Vasospastic angina: Pathophysiology, diagnosis, and emerging therapeutic approaches

Abstract

Vasospastic angina (VSA) is a distinct endotype of ischemia with non-obstructive coronary arteries characterized by transient coronary artery spasm and myocardial ischemia in the absence of significant fixed stenosis. It is an underdiagnosed and often challenging condition that can lead to recurrent angina, myocardial infarction, and sudden cardiac death. VSA arises from a multifactorial interplay of endothelial dysfunction, vascular smooth muscle hyperreactivity, inflammation, and autonomic dysregulation. While calcium channel blockers and nitrates remain the mainstay of therapy, there is a growing body of evidence in the use of novel and emerging treatments including Rho-kinase inhibitors, endothelin receptor antagonists, and anti-inflammatory agents for refractory cases. Diagnostic evaluation relies on clinical features and, when necessary, invasive coronary pharmacological provocation testing. This narrative review examines the current understanding of VSA, discusses current international guideline-based diagnostic and therapeutic strategies, and highlights novel and investigational approaches that may broaden the treatment armamentarium against it.

Key Words: Vasospastic angina; Coronary vasospasm; Ischemia with non-obstructive coronary arteries; Coronary microvascular dysfunction; Provocation testing

Core Tip: Vasospastic angina (VSA) is an under-recognized but clinically significant cause of myocardial ischemia, arrhythmia, and sudden cardiac death in patients without obstructive coronary artery disease. This narrative review provides an up-to-date revision of VSA pathophysiology, diagnostic strategies including provocation testing, and current guideline-recommended management. It also highlights promising emerging therapies—such as Rho-kinase inhibitors, endothelin receptor antagonists, and immunomodulatory agents—offering new hope for patients with refractory symptoms. Recognizing and treating VSA proactively can reduce adverse events and improve quality of life in this high-risk yet often overlooked condition.

INTRODUCTION

Angina is the prototypical symptom of ischemic heart disease, which affects almost 200 million patients worldwide[1]. Ischemia with non-obstructive coronary arteries (INOCA) refers to the presence of anginal symptoms in the presence of objectively demonstrable ischemia in the absence of significant coronary artery disease (typically defined as < 50% stenosis on angiography)[2]. INOCA is associated with major adverse cardiac events (MACE), repeated admission for unnecessary invasive procedures, and diminished quality of life[3-6]. It is prevalent, with an estimated 3-4 million patients (predominantly women) in the United States alone. Up to around two-thirds of patients undergoing invasive coronary angiography for angina will have no significant coronary artery disease. Of these, up to a quarter of patients will have documented ischaemia and more than half of those patients will have microvascular angina and/or vasospastic angina[2,7,8]. These patients often have recurrent chest pain and repeated healthcare visits yet historically have been under-diagnosed and undertreated[9].

Multiple mechanisms (or endotypes) can cause INOCA. The two major endotypes are coronary microvascular dysfunction (CMD) and coronary vasospasm, and multiple mechanisms can co-exist[10]. Coronary vasospasm is a major cause of myocardial ischemia in INOCA and can cause not only angina, but also myocardial infarction, arrhythmias, and sudden cardiac death in the absence of fixed lesions[11-13] (Figure 1). This narrative review will focus on the novel therapies for vasospastic angina (VSA) and to revise on its current management based on international guidelines, as well as its pathophysiology, diagnosis, and future directions in this evolving field.

Figure 1 A 57-year-old patient with vasospastic angina. A: Dramatic ST-elevation in the inferolateral leads associated with a complete heart block; B: Reversion back to his baseline electrocardiogram within 5 minutes. ECG: Electrocardiogram.

