Microvascular Angina: Diagnosis, Assessment, and Treatment

Part 1: Describing the problem of no obstructive coronary artery disease in patients with angina symptoms for which the cause needs to be investigated

Background

Almost half of patients with symptoms of angina pectoris have no obstructive coronary artery disease (NOCAD) revealed by coronary angiography. Many of these patients have a normal or near normal coronary angiogram. This conundrum presents a diagnostic challenge to clinicians, leading to uncertainties regarding appropriate treatment and patient information. The term microvascular angina (MVA), which suggests that coronary microvascular dysfunction (CMD) is the mechanism of angina in patients, was introduced to provide a clinical definition for the significant proportion of patients who present with symptoms and/or signs of myocardial ischaemia yet without obstructive coronary artery disease ([CAD] in most studies defined as absence of epicardial coronary stenosis >50%) at coronary angiography. Around 40–50% of patients fall into this category, with a high frequency of angina without constructive CAD (ANOCA) found more commonly in females compared to males (10%). It is estimated that in the USA and Europe around 3–4 million individuals who present with symptoms of myocardial ischaemia have no obstructive CAD, and the disease is often unrecognised and undertreated. MVA was originally described as a cause of chest pain in patients with normal coronary arteries on angiography, which may include abnormal functioning of endothelial and smooth muscle cells that line the heart arteries. MVA associates with vascular risk factors and atherosclerosis is a common finding with coronary angiography.

For this subgroup of patients with ANOCA, CMD may result in transient myocardial ischaemia and a reduced coronary flow reserve (CFR). As microvascular dysfunction may also be present in conjunction with obstructive CAD and/or myocardial diseases, the clinical entity of MVA is based on what has historically been known as Type I CMD, i.e., microvascular dysfunction in the absence of CAD and myocardial diseases.

Patients with obstructive CAD (mostly defined as ≥50% luminal stenosis and/or fractional flow reserve [FFR] ≤0.80) have established diagnostic pathways with wide availability and access to evidence-based treatment. However, patients with MVA may not only receive an incorrect diagnosis, but until recently, were also considered to be at low risk of cardiovascular events. This assumption is based on little solid evidence to date, with more recent data showing increased risk of cardiovascular events in at least a subpopulation of patients without obstructive CAD on angiography. Therefore, the emphasis now is to facilitate the adoption of clinically-available diagnostic methods to rule-in or rule-out the diagnosis of microvascular and vasospastic angina, complementing coronary angiography. Stratified medicine involves the identification of patient subgroups within an undifferentiated population. The subgroups, defined as endotypes, are distinguished by specific disease mechanisms amenable to targeted therapy.

Consolidation of the nomenclature for chronic (stable) coronary syndromes will help to clarify some of the uncertainties and knowledge gaps caused by dysfunction of the coronary microcirculation. Historically, the poorly understood enigma of anginal symptoms and/or signs of myocardial ischaemia coupled with no obstructive CAD on angiography used to be referred to as Syndrome X. This term was unhelpful, especially to affected patients (commonly women), who were prone to misdiagnosis, under-recognition, and sub-optimal management. The contemporary literature has evolved to champion more specific terms such as ANOCA, ischaemia and no obstructive CAD (INOCA), MVA, and vasospastic angina, which should not be used interchangeably. Although slightly different from a diagnostic point of view, it is also worth noting myocardial infarction (MI) with nonobstructive coronary arteries in which the presence of acute MI criteria with the absence of obstructive CAD also presents clinicians with similar diagnostic challenges and patient management.

This multitude of definitions mirrors the heterogeneity of clinical presentations, and at the same time seems to have hampered a systematic approach in terms of both clinical practice and research. The Coronary Vasomotion Disorders International Study (COVADIS) group proposed a standardised set of criteria for the diagnosis of MVA consisting of angina symptoms, absence of obstructive CAD (i.e., <50% stenosis or FFR >0.80), objective evidence of myocardial ischaemia on stress testing, and functional impairment of coronary microvasculature. Per expert consensus, all four criteria must be present for the diagnosis of definitive MVA. On the other hand, MVA is considered if symptoms of INOCA on angiography are present, in addition to either objective evidence of myocardial ischaemia or microvascular impairment.

The primary focus of this article is to highlight to practicing clinicians the clinical relevance of identifying (rule-in, rule-out) MVA in patients with ANOCA. The authors review the evidence on long-term prognosis, the standardisation of diagnostic pathways including the assessment of coronary microcirculation, and the evolving treatment strategies.