Coronary artery spasm (CAS) is a well-established mechanism contributing to a wide spectrum of acute and chronic coronary syndromes, ranging from angina pectoris to myocardial infarction and sudden cardiac death [1]. Although CAS is a known cause of coronary syndromes, its clinical identification is challenging. Guideline-recommended invasive tests are complex and risky, involving catheterization, radiation exposure, nephrotoxic contrast agents, and procedural risks [2–4]. Consequently, CAS is often underdiagnosed and undertreated [5], which may lead to inappropriate interventions. For example, coronary stenting in the context of CAS is generally ineffective and can even be harmful [6], while β-blockers may exacerbate CAS and worsen symptoms [7]. In this review, we examine the recent literature and propose a practical, stepwise diagnostic approach—beginning with clinical history, progressing through standard functional testing, and culminating in targeted provocation testing—to improve the recognition and management of CAS.

Epidemiologic data show wide differences in the prevalence of CAS in different countries. The frequency of CAS seems to be greater in Asian than in Western populations, in females compared to males, and the prevalence tends to decrease after the age of 70 years. However, it is important to emphasize that CAS is found everywhere, at all ages, and in all populations, when it is appropriately looked for [1].

A patient’s clinical history can be highly suggestive of CAS when angina presents with four key features: (1) occurrence at rest, particularly at night; (2) a diurnal pattern, often more pronounced in the early morning hours; (3) worsening or lack of control with β-blocker therapy; and (4) precipitation by hyperventilation. Another important clue is the presence of angina with non-obstructive coronary arteries (ANOCA), although CAS can occur at any level of underlying organic coronary artery disease (CAD) [8].

A powerful indicator is the recurrence of angina following successful coronary stenting, especially when angiography confirms patency of the stented segment. CAS should also be considered in cases of syncope or cardiac arrest, particularly when preceded by chest pain and in the absence of obstructive CAD [9].

Although the mechanisms are complex, heterogeneous, and partially unknown, the clinical recognition of drug-induced CAS is easy, and the therapy consists of the immediate withdrawal of the suspected drug and the start of a cardioprotective treatment with calcium-channel blockers and nitrates, avoiding β-blockers that may exacerbate spasm through blockade of β₂-vasodilation, leaving unopposed the α₁ vasoconstriction. Particular attention should be given to the occurrence of CAS in clinical settings far removed from traditional cardiology practice. In these contexts, CAS may be triggered by drugs whose rare but potentially life-threatening adverse effects include CAS (Table 1). Such reactions have been reported with medications commonly used in various specialties:

Gynecology and obstetrics, such as ergot-derivatives for uterine bleeding [10] or misoprostol to facilitate hysteroscopy [11];

The broad range of triggers reflects the complexity of coronary tone regulation, primarily involving α₁-adrenergic vasoconstrictive receptors, and to a lesser extent, histamine H1 receptors.

Drug-induced CAS can occur through four main mechanisms affecting endothelial cells, vascular smooth muscle cells, autonomic neurons, and inflammatory cells:

1.

Endothelial cells: Endothelial dysfunction reduces nitric oxide-mediated vasodilation and enhances vasoconstriction.

Despite the complex and often heterogeneous underlying mechanisms, clinical recognition is typically straightforward if one thinks of it. Management involves stopping the suspected drug and starting therapy with calcium channel blockers and nitrates. Avoid β-blockers, as they can worsen CAS by blocking β₂-mediated vasodilation and leaving α₁-mediated vasoconstriction unopposed.

CAS can be revealed during functional testing in two distinct scenarios: either as an incidental finding during routine ischemia testing for CAD, or as the result of targeted provocation testing when CAS is clinically suspected.

Although lifestyle modifications and behavioural and pharmacological control of modifiable risk factors are crucial in patients with obstructive CAD, these have limited implications for the control of CAS and the prevention of CAS-related cardiac events. Clinical studies have shown that only smoking and the use of alcohol show a significant association with the occurrence of CAS. Indeed, smoking and alcohol use have also occasionally been associated with triggering CAS. Thus, avoiding smoking and alcohol abuse should be recommended to all patients with CAS [3, 9].

The diagnosis of coronary vasospasm identifies a specific endotype within the heterogeneous INOCA (ischemia with non-obstructive coronary arteries) population, representing a directly treatable target. Current European Society of Cardiology guidelines [2] recommend calcium channel blockers as first-line therapy, followed by nitrates, while advising against β-blockers. These may paradoxically exacerbate vasospasm by allowing unopposed α-adrenergic vasoconstriction without the counterbalancing β₁-mediated vasodilation. Importantly, stenting of coronary stenoses is not recommended, as symptom recurrence frequently occurs even after technically successful percutaneous coronary intervention (PCI), suggesting that the underlying vasomotor dysfunction rather than fixed stenosis drives symptoms.

CAS should always be considered in the presence of a suggestive clinical history and a mismatch between coronary anatomy and functional findings. The diagnosis is particularly likely when myocardial ischemia is precipitated by drugs with known vasospastic potential, including recreational substances such as cocaine, or medications used in oncology (e.g., capecitabine), psychiatry (e.g., propranolol), neurology (e.g., triptans), pneumonology (e.g., methacholine), rheumatology (e.g., aspirin), or gynecology (e.g., misoprostol). Even when not specifically sought, CAS may be incidentally detected during evaluation for CAD, particularly in patients exhibiting ST-segment elevation during the recovery phase—after a negative peak stress—of exercise, dipyridamole, or dobutamine stress testing.

If CAS remains clinically suspected despite negative findings on ambulatory ECG monitoring and standard stress testing, a provocative test in ANOCA with ergonovine or hyperventilation may be performed in the echocardiography laboratory. In this context, the induction of an RWMA serves as both a diagnostic endpoint and a surrogate marker of epicardial CAS.

In patients with persistent symptoms and ANOCA, where the diagnosis remains elusive, a multi-stress, multi-marker approach can help differentiate microvascular etiologies. An abnormal CFV reserve < 2.0 during vasodilator stress indicates an underlying structural (organic) coronary microvascular disease, whereas a hyperventilation test with paradoxical reduction in CFV despite an increase in rate-pressure product is indicative of vasospastic coronary microvascular disease.

Overall, the proposed noninvasive approach holds significant potential to reduce costs, risks, and environmental impact compared to a catheterization lab-driven strategy, which carries inherent harms such as invasive procedures, coronary artery manipulation, intracoronary drug injection, nephrotoxic iodine contrast administration, and radiation exposure. Furthermore, the noninvasive method expands the diagnostic domain by overcoming the logistical and practical constraints of invasive techniques while enabling serial patient assessments to monitor therapeutic effects and disease progression. Large-scale multicenter validation is now required before clinical adoption, and this is currently underway as part of the SESPASM subproject within the Stress Echo 2030 study.