DEFINITION, EPIDEMIOLOGY, AND RISK FACTORS OF VASOSPASTIC ANGINA

Coronary vasospasm refers to a transient, intense constriction of a coronary artery (usually > 90%) sufficient to cause myocardial ischemia. It most classically manifests as VSA – episodic angina at rest which may exhibit a circadian pattern and can happen at rest, often precipitated by hyperventilation; with transient ischemic electrocardiogram (ECG) changes, often ST-segment elevation, and was originally described by Dr Myron Prinzmetal in 1959[14,15]. Work in the 1970s established myocardial ischemia could result from dynamic coronary narrowing even in angiographically normal vessels[16,17]. Episodes are usually relieved promptly with nitroglycerin and suppressed with calcium channel blockers (CCB)[14]. Vasospasm may affect the epicardial coronary arteries which in a focal or diffuse manner, and can involve multiple coronary territories, or smaller intramyocardial arterioles (microvascular spasm), or both[18,19].

The true prevalence of coronary spasm is difficult to ascertain because it requires provocative testing for confirmation[20]. A prospective study of 187 patients with angina and non-obstructive coronaries, found 68% had a positive acetylcholine provocation test for vasospastic angina however more than half of these patients have associated microvascular abnormalities[7]. Moreover, there seems to be a higher incidence of vasospastic angina in Japanese and Taiwanese patients compared with Caucasian patients, and multi-territory spasm being more common[21-23]. A recent meta-analysis of over 14000 patients with no obstructive coronary artery disease reported that the overall prevalence of CMD was 41%, with women significantly more likely to be affected than men (RR: 1.45; 95%CI: 1.11-1.90). In contrast, there was no statistically significant difference in the overall prevalence of coronary vasospasm—which included both epicardial and microvascular subtypes—between genders (28% in women vs 25% in men; P = 0.654)[20]. However, a separate meta-analysis specifically evaluating spasm subtypes reported that microvascular spasm was more common in women (64% vs 36%), whereas epicardial spasm was more prevalent in men (61% vs 39%)[24]. Furthermore, a large retrospective Korean study involving over 52000 patients hospitalized for VSA reported that approximately 75% of hospitalizations occur in patients aged between 40-69 years. Interestingly, advancing age was independently associated with a higher risk of rehospitalization[25].

Cigarette smoking is the most well-established risk factor for coronary artery spasm. Smoking not only correlates with the incidence of vasospastic angina but can acutely trigger spasm episodes via catecholamine-mediated effects on coronary tone[26]. Alcohol (especially binge drinking) is another known risk factor and precipitant – episodes of vasospastic angina can be triggered by heavy drinking or occur during alcohol withdrawal, and avoidance of alcohol excess is advised[27,28]. Emotional stress and hyperventilation can also precipitate spasm in some patients[29]. Control of traditional cardiovascular risk factors like hypertension, hyperlipidemia, and diabetes have limited implications for controlling vasospastic angina and do not significantly affect its long-term prognosis. Nonetheless, general risk factor optimization is recommended for overall cardiovascular health[28,30].

Certain environmental triggers such as exposure to cold air or a cold environment is a known precipitant for VSA. Population data show a clear winter/spring excess of vasospastic events, and cold-pressor provocation reproduces spasm in up to two-thirds of susceptible patients[31]. Several medications and recreational drugs can provoke spasm, including ergot alkaloids, non-selective blockers, sympathomimetic agents, parasympathomimetics, and psychoactive stimulants such as cocaine, amphetamines and marijuana[29].

A genetic predisposition to coronary vasospasm has been increasingly recognized, supported by both familial clustering[32] and the higher prevalence of vasospastic angina in East Asian populations. Several genetic polymorphisms have been implicated, most notably variants in the NOS3 gene which reduce endothelial nitric oxide production[33,34]. Additionally, mutations in genes involved in vascular smooth muscle contractility—such as Rho-associated kinase 2, variant aldehyde dehydrogenase 2 (ALDH2*2), and the East Asian-specific RNF213 variant—have also been associated with heightened susceptibility to coronary spasm[35-37].

