Introduction

Ischaemic heart disease remains the leading cause of death and lost life years in adults globally. Up to 40% of patients with a positive non-invasive stress test undergoing elective coronary angiography exhibit no evidence of obstructive epicardial coronary arteries. This frequency is notably higher among women (around 65%) compared to men (30–50%), and it is estimated to progressively increase in prevalence with the use of non-invasive imaging tests. In the context of the chronic coronary syndrome (CCS), non-obstructive coronary arteries encompass a broad spectrum of clinical phenotypes ranging from angina with non-obstructive coronary arteries (ANOCA) to ischaemia with non-obstructive coronary arteries (INOCA). The latter stems from the mismatch between myocardial oxygen demands and blood supply and it is demonstrable in up to 28% of patients with angina symptoms and functionally non-obstructive coronary artery disease (CAD).

INOCA is not a benign condition and has a relevant influence on patients’ lives, affecting their home and social lives with >70% reporting an impact on mental health. Furthermore, an increased risk for major adverse outcomes in this population is reported, predominantly represented by hospitalization for recurrent angina, heart failure or both. Clinical research in these scenarios has recently garnered significant interest, leading to improved definition, prognostic stratification and pathophysiological classification to prevent misdiagnosis and under treatment. Large vessel coronary spasms, also known as vasospastic angina (VSA), are responsible for a significant proportion of INOCA cases. Some reports suggest that coronary vasospasm is responsible for up to 40% of cases of stable angina with non-obstructive coronaries. One study reported 54% of 304 patients experiencing angina to have <50% stenosis, with vasospasm elicited in 66% of these using acetylcholine (ACh).

Coronary spasm can also occur within the microvasculature and is referred to as microvascular spasm, presumably occurring at the level of the pre-arteriolar and arteriolar vessels. It should be differentiated from VSA based on the underlying pathophysiological mechanism and the involved vascular compartment. Coronary microcirculation dysfunction (CMD), which is a reduced vasodilatory ability of coronary microcirculation, is the other major endotype of INOCA. The present narrative review provides an overview of VSA summarizing the current available data on pathophysiology, diagnostic algorithm and management strategies according to the latest research evidence.

Pathophysiology and risk factors of VSA

Chest pain secondary to VSA typically occurs at rest given the fact that it is not associated with increased oxygen demand but it may also be induced by exertion during a ‘hot phase’ in which the exercise-related catecholamine release may trigger an angina episode. It might be characterized by a circadian pattern (typically awakening in the early hours of the morning) and be suddenly precipitated by stress or hyperventilation after a quiescent period (cold phase). A diurnal circadian rhythm in VSA symptoms has been described since the late 1950s. A significantly higher number of nocturnal or early morning attacks are reported compared to the rest of the day, even though it is often not clinically apparent. A potential mechanism underlying the cyclic symptoms occurrence is the circadian variation in the tone of coronaries. VSA is related to the epicardial segments’ hyperreactivity to vasoconstrictive stimuli, which occurs spontaneously but may also be induced to establish the diagnosis. The abnormal response of the vascular smooth muscle cells (VSMCs) is entrenched by the process of inflammation and fibrocellular proliferation. VSMC contraction is initiated by Ca²⁺/calmodulin-activated myosin light chains (MLC) kinase which leads to phosphorylation of the regulatory MLC. Both the increased Ca²⁺ inflow and Ca²⁺ hypersensitivity of contractile proteins in the VSMCs have been proposed to represent the fundamental mechanism responsible for coronary artery hypercontraction. The role of endothelium in the physiological regulation of coronary vascular tone is fundamental, mainly through the release of vasodilators, such as nitric oxide (NO). Accordingly, vasodilation may be impaired by significant endothelial damage, thus favouring spasms in response to vasoconstrictor stimuli. Several vasoactive stimuli (e.g. ACh, histamine, serotonin) cause vasodilation through NO release by the endothelium, but, at the same time, they may cause vasoconstriction through direct VSMC stimulation. In the case of endothelial dysfunction, their release in the vessel wall can lead to constriction.

Both genetic and nonbiological factors contribute to the pathophysiology of vasospasm. Genetic factors may encompass reduced endothelial NO production, upregulation of alpha-adrenergic receptors and inappropriate platelet activation increasing endothelial production of vasoconstrictive factors, resulting in vasoconstriction. Low-grade inflammation, an altered autonomic nervous system response and oxidative stress (OS) may also be genetically influenced contributors (Figure 1). In particular, OS activates perivascular cells, macrophages and fibroblasts, which induces the production and release of radical oxygen species (ROS). This triggers VSMC proliferation and migration with subsequent induction of adhesion molecules. Activation of protein kinase C also occurs and inflammatory processes are activated at the level of gene transcription by upregulation of the transcription nuclear factor kB located in the cytoplasm of lymphocytes, monocytes, endothelial cells and VSMCs, thus activating interleukins, interferon, tumour necrosis factor-α and adhesion molecules. Cigarette smoking has been reported as the most important risk factor for VSA, unlike hypertension and diabetes, and the relationship with dyslipidaemia remains unclear. Association of VSA with migraine and Raynaud’s phenomenon has been reported.

