided by Sestito A, Lanza GA, Crea F. Lack of effect of nitrates on exercise stress test nitrates on exercise stress test of Lack of effect Crea F. A, Lanza GA, Sestito results in patients with microvascular angina. 229-234. 124. disease. 2016;37:1514-1516. sion medicine. Eur Heart J. 123. H, D’Amati G, Donato L, Camici PG. Perindopril and indapa- Parker Pisani P, and improve flow in arterial mide reverse coronary microvascular remodelling hypertension. 126. - calcium channel blocker in patients with cardiac syn combination of statin and Artery Dis. 2014;25:40-44. drome X. Coron 122. - level to cardiovascular outcomes with rosuvasta sensitivity C-reactive protein Trial Use of statins in Prevention: an Intervention tin in the Justification for 2010;106:204-209. Am J Cardiol. Evaluating Rosuvastatin (JUPITER). 121. 118. Foundation from the British Heart artery disease: lessons tive coronary Trial. CorMicA obstruc- anginawithout Berry C.Howtodiagnoseandmanage TJ, 119. Cain VA, Nissen SE; ASTEROID Investigators. Effect of rosuvastatin therapy rosuvastatin therapy of Effect ASTEROID Investigators. SE; Nissen VA, Cain angiography: by quantitative coronary artery stenoses assessed on coronary of rosuvastatin on intravascular ultrasound- effect a study to evaluate the 2008;117:2458-2466. burden. Circulation. derived coronary atheroma 120. Supplemental Table 1 COVADIS diagnostic criteria for vasospastic anginaa Vasospastic angina diagnostic criteria elements 1. 1. Nitrate-responsive angina—during spontaneous episode, with at least one of the following: a. A. Rest angina—especially between night and early morning b. B. Marked diurnal variation in exercise tolerance—reduced in morning c. C. Hyperventilation can precipitate an episode d. D. Calcium channel blockers (but not β-blockers) suppress episodes 2. 3. 2. Transient ischaemic ECG changes—during spontaneous episode, including any of the following in at least two contiguous leads: a. A. ST segment elevation ≥0.1 mV b. B. ST segment depression ≥0.1 mV c. C. New negative U waves 4. 5. 3. Coronary artery spasm—defined as transient total or subtotal coronary artery occlusion (>90% constriction) with angina and ischaemic ECG changes either spontaneously or in response to a provocative stimulus (typically acetylcholine, ergot, or hyperventilation)

a‘Definitive vasospastic angina’ is diagnosed if nitrate-responsive angina is evident during spontaneous episodes and either the transient ischaemic ECG changes during the spontaneous episodes or coronary artery spasm criteria are fulfilled. ‘Suspected vasospastic angina’ is diagnosed if nitrate-responsive angina is evident during spontaneous episodes but transient ischaemic ECG changes are equivocal or unavailable and coronary artery spasm criteria are equivocal. Beltrame et al. European Heart Journal 2015;38(33):2565-2568

Supplemental Table 2: Possible symptoms of INOCA

Typical angina Meets all 3 of the following characteristics: - 1. Squeezing, tight, substernal chest discomfort, burning, pressure - 2. Provoked by exertion or emotional stress - 3. Relieved by rest and/or nitrates within minutes Atypical angina - Meets 2 of these characteristics Additional features - Discomfort may occur at rest as well as following exercise which may be present - Discomfort may last longer than minutes in INOCA - Discomfort is poorly responsive to nitrates - Crescendo-decrescendo character to pain - Stress-related symptoms - Extreme tiredness which may occur after anginal episode - Dyspnoea, anxiety, pain between shoulder blades, indigestion, nausea, fatigue, weakness, vomiting, sleep disturbances - More prevalent in women Non-anginal chest - Lack of any or meets only 1 of the above characteristics discomfort Supplemental Table 3: Pros and cons of non-invasive techniques to evaluate

CFR

Methods PRO CONS TTDE • Low cost • Requires extensive training • Lack of ionizing radiation • More feasible on LAD, less • Potentially broad access satisfactory on the other • Good reproducibility and arteries validity against invasive measures • Proven predictive of adverse outcome MCE • Lack of ionizing radiation • No clinical validation • Potentially broad access • Rare but severe adverse reactions are reported to some ultrasound contrast agents PET • Well-validated, accurate and • Less availability reproducible • Costly • High-sensitivity, spatial • Ionizing radiation resolution, reduced radiation dose with new generation machines • Proven predictive of adverse outcome MRI • Better availability than PET • Dark rim artefacts in the sub- • Less expensive than PET endocardium need to be • High spatial and temporal differentiated from true resolution perfusion defects • Lack of ionizing radiation • Lacks validation and reproducibility studies CCTA • Anatomical test • Lacks information on coronary • High sensitivity for coronary vasomotion artery disease • Ionising radiation exposure • High sensitivity for coronary • Needs for heart rate control atherosclerotic plaque and beta-adrenergic blockade • False negative results • CT-derived • Opportunity to combine • High effective radiation dose CFR accurate anatomic • Increased contrast medium and functional assessments of dose both the myocardium and the • Needs for heart rate control coronary arteries and beta-adrenergic blockade • Required further clinical validation • Ionizing radiation • Lacks evidence from randomised trials

CFR = coronary flow reserve; CCTA= Coronary Computed tomographic angiography; MCE= Myocardial contrast echocardiography; MRI= magnetic resonance imaging; PET= Positron emission tomography; TTDE= Transthoracic Doppler echocardiography.