PATHOPHYSIOLOGY

VSA is characterized by transient coronary artery spasm resulting in myocardial ischemia without significant fixed stenosis. The underlying pathophysiology is multifactorial, with key contributions from endothelial dysfunction, hyperreactivity of vascular smooth muscle cells, inflammatory processes, and autonomic dysregulation. The interplay of these mechanisms promotes exaggerated vasoconstrictive responses (Figure 2).

Figure 2 Vasospastic angina results from a transient coronary artery spasm due the interplay of endothelial dysfunction, vascular smooth muscle hyperreactivity, inflammation, and autonomic imbalance. These factors collectively lower the threshold for inappropriate coronary vasoconstriction. NO: Nitric oxide; ET-1: Endothelin-1; 5-HT: 5-hydroxytryptamine (serotonin); H: Histamine.

Endothelial dysfunction

A central contributor to coronary spasm is endothelial dysfunction. Normally, endothelial release of nitric oxide (NO) causes vasodilation and inhibits smooth muscle contraction. In VSA, this pathway is impaired, resulting in deficient NO activity in the coronary arteries prone to spasm[38,39]. The loss of NO’s protective effect permits unchecked vasoconstriction and explains why endothelium-dependent vasodilators (e.g. acetylcholine) paradoxically provoke intense constriction in spastic segments. Clinically, intracoronary acetylcholine (ACh) provocation induces focal coronary spasm in susceptible patients, a diagnostic phenomenon that underscores the role of endothelial dysfunction in VSA[40]. Genetic evidence further supports this mechanism – a common polymorphism in the endothelial NO synthase gene (T-786C) has been associated with increased susceptibility to coronary artery spasm[41]. Endothelial dysfunction also shifts the balance toward vasoconstrictors; for instance, patients with VSA have significantly elevated circulating endothelin-1 (ET-1) levels, a potent endothelium-derived vasoconstrictor that can precipitate coronary spasm[42,43]. This combination of reduced NO (vasodilator) activity and excess vasoconstrictor influence creates a milieu favoring inappropriate coronary vasoconstriction.

Vascular smooth muscle hyperreactivity

The vascular smooth muscle cells (VSMCs) in VSA are hypercontractile and overly sensitive to vasoconstrictive stimuli. Multiple vasoconstrictors (such as ET-1, serotonin, and histamine) may contribute to spasm by triggering exaggerated contraction of the smooth muscle[44,45]. A key intracellular pathway involves RhoA/Rho-kinase activation, which heightens smooth muscle contractility by inhibiting myosin light chain phosphatase and increasing myosin light chain phosphorylation. Upregulation of Rho-kinase activity has been strongly implicated in the pathogenesis of vasospasm[46]. Notably, pharmacologic blockade of Rho-kinase has demonstrated remarkable efficacy in abolishing coronary spasms. In patients with vasospastic angina, intracoronary infusion of the Rho-kinase inhibitor fasudil causes prompt resolution of provoked coronary spasm[46,47], highlighting the central role of this pathway in mediating hypercontraction. These findings from basic and clinical research indicate that an intrinsic hypercontractile tendency of the vascular smooth muscle—due in part to enhanced calcium sensitivity from the Rho-kinase signaling cascade—is a critical determinant of coronary vasospasm.

Inflammation, atherosclerosis, and other factors

Chronic low-grade inflammation and oxidative stress are thought to predispose patients to VSA by aggravating both endothelial dysfunction and smooth muscle reactivity. Individuals with VSA often have elevated inflammatory markers; for example, high-sensitivity C-reactive protein levels tend to be higher in VSA patients even without overt coronary stenosis. Increased ¹⁸F-Fluorodeoxyglucose uptake has also been demonstrated in pericoronary adipose tissue and myocardium in VSA patients[48]. Such findings suggest that systemic inflammation may lower the threshold for vasospasm, possibly by impairing endothelial NO production or by enhancing local release of vasoconstrictors[49]. Additionally, autonomic nervous system imbalances can trigger spasm. Heightened vagal tone at night or during rest may facilitate ACh-mediated vasospasm, whereas adrenergic surges in the morning or during stress may facilitate attacks in susceptible individuals[50-52].

