LABORATORIO DE URGENCIAS

An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries

Vijay Kunadian(UK, Document Chair), Alaide Chieffo(Italy, Document Co-Chair), Paolo G. Camici(Italy), Colin Berry(UK), Javier Escaned(Spain), Angela Maas(Netherlands), Eva Prescott(Denmark), Nicole Karam(France), Yolande Appelman(Netherlands), Chiara Fraccaro(Italy), Gill L.Buchanan(UK), Stephane Manzo-Silberman(France), Rasha Al-Lamee(UK), Evelyn Regar(Germany), Alexandra Lansky(USA,UK), J. Dawn Abbott(USA), Lina Badimon(Spain), Dirk J. Duncker(Netherlands), Roxana Mehran(USA), Davide Capodanno(Italy) and Andreas Baumbach(UK, USA)

                                                                               European Heart Journal (2020) 0, 1–21

Preamble

This consensus document, a summary of the views of an expert panel organized by the European Association of Percutaneous Cardiovascular Interventions (EAPCI), appraises the importance of ischaemia with non-obstructive coronary arteries (INOCA).
This document is put together in collaboration with the European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation and endorsed by COVADIS (Coronary Vasomotor Disorders International Study) group. The EAPCI INOCA consensus document was proposed by the EAPCIWomen’s Committee and its members.
The chairs and writing group task force of this document were selected by the EAPCI Scientific Documents and Initiatives Committee (EAPCI SDAIC) and EAPCI Women’s Committee.
The writing group task force members are represented from the EAPCI Women’s Committee, EAPCI SDAIC, COVADIS Steering Committee/members, and European Society of CardiologyWorking Group on Coronary Pathophysiology & Microcirculation.
The formal approval for this document was provided by the European Society of Cardiology (ESC) Clinical Practice Guidelines Committee and coordinated by the EAPCI office.
The writing task force members have provided declaration of interest forms for all relationships that might be perceived as real or potential sources of conflicts of interest.
This consensus document provides a definition of INOCA and guidance to the clinical and research community on the diagnostic approach and management of INOCA based on existing evidence and best current practices and identifies areas for further investigation.

Introduction

Angina pectoris, the most common symptom of ischaemic heart disease (IHD), affects approximately 112 million people globally.1
The 2019 ESC guidelines provides guidance on the diagnosis and management of patients with chronic coronary syndromes (CCS).2 A large proportion of patients (up to 70%) undergoing coronary angiography because of angina and evidence of myocardial ischaemia do not have obstructive coronary arteries but have demonstrable ischaemia.2,3

Studies carried out in the past two decades have highlighted that coronary microvascular dysfunction (CMD) and epicardial vascular dysfunction are additional pathophysiologic mechanisms of IHD.4 Coronary microvascular dysfunction and epicardial vasospasm, alone or in combination with coronary artery disease (CAD), are adjunctive mechanisms of myocardial ischaemia.
However, these conditions are rarely correctly diagnosed and, therefore, no tailored therapy is prescribed for these patients. As a consequence, these patients continue to experience recurrent angina with impaired quality of life, leading to repeated hospitalizations, unnecessary coronary angiography and adverse cardiovascular outcomes in the short- and long term.5,6
This consensus document provides a definition of ischaemia with non-obstructive coronary arteries (INOCA) and guidance to the clinical community on the diagnostic approach and management of INOCA based on existing evidence and best current practices. In addition, having a universal definition of INOCA and identifying gaps in knowledge will serve to encourage research to improve
outcomes for this patient population. Discussion of angina caused by CMD in the context of cardiomyopathy (hypertrophic, dilated), myocarditis, aortic stenosis, infiltrative diseases of the heart,
percutaneous/surgical interventions, and other possible mechanisms7 (Figure 1) such as inflammation, systemic inflammatory or autoimmune disease (lupus, rheumatoid arthritis), platelet /coagulation disorders, primary metabolic abnormalities, as well as by myocardial bridging, is beyond
the scope of this consensus document. A failure to diagnose epicardial CAD in a patient with documented angina/ischaemia should promote a subsequent search pathway to elucidate INOCA endotypes before a search for non-cardiac causes of chest discomfort is explored.