Figure 1. Risk factors and pathophysiology of vasospasm.
Ca²⁺, calcium; NO, nitric oxide; OS, oxidative stress; VSMCs, vascular smooth muscle cells.

Microvascular spasm

The diagnosis of microvascular spasm is based upon the provocative spasm testing (see below), where ACh provokes chest pain and ischaemic electrocardiogram (ECG) changes in the absence of large vessel spasm, that is, a presumptive conclusion that the microvasculature is responsible for the provoked myocardial ischaemia. Based on the diagnostic criteria, microvascular spasm is diagnosed in the absence of coronary artery (large vessel) spasm although potentially the two entities may coexist. However, whether the extensive published literature in patients with VSA (i.e. large vessel spasm) applies to patients with microvascular spasm is unknown and until further research is available, this established literature on large vessel spasm should be considered only in reference to the latter.

With this important consideration, microvascular spasm is attributed to an increased release of vasoconstrictive substances, associated with an increased susceptibility of VSMCs or an abnormal activity of sympathetic tone. Furthermore, until recently, there have been no therapies evaluated for microvascular spasms and the optimal management strategy for this condition necessitates further studies. Microvascular spasms and CMD are conventionally grouped as causes of microvascular angina to distinguish the involved distal segments from larger vessels.

Prognosis of coronary artery spasm

Timely recognition of symptoms and suspicion of coronary artery spasm may prevent the occurrence of adverse events such as sudden cardiac death (SCD), MI and syncope. Patients suffering from VSA frequently experience recurrent angina during follow-up, ranging from 10% to 53%, a characteristic in line with the results of the CorMicA (CORonary Microvascular Angina) trial.

Patients with epicardial and microvascular spasms have an impaired prognosis compared to individuals without spasms, even though the prevalence of cardiovascular mortality seems low between the two entities. Conversely, nonfatal-MI significantly occurs more often in epicardial spasm patients (4%) compared with the microvascular spasm group (0.7%) and ANOCA patients without coronary artery spasm. In patients with VSA, more than half of all reported major adverse cardiovascular events (MACE), including cardiac death, nonfatal-MI, unstable angina and hospitalization, is driven by hospitalization for unstable angina ranging from 52% to 90% of MACE.

Provocative testing

Gold-standard testing for coronary vasospasm uses angiography and spasm-inducing pharmacological stimuli such as ACh and ergonovine, both of which have a high sensitivity and specificity to confirm the presence of epicardial vasospasm after exclusion of flow-limiting obstructive CAD and other forms of microvascular dysfunction. ACh acts on the muscarinic cholinergic receptors and ergonovine acts on the serotonin receptors in VSMCs. Spasms caused by ACh have been reported to be distal and diffuse, whereas those caused by ergonovine are proximal and focal. The muscarinic ACh receptors (mAChRs) are important for vascular homeostasis. Their activation at the endothelial level leads to NO-mediated vasodilatation, whereas activation of mAChRs on the VSMCs causes vasoconstriction. Depending on the integrity of the endothelium and the reactivity of the VSMCs, the net effect of ACh administration could be vasodilatation or vasoconstriction. Due to its short half-life, ACh can be administered directly into the coronary arteries. According to the 2019 European Society of Cardiology (ESC) guidelines on CCS, ACh provocative testing may be considered to assess coronary spasm (IIa recommendation) in patients with suspected VSA. It is characterized by high sensitivity and specificity (90% and 99%, respectively). ACh use is preferred over ergonovine because the latter is more likely to provoke extended vasospasm. Alternatively, non-pharmacological stimuli include hyperventilation and cold pressor testing, albeit characterized by low sensitivity. Other simultaneous assessment modalities include symptom monitoring and electrocardiography.

A positive provocation test comprises reproduction of usual angina, ischaemic ECG changes (ST-segment depression or elevation ⩾0.1 mV or new negative U waves) in at least two contiguous leads, and ⩾90% vasoconstriction. Microvascular spasm is characterized by a lumen reduction <90%, symptoms and ECG changes usually occur with a lower dose of ACh. However, there is a lack of a standardized recommended practical ACh protocol and instead, varies according to different centre’s experiences.