Although coronary vasospasm has traditionally been considered a functional disorder, accumulating evidence from intravascular imaging indicates that vasospasm often localizes to sites of underlying atherosclerosis, even in patients without significant obstructive coronary artery disease. Optical coherence tomography (OCT) studies have shown that patients with vasospasm exhibit significantly higher lipid indices, and a greater prevalence of vulnerable plaques compared to those without vasospasm (66% vs 38%, P = 0.04)[53]. In one study, plaque was detected in 98.8% of OCT-assessed spasm sites, with OCT-defined erosion observed in 26% of cases[54]. Complementing these findings, intravascular ultrasound has demonstrated that all focal spasm sites in patients with variant angina showed atherosclerotic plaques with a high plaque burden and a predominance of negative arterial remodeling[55]. These imaging findings highlight endothelial dysfunction as a common driver of both vasospasm and atherosclerotic plaque evolution, revealing how subclinical atherosclerosis often co-localizes with VSA. Consequently, therapies that restore endothelial function and stabilize plaques, such as statins, offer a sound mechanistic rationale for improving outcomes in VSA[56].

DIAGNOSIS

Diagnostic criteria

To standardize the diagnosis of vasospastic angina, the international Coronary Vasomotion Disorders International Study Group (COVADIS) proposed a formal diagnostic criteria in 2015[14]. These criteria require a combination of classic clinical features of vasospastic angina, demonstration of myocardial ischemia during spontaneous episodes, and demonstration of coronary artery spasm (> 90% constriction) as summarized in Table 1 and classifies it between “definite VSA” or “suspected VSA”. In essence, VSA can be diagnosed definitively if a patient experiences nitrate-responsive angina together with either transient ischemic ECG changes during the episode or evidence of coronary artery spasm on angiography. If the classic clinical history is present but objective documentation (ECG or angiographic spasm) is lacking, the syndrome may be labeled as “suspected VSA”. Given the transient nature of the ECG changes, the European Society of Cardiology (ESC) 2024 guidelines for chronic coronary syndrome recommended that resting ECGs should be done during episodes of angina (Class I, level C evidence) and ambulatory ST-segment monitoring be considered in patients with frequent symptoms (Class IIa, Level B evidence)[8].

Table 1 Coronary vasomotion disorders international study group criteria for diagnosis of vasospastic angina.

COVADIS criteria for diagnosing vasospastic angina[14]
1 Nitrate responsive angina during spontaneous episode, with at least one of the following:
Rest angina – especially between night and early morning
Marked diurnal variation in exercise tolerance – reduced in morning
Hyperventilation can precipitate an episode
Calcium-channel blockers (but not -blockers) suppress episodes
2 Transient ischemic ECG changes during spontaneous episode, including any of the following in at least two contiguous leads:
ST segment elevation 0.1 mV
ST segment depression 0.1 mV
New negative U waves
3 Coronary artery spasm on invasive coronary angiography, defined as transient total or subtotal coronary artery occlusion (> 90% constriction) with angina and ischemic ECG changes, either spontaneously or in response to a provocative stimulus (typically acetylcholine, ergot, or hyperventilation)
Definite VSA: Criteria 1 + either criterion 2 or criteria 3 are fulfilled
Suspected VSA: Criteria 1 fulfilled but Criteria 2 is equivocal or unavailable, and Criteria 3 is equivocal

Coronary Vasomotion Disorders International Study Group criteria for diagnosing vasospastic angina. COVADIS: Coronary Vasomotion Disorders International Study Group; ECG: Electrocardiogram.