INOCA endotypes

In the setting of CCS, a mismatch of demand-supply of coronary artery blood flow may lead to transient or recurrent cardiac chest pain related to myocardial ischaemia due to inadequate cellular availability of adenosine-50-triphosphate.8 Although obstructive CAD is a frequent and well-acknowledged cause of myocardial ischaemia, many stenoses judged as severe on visual assessment, are not flow-limiting.
Functional misclassification of obstructive lesions frequently occurs in the range of 40–80% stenosis severity, being particularly high in case of patients with multiple coronary lesions.9–11 The most recent ESC guidelines recommend the use of myocardial fractional flow reserve or instantaneous wave-free ratio to identify patients at high event risk who will benefit from revascularisation.2 Cardiac ischaemia may also be caused by vascular dysfunction without obstructive CAD, a condition recently termed INOCA. In INOCA, the mismatch between blood supply and myocardial oxygen demands may be caused by CMD and/or epicardial coronary artery spasm, typically in the setting of non-obstructive coronary atherosclerosis.12, 13,14. These mechanisms may also cause ischaemia in patients with concomitant obstructive CAD and atherosclerosis with outward remodelling but these cases are not
included in INOCA by definition.

Microvascular angina

Microvascular angina (MVA) is the clinical manifestation of myocardial ischaemia caused by CMD. In this clinical entity, myocardial ischaemia may result from structural remodelling of the microvasculature (leading to fixed reduced microcirculatory conductance) or vasomotor disorders affecting the coronary arterioles (causing dynamic arteriolar obstruction).15,16 Both vascular
dysfunction mechanisms may co-exist and contribute to MVA. An updated standardization of criteria for MVA in patients presenting with angina pectoris or ischaemia-like symptoms in the absence of
flow-limiting CAD has been proposed by the COVADIS group15

Epicardial vasospastic angina

Vasospastic angina (VSA) is the clinical manifestation of myocardial ischaemia caused by dynamic epicardial coronary obstruction caused by a vasomotor disorder. In 1959, Prinzmetal described the clinical and electrocardiographic manifestations (transient ST-segment elevation) of a disorder thought to be due to epicardial coronary artery spasm.17 Subsequently, other forms of vasomotor disorders causing chest pain with transient ST-segment depression or T-wave inversion were described. Overall, these clinical entities caused by epicardial vessel spasm were grouped under the term VSA. Standardization of diagnostic criteria for VSA has been previously described by the COVADIS group 18
Microvascular angina and epicardial VSA can co-exist which is associated with worse prognosis.19

Epidemiology
Prevalence in the general population and according to sex and age

The majority of patients referred for assessment for angina do not have obstructive coronary arteries. In unselected populations referred for assessment less than 10% have obstructive CAD.3,20
In all studies, there is a strong female preponderance for the condition.
Large US multicentre study showed nearly 39% of the patients selected for coronary angiography because of suspected angina and/or positive stress test have non-obstructive CAD.21 This frequency is higher among women (approximately 50–70%), compared to men (30–50%).
In a retrospective registry from Eastern Denmark including 11 223 patients with angina referred for coronary angiography between 1998 and 2009, 65% of women vs. 33% of men had non-obstructive CAD, with an increasing rate over the 10-year study period in both sexes, reaching up to 73% among women in 2009.5
Similarly, almost two-thirds (62%) of women referred for coronary angiography and enrolled in the National Heart, Lung and Blood Institutesponsored Women’s Ischaemia Syndrome Evaluation (WISE), did not have a significant obstructive stenosis. Women with non-obstructive CAD were younger than those with obstructive CAD.22