Intracoronary (IC) ACh provocative testing was first established in Japan. Rapid high-dose ACh bolus infusions have been validated and detailed in VSA guidelines. The procedure consists of sequential injections of 20, 50 or 100 μg of ACh in solution in 37°C physiological saline (adjusted to obtain 5 mL solution volume for each quantity of ACh) into the left coronary artery over a period of 20 s. Coronary angiography is performed 1 min after the start of each injection. A reduced dosage (20 or 50 μg, each in 5 mL solution) over a period of 20 s is recommended to assess the right coronary artery (RCA). After the ACh bolus, IC nitroglycerin is administered to assess basal epicardial artery tone (Figure 2).

Figure 2. Validated original provocative ACh testing for VSA assessment (high-dose ACh boluses) and endothelial function assessment test (low-dose ACh boluses). Several alternatives to the original ACh test have been adopted in recent years, although not validated as the standard protocol.
ACh, acetylcholine; AF, atrial fibrillation; AV, atrioventricular; IC, intracoronary; LCA, left coronary arteries; RCA, right coronary artery; RV, right ventricle; VSA: vasospastic angina; µg, micrograms.

In recent years, several alternatives to the original test have been adopted in different centres, although not validated as the standard protocol, such as hybrid approaches using high-dose ACh administered over 2–3 min (slow bolus) and not including the 100 μg infusion in case of significant bradycardia. Considering the very short half-life of ACh, these methods could result in reduced ACh plasma concentrations compared to the conventional 20-s rapid-bolus administration, and subsequently, uncertain diagnostic assessment.

On the other hand, endothelial function studies use low-dose ACh infusion (generally 10−6 mol/L = 0.18 µg/min and 10−5 mol/L = 1.8 µg/min) administered over 2–3 min. In this case, vasoconstriction is representative of endothelial dysfunction, whereas coronary vasodilation corresponds to intact endothelium-dependent vasodilation (Figure 2).

Complication rates associated with ACh use are quite low and it encompasses transient atrioventricular block (4.2%), sinus block (0.8%) and paroxysmal atrial fibrillation (AF) (3.5%), preventable by insertion of a temporary pacemaker prior to ACh injection of the RCA. However, some operators prefer to avoid RCA testing or administer the ACh slower, leading to the unreliability of the findings.

In a recent study by Montone et al., a previous history of paroxysmal AF, moderate-to-severe left ventricular diastolic dysfunction and higher QT dispersion at baseline ECG have been demonstrated to be the only predictors of complications during the ACh provocative test. At a medium- to long-term follow-up, the occurrence of complications during the ACh test was not associated with a worse prognosis.

The detection of the mixed forms including both spasm disorders (epicardial and microvascular) is currently limited to cases in which microvascular spasm occurs at lower ACh doses than epicardial spasm. Thus, the coexisting mechanisms may be underdiagnosed. The concept of rechallenging coronary arteries (ACh rechallenge) with ACh immediately after IC administration of an antivasospastic substance has been proposed to detect coexisting different spasm endotypes. In a recent study, to assess the reinducibility of microvascular and epicardial spasm, ACh rechallenge was systematically performed 3 min after IC injection of nitroglycerin by readministration of the spasm provocation dose into the previously spastic coronary artery. ACh rechallenge may unmask combined spasm disorders. In 48% of patients with epicardial spasms, ACh rechallenge revealed coexisting nitroglycerin-persistent microvascular spasms, demonstrating that nitroglycerin is much more effective in preventing epicardial spasms than microvascular spasms. These findings require further investigation.

Diagnosis

International standardized criteria have been established by the Coronary Vasomotion Disorders International Study (COVADIS) group. For a definitive diagnosis of VSA, the following criteria are required: (1) nitrate-responsive angina symptoms with at least one of the following (a) rest angina, (b) diurnal variation in symptoms, (c) hyperventilation-induced angina or (d) symptom improvement with calcium-channel blockers (CCBs); (2) transient ischaemic ECG changes during spontaneous symptoms; (3) documented coronary artery spasm (>90% constriction) occurring spontaneously or in response to provocation testing (with pain and ischaemic ECG changes). If only two of these criteria are met, the patient is diagnosed with ‘suspected VSA’.

Evidence supports sex-related differences in the vasomotor response to provocative testing, with a higher prevalence of epicardial spasms among men and of microvascular spasms among women. Moreover, ethnic differences exist as a predisposing factor. Several studies have reported a higher prevalence of VSA in Asian populations. History of associated symptoms such as migraine, Raynaud’s phenomenon and Kounis syndrome may increase suspicion of a diagnosis of VSA.