Transthoracic Doppler echocardiography (TTDE)

Coronary blood flow velocity can be evaluated at baseline and during hyperaemia by pulsed-wave Doppler echocardiography, with the sample volume placed on the colour signal in the mid- or distal tract of the left anterior descending coronary artery (LAD).

The incidence angle should be minimized (<40°). Measurements are performed offline by contouring the spectral Doppler signal and only the diastolic component is usually measured1, 2. Good reproducibility as well as agreement with invasive assessment has been documented1, 3, 4 The limitation of this technique is the ability to assess LAD and not other vessels.

Myocardial contrast echocardiography (MCE)

Myocardial blood flow and myocardial blood volume can be assessed through intravenously injected, echogenic, gas-filled microbubbles that are similar in size and rheological properties to red blood cells and are detected in the myocardium by high- intensity ultrasound pulses. Myocardial perfusion abnormalities during dipyridamole infusion in patients with otherwise normal wall motion seems to be a marker of CMD5,

Positron emission tomography (PET)

PET provides non-invasive, accurate, and reproducible quantification of regional myocardial blood flow, by means of continuous monitoring of the radioactivity emitted by an intravenously administered tracer, in the circulation and the myocardium.

Different PET tracers are used to assess myocardial blood flow such as 15O-labelled

15 13 13 82 + 18 water (H2 O), N-labelled ammonia ( NH3), Rb (cationic K analogue) and F- flurpiridaz7-15. Different studies have tested the short-term reproducibility of myocardial

15 13 16, 17 blood flow measurements using PET with H2 O and NH3.

Cardiac magnetic resonance (CMR)

Myocardial perfusion can be assessed by CMR through the first-pass kinetics of T1- enhancing extracellular gadolinium-based contrast media. The contrast medium, diffusing from the microvasculature into the interstitial space, results in an increase in signal intensity that is proportional to the perfusion and blood volume of the tissue, the extravascular compartment size, and capillary permeability. A delayed signal increase and persistently hypointense regions are indicative of reduced perfusion18-24.

Interpretation of the data can be semi-quantitative using the signal intensity index and/or the up-slope rate or fully quantitative23, 25, 26. Pixel-mapping of myocardial perfusion holds promise for bringing quantitative measurements of myocardial blood flow (MBF) in real-time, into the clinic, to facilitate diagnosis and decision-making 23,

25, 26.

CCTA, CT-derived CFR and CT-perfusion

Coronary computed tomographic angiography (CCTA) is an anatomical imaging method that does not currently provide information on coronary vasomotion or microvascular disease. In patients referred for assessment of angina, a CCTA strategy expectedly alters the diagnosis27, treatment and outcome for CAD (specifically, non- fatal MI) but mortality is not affected28. On the other hand, a CCTA strategy is associated with an increase in angina and a reduction in quality of life in all-comers29.

Although there may be several contributing factors, one important reason could be false-negative CCTA results and discontinuation of therapy in patients with INOCA, most of whom are female. The ESC practice guidelines for CCS30 champion a patient- centred approach with functional and anatomical tests both being first-line options. CCTA is a good non-invasive strategy for ruling out obstructive CAD. However, the large proportion of patients with symptoms due to vascular dysfunction (CMD or vasospastic) are not diagnosed by the method.

CT-derived CFR combines anatomical and physiological evaluation of the coronary circulation. Quantitative, dynamic CT perfusion imaging is based on first-pass detection of the maximum slope of the time-attenuation curve in the target tissue, divided by the maximum arterial input function31.

PET and TTDE have thus far been used to detect ischaemia, are validated and have been shown to carry prognostic information in multiple studies32. In the 2019 ESC guidelines30, PET, TTDE and MRI have a IIb recommendation (i.e. may be considered) for the detection of CMD. However, perfusion assessment lacks the sensitivity to diagnose the relative contributions of epicardial and microvascular disease to myocardial blood flow reduction. In addition, some patients with a propensity to vasospastic chest pain syndromes may have normal findings from pharmacological and exercise stress testing. These caveats emphasise the need for invasive evaluation of coronary arteries and microvasculature to derive definitive conclusions on the causes of INOCA.

Supplemental Table 4: Options for pharmacological testing of coronary reactivity using acetylcholine

Administration Dosing Considerations## Reference Pump infusion Sequential infusion of Standardised approach [33-35] acetylcholine at Logistically less concentrations straightforward than a approximating 0.182, manual approach 1.82, and 18.2 µg/mL (10- 6, 10-5, and 10-4 mol/L, respectively) at 1 ml/min for 2 minutes via a mechanical infusion pump Manual Sequential manual More straightforward [36, 37] infusion* infusion of acetylcholine than by mechanical at concentrations infusion, but possibly approximating 2µg, 20µg, less standardized. 100µg and 200µg over a period of 3 minutes Manual infusion should (some centres inject over be slow (1 – 2 ml/min) 20 seconds) via the and controlled in order diagnostic catheter for to avoid excessive, assessment of the LCA. variable volume altering coronary flow. Assessment of the RCA is usually performed when the LCA shows no abnormal result and doses of 50µg or 80µg are applied.

## Informed consent should take account of unlicensed, parenteral use of acetylcholine. Acetylcholine should only be administered by an experienced interventional cardiologist working as a member of a clinical team.

*Further studies are needed to determine the optimal dose of intracoronary bolus of acetylcholine

Supplemental Table references

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