Prevalence of coronary microvascular dysfunction

Prevalence of CMD in patients with angina and no obstructive CAD undergoing invasive angiography depends on the methods and cut-off applied. In the iPower study, 26% of 963 symptomatic women with no obstructive CAD had coronary flow velocity reserve (CFVR) below two when assessed by transthoracic Doppler echo.23 However, these studies should be interpreted in the context that non-invasive estimation of CFVR has several limitations.24,25
Other studies assessing CMD invasively or by positron emission tomography with different cut-offs have found 39–54% have CMD.21,26
In a large study with invasive assessment of CMD in 1439 men and women with chest pain and no obstructive CAD included over a period of 19 years, 30% had abnormal CFVR in response to
adenosine.27
The association between traditional cardiovascular risk factors and INOCA is not well established. Smoking has been associated with CMD.28 Age, diabetes, hypertension, and dyslipidaemia were associated with impaired CMD both in the iPower study and WISE study.21,23 Other studies have shown that diabetes was uncommon among patients presenting with angina and non-obstructive CAD, while hypertension and dyslipidaemia were relatively more prevalent.27,29
Coronary microvascular dysfunction is associated with proinflammatory markers in women with INOCA.30,31 In the WISE cohort, novel risk variables like those associated with inflammation
seemed to play a role in CMD.32 For instance, systematic lupus erythematosus and rheumatoid arthritis are associated with CMD and are frequently encountered in patients with angina and CMD.33,34 After menopause, inflammatory diseases occur more often in women compared to men, which may contribute to sexdifferences in CMD.35
Although large studies are lacking, there is increasing evidence that psychosocial stress is more involved in coronary vasomotor disorders and variant manifestations of IHD compared to obstructive CAD.36 These seem to affect men and women differently.37 Women have elevated levels of highsensitive C reactive protein (hsCRP), and a lower monocyte and eosinophil count than men. A significant positive association between Beck Depression Inventory cognitive symptoms with elevatedhsCRP level is observed in men, but not in women.37

Prevalence of coronary artery spasm

The Japanese population has a higher prevalence of angina related to coronary vasomotor disorders 38 compared with western populations.
In addition, the frequencies of multiple coronary spasm (>_2 spastic arteries) by provocative testing in Japanese (24.3%)39 and Taiwanese populations (19.3%)40 are markedly higher than those in
Caucasians (7.5%).41 Interestingly, VSA is more prevalent among men than women.40 Most patients with VSA are between 40 and 70 years of age, and the prevalence tends to decrease after the age of
70 years.40
Previous Asian studies of patients with non-obstructive CAD have shown that the prevalence of coronary vasomotor disorders is around 50% in patients with angina.42,43 European studies have also shown a high prevalence of epicardial vasospasm when systematically tested.44,45 However, due to differences in stress protocols and definitions applied, the studies are not directly comparable.
Female patients were more sensitive to acetylcholine with vasomotor dysfunction occurring at lower acetylcholine doses compared with male patients. Smoking is a risk factor for VSA, unlike diabetes and hypertension, and the relationship with dyslipidaemia is unclear.46,47

Pathophysiology and endotypes
Microvascular angina and epicardial coronary artery spasm

In the absence of flow-limiting coronary artery disease, myocardial ischaemia can result from specific pathways of microcirculatory dysfunction.16
Two microcirculatory dysfunction endotypes account for most cases of MVA: structural microcirculatory remodelling and functional arteriolar dysregulation. In other words, microvascular dyfsunction may be structural, functional or both.16,48
   (i) Structural remodelling of the coronary microvasculature is associated with a decrease in microcirculatory conductance and impaired oxygen delivery capacity.49 This is typically caused by inward remodelling of coronary arterioles, with an increase in wall to lumen ratio, loss of myocardial capillary density (capillary rarefaction) or both.50
Remodelling may occur as a result of cardiovascular risk factors, atherosclerosis, left ventricular hypertrophy, or cardiomyopathies.50 A direct consequence of these pathological changes is a reduction of the vasodilatory range of the coronary microcirculation, limiting maximal blood and oxygen supply to the myocardium. Furthermore, remodelled arterioles are hypersensitive to vasoconstricting stimuli.51
The haemodynamic correlates of structural microcirculatory remodelling in response to a non-endothelium-dependent vasodilator, like adenosine, are (i) a reduced coronary flow reserve (CFR) and (ii) an increase in minimal (hyperaemic) microcirculatory resistance.
   (ii) Functional arteriolar dysregulation typically takes place in medium and large size arterioles, in which flow-mediated vasodilation is predominant.16 Under physiological conditions, an increase in myocardial oxygen consumption generates an upstream vasodilatory cascade in coronary resistance vessels. This is initiated by metabolically triggered vasodilation of distal arterioles,that are particularly sensitive to certain
metabolites, and it is followed by flow-mediated (endothelium-dependent) vasodilation of larger arterioles located upstream, as well as epicardial vessels.52 In the presence of endothelial dysfunction, dysregulation of the described upstream vasodilatory cascade occurs. Thus, endothelial dysfunction is associated with impaired vasodilation and even paradoxical vasoconstriction of upstream arteries and arterioles when myocardial oxygen demands increase which may be the result of hypersensitivity to vasoconstrictor stimuli.53
Some of the haemodynamic correlates of arteriolar dysregulation, observed during intracoronary acetylcholine challenge, are (i) a limited vasodilatory response to the drug (less than 1.5times resting flow), (ii) a marked reduction in blood flow, equivalent to the no-reflow phenomenon, without epicardial vessel spasm -denoting arteriolar spasm- and (iii) the development of diffuse narrowing of
distal epicardial vessels without focal, tight coronary spasm. Theabove-mentioned changes frequently run along the development of anginal symptoms and ischaemic electrocardiogram changes, which
confirm the ischaemia-generating potential of this endotype ofmicrocirculatory dysfunction.
Effects of fluctuating o estrogen levels on epicardialvessel and arteriolar vasomotion have been postulated as explanations for a higher frequency of symptoms in premenopausal women without obstructive CAD.54
Epicardial vessel spasm typically has an origin in a hyper-reactive epicardial coronary segment that undergoes maximal contraction when exposed to vasoconstrictor stimulus.55 Among such triggering
stimuli are smoking, drugs, peaks in blood pressure (BP), cold exposure, emotional stress, and hyperventilation.
Severe coronary vasospasm may also occur in the context of allergic reactions (Kounis syndrome). Coronary segments adjacent to implanted drug-eluting stents may also become prone to undergo coronary spasm.56
The substrate of coronary spasm can be found in abnormal function of both vascular smooth muscle and endothelial cells. A primary and non-specific hyper-reactivity of coronary vascular smooth muscle
cells has been consistently demonstrated in patients with variant angina and appears to be a key component of epicardial vessel spasm.
Available evidence suggests that endothelial dysfunction facilitates the induction of spasm in predisposed coronary segments.57

