1. Introduction
Ischaemic heart disease is a leading cause of global mortality and morbidity. Research has traditionally focused on epicardial coronary artery stenosis due to atherosclerosis. However, large studies show that only 35–60% of patients with angina symptoms have obstructive coronary artery disease detected via elective angiography. The European Society of Cardiology’s (ESC) updated definition of Chronic Coronary Syndromes (CCSs) emphasizes recognizing the impact that structural and functional alterations to the microvasculature may have on transient episodes of myocardial hypoperfusion, which may manifest as angina or angina-equivalent symptoms.
Patients with angina and unobstructed coronary arteries (ANOCAs) have previously been reassured about their condition’s benign nature, but evidence now indicates an unfavourable prognosis, including a higher risk of Major Adverse Cardiovascular Events (MACEs) and mortality. The condition not only has a great impact on health resource utilisation, with increased costs relating to repeat hospitalisations, invasive catheterisation and anti-ischaemia drug treatment, but also has a large functional and macroeconomic impact relating to reduced quality of life of the affected patients.
Despite international guidelines recommending invasive coronary functional testing for persistently symptomatic ANOCA patients, barriers to adoption remain, such as the need for procedural expertise, potential complications, additional time required to undertake the procedure and its costs. However, there is compelling evidence as to the cost-effectiveness of this testing, and the benefits that stratified medical therapy according to the endotype of the disease has on patients’ symptom burden and quality of life. The purpose of this paper is to summarise the existing evidence with regard to the diagnosis and management of coronary microvascular dysfunction and vasospastic angina as important ANOCA endotypes.
2. Normal Coronary Vascular Structure and Function
The coronary vascular tree consists of two compartments: the epicardial, which includes arteries and veins, and the microvascular, comprising arterioles, capillaries and venules. Epicardial coronary arteries are conduit vessels that contribute less than 5% resistance to blood flow. Coronary arterioles, which account for about 60% of resting vascular resistance, are crucial for regulating coronary blood flow. These arterioles branch into smaller ones that penetrate the myocardium and lead to capillaries. While capillaries represent only 25% of resting vascular resistance (with venules and veins making up the remaining 10%), they contain 90% of myocardial blood volume and are key sites for metabolic exchange with myocardial tissue.
Large arterioles and coronary arteries are primarily controlled by the endothelium. Shear stress from blood flow triggers nitric oxide (NO) release, causing vascular smooth muscle cells (VSMCs) to relax in a process called flow-mediated vasodilation. Medium-sized arterioles respond to changes in blood pressure through Ca2+-mediated VSMC vasoconstriction, an endothelium-independent myogenic response. Small arterioles are influenced by local metabolites, like adenosine and carbon dioxide, which diffuse into VSMCs and cause vasodilation and increased perfusion. Additionally, the autonomic nervous system affects coronary blood flow by altering metabolite release and directly stimulating alpha and beta-adrenoceptors on VSMCs. Together, these mechanisms regulate vasomotor tone to align myocardial perfusion with demand.
3. Classification and Pathophysiology of ANOCA
The term ANOCA is used to describe patients who present with angina in the context of non-obstructive coronary arteries. Of these, depending on the type of the test performed, only 10–30% of patients have demonstrable ischaemia on stress testing (termed Ischaemia in Non-Obstructed Coronary Arteries (INOCA)). ANOCA/INOCA can be further subdivided into endotypes: (i) coronary microvascular dysfunction (CMD), which can be further subdivided into structural and functional CMD (either endothelium-dependent or independent); (ii) vasospastic angina (VSA), a result of epicardial coronary spasm or microvascular spasm; (iii) both CMD and VSA; (vi) non-cardiac chest pain. A recent meta-analysis has shown that, amongst patients presenting with cardiac chest pain and unobstructed coronary arteries, the prevalence of CMD was 41% (with women more likely to be affected), and the overall prevalence of epicardial or microvascular spasm was 49%, with both sexes equally affected. Interestingly, in three studies within the meta-analysis, which evaluated a total of 541 patients for both CMD and spasm, the prevalence of CMD alone was 23%, coronary spasm alone (either epicardial or microvascular) 19%, and coexistent CMD and coronary vasospasm 23%, which further supports the need for complete functional assessment of coronary physiology in patients presenting with ANOCA.
