Up to half of all patients undergoing coronary angiography with symptoms and/or signs of angina have no obstructive epicardial coronary artery disease (ANOCA).1

These patients rarely receive a definitive diagnosis and are frequently labeled and managed inappropriately.2 Depending on the patient population studied and the techniques used, up to two-thirds are found to have an underlying coronary vascular function disorder.3,4 The most common causes are microvascular angina (MVA), vasospastic angina (VSA) or both. These functional conditions cannot be excluded by anatomic tests such as non-invasive coronary computed tomography (CT) or invasive coronary angiogram (ICA).5

Coronary vasomotion disorders (CVDs) cause a relative supply-demand mismatch of myocardial blood flow and nutrients relative to their requirements, inducing myocardial ischemia that may be transient, recurrent, and/or chronic.1 This umbrella term incorporates a wide range of pathophysiological abnormalities, such as endothelial dysfunction, microvascular remodeling, microvascular and epicardial spasm and enhanced cardiac pain.2

Persistent symptoms frequently lead to subsequent repeated ICA, emergency room visits and hospitalizations, and has been associated with a reduced quality of life and substantial economic burden.6,7

The Coronary Vasomotion Disorders International Study Group (COVADIS) diagnostic criteria8,9 and the recent European consensus document on ischemia with no obstructive coronary artery disease (INOCA)10 were designed to overcome divergences in diagnostic criteria by providing standardized definitions of INOCA endotypes along with guidance on the diagnostic approach and management of these clinical entities. Furthermore, the CorMica trial underlined the importance of invasive diagnosis by demonstrating improvement in symptoms and quality of life comparing standard care with CFT guided treatment.11

Few real-world studies in Europe12–14 have prospectively evaluated multiparametric and sequential invasive coronary function test (CFT) protocols. Hence, we aimed to assess the safety and feasibility of CFT, as well as the prevalence and type of CVD in patients with ANOCA, according to the European consensus document.10

This study was approved by the Ethics Committee of Centro Hospitalar Universitário de Lisboa Central. The study was conducted according to the Declaration of Helsinki. All participants signed written informed consent.

We present a case series of twenty patients with ANOCA who underwent a standardized CFT based on the European consensus document.10 To the best of our knowledge, it is the first prospective study in Portugal that comprehensively assessed coronary functional abnormalities for both epicardial coronary arteries and coronary microcirculation in such a population.

The major findings of our study are: (1) CFT is feasible and safe in clinical practice, providing definitive diagnosis of the underlying cause of angina, allowing stratified treatment of the distinct CVD entities and (2) in patients with ANOCA, coronary functional abnormalities, including epicardial CS, reduced microvascular vasodilatation and increased microvascular resistance are prevalent (75% in this selected cohort) and frequently coexist.

Most of ANOCA patients have a combination of functional and structural abnormalities of coronary microcirculation, including impaired dilatation and excessive coronary microvascular constriction.17,18 Impaired dilatation may be the consequence of abnormalities in endothelium-dependent mechanisms, frequently associated with diabetes, obesity, smoking, and other CVRF, and/or endothelium-independent mechanisms. The presence of an abnormal endothelium-dependent function may be diagnosed by Ach provocation test, where a limited microvascular vasodilatory response or even a paradoxical microvascular vasoconstriction is recorded.19 On the other hand, abnormal endothelium-independent function can be diagnosed as a reduced CFR and/or an increased IMR during a steady-state hyperemia induced by intravenous adenosine infusion, in the absence of significant epicardial stenosis.10,17

This single invasive procedure allows for CVD diagnosis, overcoming issues of specificity and sensitivity associated with non-invasive ischemia tests. CFT has a high diagnostic yield of identifying MVA and VSA with small additional procedural risks (up to 0.7%)20 and has been recently endorsed by European guidelines on chronic coronary syndromes.21

The CFT proved to be a safe procedure in our cohort, without related SAE. Furthermore, our CFT protocol through routine radial access enabled CVD evaluation at a reasonable expense of time and contrast volume.

Our study findings are consistent with prior studies,2,3,12,22 which have also reported on the high prevalence of coronary endothelial dysfunction and microcirculatory abnormalities in the population of patients with INOCA or ANOCA.

In our series, 75% of patients were found to have CVD. Isolated MVA was present in 25%, and 10% of the patients had both conditions (MVA and VSA). A similar prevalence of 30% was reported in a large study with invasive assessment of MVA.3 Traditional CVRF associated with increased risk for MVA23 were also noted in the majority of our patients with MVA diagnosis. Only two patients had a LVEDP >15 mmHg, both with LVEF > 55% and isolated MVA. Thus, the LVEDP was probably related to diastolic dysfunction associated with hypertension and/or diabetes. Isolated VSA was found in 40% of patients. The reported prevalence of CS in literature ranges between 33% and 62%, depending on the provocation test protocol and the population included.16,24 In this study we used a maximum Ach dose of 200 μg which is consistent with most contemporary protocols1,16 and has been shown to be safe.16

Interestingly, only 25% of patients who underwent CFT had completely normal testing, probably revealing selection bias (highly symptomatic population with significant CVRF burden justifying referral for ICA). Furthermore, most of the patients with final diagnosis of non-cardiac chest pain presented initially with atypical angina or anginal equivalent. This observation warrants further studies on cost-effectiveness of invasive CFT in patients presenting with non-typical angina.

Providing a diagnosis to patients with INOCA/ANOCA can be helpful in preventing repeated stress testing and ICA, and also on guiding therapy. Besides lifestyle interventions, first-line therapy for patients with MVA consists of a beta-blocker, unless microvascular spasm is concomitant. On the contrary, beta-blockers may potentiate coronary vasospasm and should be avoided in VSA and microvascular spasm. The significant difference in therapies according to CVD phenotypes mandates a definitive diagnosis. This has been corroborated in our study where 70% of patients required antianginal therapy adjustment after obtaining a definitive diagnosis with CFT. This new interventional diagnostic tool has the potential to change the paradigm of revascularization-oriented interventional cardiology and provide patients a truly individualized therapy, which in turn may lead to symptom improvement and has the potential to lower the overall health care burden.

Nevertheless, more studies are needed to refine diagnostic and therapeutic strategies in order to improve CVD detection, to reduce disease progression and also to determine whether clinical benefits found in CorMica trial are reproducible in a real-world cohort of patients.

This case series highlights the different phenotypes of patients with ANOCA. CFT was feasible and safe in a cohort of patients with ANOCA. CVD were prevalent in this selected group of patients, and some presented mixed phenotypes of CVD. CFT may provide a definitive diagnosis in patients with persistent angina and tailor the stratification of pharmacological therapy.

The authors have no conflicts of interest to declare.