Clinical presentation

Patients with INOCA present a wide spectrum of symptoms and signs that are often misdiagnosed as of non-cardiac origin, leading to under-investigation and under-treatment. 
Patients with INOCA may present with symptoms similar to angina occurring with obstructive CAD .58,59 INOCA, like obstructive CAD, can also present with other symptoms such as breathlessness, pain between the shoulder blades, indigestion, nausea, extreme fatigue, weakness, vomiting, and/or sleep disturbances.
It is important to recognize there is gender variation in the clinical manifestation of both obstructive and non-obstructive CD.60–62 These differences in presentation are of particular relevance
in young and middle-aged women and also men2,63 who do not present with classical anginal symptoms.64,65. With the same symptoms, women are much less likely to have obstructive CAD and
much more likely to have CMD as a cause of their symptoms. In addition, because symptoms may be uncharacteristic, many cases of CMD may go undiagnosed.
Importantly, INOCA is associated with a wide variation in clinical presentation and symptom burden may vary over time. These symptoms should not be automatically classified as non-cardiac in origin,
particularly given the fact that women have a much higher prevalence of INOCA than men.66

Short- and long-term prognosis

The prognosis of patients with INOCA is far from benign. Angina with no obstructive CAD is associated with impaired quality of life for patients,6,67 higher risk of disability,68 as well as a higher incidence of adverse events5 including increases in mortality, morbidity, and healthcare costs with higher recurrence rates of hospital readmissions, higher rates of repeated coronary angiograms.69–74 In the WISE study, persistent chest pain, smoking, CAD severity, diabetes, and increased QTc interval were significant independent predictors of cardiovascular events defined as cardiovascular death, myocardial infarction (MI), congestive heart failure, or stroke.75
In a meta-analysis, 74 incidence of all-cause death and non-fatal MI in patients with non-obstructive atherosclerosis was much higher (1.32/100 personyears) than in those with angiographically normal epicardial vessels (0.52/100 person-years). Proven myocardial ischaemia by noninvasive imaging techniques (stress echocardiography or nuclear imaging) was associated with a higher incidence of events (1.52/100 person-years) compared to ischaemia detected by exercise electrocardiographic
stress testing 0.56/100 person-years.
It must be noted, the condition is heterogeneous and not all patients with angina and no obstructive CAD have ischaemia as a cause of their symptoms. However, when ischaemia is documented through CMD or endoth