3.1. Structural CMD
Structural CMD comprises a disorder of microvascular circulation defined as reduced coronary flow reserve (CFR) in association with an increased minimal microvascular resistance (MMR). The proposed pathophysiology includes changes to vessel architecture, such as capillary rarefaction or arteriolar obliteration. However, patients with structural CMD have also been shown to exhibit endothelial dysfunction, which leads to diminished peak coronary blood flow augmentation and increased demand during exercise. Patients with structural CMD often have established coronary disease risk factors, such as diabetes or hypertension, and show an augmented blood pressure response to exercise, which further increases myocardial oxygen demand and predisposes them to ischaemia. It has been proposed that those patients benefit from lifestyle modification (e.g., weight loss or smoking cessation) and treatment leading to afterload reduction and vascular remodelling, for example, with angiotensin-converting enzyme inhibitors (ACEis) or statins.
3.2. Functional CMD
Historically, the pathophysiology of CMD was considered to result from high vascular resistance during increased demand for vasodilation (which nowadays is termed structural CMD). Interestingly though, these patients represent less than 50% of those with impaired CFR. Functional CMD appears to result from increased demand for myocardial oxygenation at rest or disordered coronary autoregulation. This leads to sub-maximal vasodilation in resting conditions, with the inability of those patients to further augment coronary blood flow in periods of stress, leading to an overall reduced CFR in the presence of normal or decreased MMR. This still has important clinical significance due to the impact of reduced CFR on prognosis. It has been hypothesised that functional CMD can act as a precursor to structural CMD, as chronically raised coronary blood flow may precipitate structural vascular changes, a process common in other vascular beds, such as renal or pulmonary. This association has not been proven and no disease-modifying therapies have been developed specifically for functional CMD, although, in theory, therapies modulating cardiac metabolism could be of benefit.
3.3. Vasospastic Angina (VSA)
In contrast to CMD, which results from impaired vasodilation of the microvasculature, vasospastic angina is a disorder resulting from vasoconstriction of the coronary arterial system. VSA typically involves the epicardial coronary arteries, but microvascular spasm, resulting from vasoconstriction of pre-arterioles and arterioles, has also been described, and both entities can co-exist. VSA typically occurs at rest and in a circadian pattern but may be triggered by catecholamine surges after exercise or stress. VSA occurs spontaneously, but it can also be induced through acetylcholine (ACh) provocation testing in the cardiac catheterisation laboratory. Epicardial VSA has been attributed to abnormal reactivity of the epicardial arteries to vasoconstrictive stimuli affecting the VSMCs. This is especially profound in the context of endothelial dysfunction—in a normally functioning endothelium, vasoactive agents, like ACh or histamine, lead to vasodilation through NO release, whereas, in dysfunctional endothelium, these agents lead to vasoconstriction through activation of VSMCs. In microvascular spasms, there is an increased local release of vasoconstrictive substances, associated with an increased susceptibility of VSMCs, or an abnormal activity of sympathetic tone. Cigarette smoking is the primary risk factor for VSA, with hypertension, diabetes and hypercholesterolemia being less common contributors.
4. Risk Factors and Associations with Other Cardiovascular and Systemic Conditions
All common cardiovascular risk factors, including smoking, age, hypertension and dyslipidaemia have been found to be associated with CMD, and are especially prevalent in patients with structural CMD. Not accidentally, these risk factors, in addition to diabetes, chronic kidney disease and obesity, are also associated with heart failure with preserved ejection fraction (HFpEF). In recent years, research has found links between HFpEF and CMD, although the cause-and-effect relationship between both entities has not yet been established. The PROMIS-HFpEF study confirmed the presence of CMD in 75% of HFpEF patients and its association with markers of HF severity, with other studies highlighting >5-fold risk of HFpEF hospitalization and a higher rate of MACE and mortality in patients with co-existent CMD. A cohort study by Rush et al. assessing the prevalence of endothelium-dependent and independent CMD in HFpEF has found a predominance of the latter type, which suggests that factors such as abnormal vascular remodelling, extrinsic vascular compression and microvascular rarefaction are more likely to be contributory than endothelial and vascular smooth muscle dysfunction, although endothelial dysfunction is associated with worse cardiovascular prognosis.
Importantly, the co-existence of CMD and obstructive coronary artery disease (CAD) in both chronic and acute scenarios must be recognised. Both CMD and CAD exert a synergistic effect on the myocardium, compounding myocardial ischaemia. For example, epicardial CAD leads to reduced blood flow distal to stenosis, resulting in abnormal microvascular remodelling and vasodilator capacity, hindering collateral flow formation and contributing to stress-induced ischaemia. Moreover, co-existent CMD may lead to an underestimation of the degree of severity of stenosis as measured by fractional flow reserve (FFR). The presence of CMD in patients with CAD may also explain why some patients do not derive symptomatic benefit from an apparently successful PCI. Importantly, raised index of microvascular resistance (IMR) values following revascularisation procedures despite an improvement in FFR were associated with adverse clinical outcomes. Coronary microvascular obstruction (CMVO), an acute variant of CMD seen in patients with ST-elevation myocardial infarction, is still poorly understood but is associated with increased risk of left ventricular (LV) remodelling, heart failure and death. Similarly, CMD was also found in >20% of cases of myocardial infarction with unobstructed coronary arteries (MINOCAs). It is unclear whether CMD has prognostic or causative implications or is a clinically insignificant bystander—in one stress perfusion cardiac magnetic resonance (CMR) study, abnormal stress perfusion was found in 63% of patients with MINOCA, but the areas corresponded with myocardial scar only in 75% of cases.
CMD presence has also been confirmed in studies of patients with hypertrophic cardiomyopathy (HCM), with evidence of impaired myocardial blood flow in both hypertrophied and non-hypertrophied myocardium and reduced CFR in the subendocardium due to presumed extravascular compression. Not only was severe CMD proven to exist in many asymptomatic HCM patients, but it has also been found to be important prognostically, with the degree of microvascular dysfunction being a strong and independent predictor of clinical deterioration and death. Research utilising contemporary non-invasive imaging has also found an association between CMD and infiltrative cardiomyopathies, such as cardiac sarcoidosis, amyloidosis and Anderson–Fabry disease, with evidence of CMD being an early marker of disease in the latter two, which might present an optimal window for early treatment in these conditions.
In addition, inflammatory conditions, such as systemic lupus erythematosus or rheumatoid arthritis have also been found to be associated with microvascular angina, and the higher prevalence of these conditions in postmenopausal women than men might at least partly explain sex differences in CMD. While the prevalence of CMD in women and men varies significantly between large cohort studies (34–66% in women and 14–60% in men), it is uniformly associated with an increased risk of MACE in both sexes. Interestingly, the commonest MACE seen in men is cardiovascular death, whereas heart failure-related hospital admission is most frequently seen in women, suggesting a different underlying pathophysiology. A study assessing stress CMR-derived Myocardial Perfusion Reserve Index (MPRI)’s association with traditional cardiovascular risk factors has found that men with CMD tend to fit an atherosclerotic risk profile more so than women. Indeed, a study comparing women suffering from angina with or without obstructive coronary disease has found that women with ANOCA are less likely to demonstrate conventional cardiovascular risk factors but more likely to report pre-menopausal migraines or rheumatic conditions. The relationship between menopause and the prevalence of CMD among women has been frequently reported. Studies have shown that oestrogen plays a protective role in coronary microvascular function by regulating endothelial and smooth muscle cells, indicating that changing oestrogen levels at the time of perimenopause may play an important role in CMD progression.
5. Diagnosis of Coronary Microvascular Dysfunction and Vasospastic Angina
5.1. Diagnostic Algorithm for Patients Presenting with ANOCA
Both the European Association of Percutaneous Coronary Interventions (EAPCI) Expert Consensus Document and the ESC guidelines suggest a step-wise diagnostic approach to a patient presenting with anginal chest pain. The initial evaluation includes a clinical review of patient symptoms, physical examination and an electrocardiogram (ECG), with the aim of assessing risk factors for coronary disease and excluding non-cardiac disease or other alternative explanations for presentation. If clinical suspicion of angina is maintained, a non-invasive assessment should follow. This includes computed tomography coronary angiography (CTCA) or functional stress imaging. These tests can be performed in any sequence, depending on local availability and patient factors. In patients with no significant obstructive disease and/or no regional reversible ischaemia on functional testing, who have a significant burden of disease persistent despite medical treatment, invasive functional coronary assessment is recommended (ESC Class I recommendation). This process is summarised in Figure 1. Functional coronary assessment may allow identification of the underlying endotype of ANOCA, enabling stratified medical therapy as well as targeting modifiable risk factors, leading to improvement in symptoms and quality of life. The clinical criteria for diagnosing both microvascular and vasospastic angina have been defined by the Coronary Vasomotor Disorders International Study (COVADIS) group and are presented in Table 1. These allow improvements in clinical diagnosis of affected patients and appropriate stratification of endotypes for subsequent research trials.
Diagnostic algorithm for ANOCA. ANOCA—angina with no obstructive coronary artery disease, CAD—coronary artery disease, CCS—chronic coronary syndrome, CMD—coronary microvascular dysfunction, CMR—cardiac magnetic resonance imaging, CTCA—computed tomography coronary angiography, ECG—electrocardiogram, INOCA—ischaemia with no obstructive coronary artery disease, SPECT—single photon emission computed tomography, PET—positron emission tomography.