Invasive provocation testing: The gold standard for provocation testing of coronary vasospasm involves administering a provocative agent during invasive coronary angiography particularly when spontaneous episodes are not documented[14,57]. Pharmacological agents commonly used include ACh and ergonovine. Both have high sensitivity and specificity[58-60]. ACh acts on muscarinic cholinergic receptors while ergonovine on the serotonin receptors in VSMCs[3]. A positive provocation test is characterized by reproduction of usual anginal symptoms, ischemic ECG changes, and 90% coronary vasoconstriction during angiography (Figure 3). The provocation test is considered equivocal if not all three of these components were elicited[14]. The overall procedural risk is low. Significant complications have been reported as < 1% in contemporary practice which is similar to other invasive coronary procedures[61]. Data on 1244 VSA patients in a Japanese multicenter registry demonstrated that the overall incidence of arrhythmic complications during provocative testing was 6.8% but was comparable to those occurring during spontaneous VSA episodes, and did not correlate with long-term adverse outcomes[62]. The COVADIS group also sets recommendations for when to do provocative testing (Table 2)[14]. The ESC 2024 guidelines for chronic coronary syndrome recommended invasive functional testing for patients with suspected VSA and repetitive episodes to both confirm the diagnosis and determine the severity of underlying atherosclerotic disease (Class I, level C evidence)[8], while the Japanese Circulation Society (JCS) 2023 guidelines provide a Class IIa (Level C) recommendation for performing pharmacological coronary spasm provocation testing during elective coronary angiography in patients with angina and demonstrated myocardial ischemia but no significant stenosis of the epicardial coronary arteries[63].

Figure 3 Positive acetylcholine provocation testing involving the mid-left anterior descending artery. A: Baseline angiography; B: Significant vasospasm predominantly in the mid-left anterior descending artery region (orange arrow) with 50 mg of intracoronary acetylcholine; C: Reversal of vasospasm following 200 mg of intracoronary glyceryl trinitrate.

Table 2 Recommendations for provocative testing.

COVADIS recommendations for provocative testing[14]
Class I (strong indications)
History suspicious of VSA without documented episode, especially if:
Nitrate-responsive rest angina and/or
Marked diurnal variation in symptom onset/exercise tolerance, and/or
Rest angina without obstructive coronary artery disease
Unresponsive to empiric therapy
Acute coronary syndrome presentation in the absence of a culprit lesion
Unexplained resuscitated cardiac arrest
Unexplained syncope with antecedent chest pain
Recurrent rest angina following angiographically successful PCI
Class IIa (good indications)
Invasive testing for non-invasive diagnosed patients unresponsive to drug therapy
Documented spontaneous episode of VSA to determine the ‘site and mode’ of spasm
Class IIb (controversial indications)
Invasive testing for non-invasive diagnosed patients responsive to drug therapy
Class III (contraindications)
Emergent acute coronary syndrome
Severe fixed multi-vessel coronary artery disease including left main stenosis
Severe myocardial dysfunction (Class IIb if symptoms suggestive of vasospasm)
Patients without any symptoms suggestive of VSA

Indications for provocative coronary artery spasm testing. Adapted from Coronary Vasomotion Disorders International Study group. COVADIS: Coronary Vasomotion Disorders International Study Group; VSA: Vasospastic angina.

MANAGEMENT

Management of VSA includes both pharmacologic and non-pharmacologic approaches, focusing on preventing angina episodes and improving patient quality of life and outcomes. While non-pharmacological management is integral to managing VSA – such as stress management, smoking cessation, alcohol moderation, avoidance of triggers including cold exposure, and medications – we will be focusing on pharmacologic management of VSA with particular emphasis on novel and emerging treatments. Figure 4 shows a graphical summary of some of the treatment targets mentioned in this section.

Figure 4 Pharmacologic treatment targets in vasospastic angina. This figure illustrates key pathophysiological mechanisms in vasospastic angina, including endothelial dysfunction and vascular smooth muscle hyperreactivity, along with targeted therapies. NO: Nitric oxide; ET-1: Endothelin-1; SH: Serotonin and histamine; H: Histamine; CCB: Calcium channel blockers; cGMP: Cyclic guanosine monophosphate; ATP: Adenosine triphosphate.

PHARMACOLOGIC MANAGEMENT

Calcium channel blockers

CCBs are the first-line treatment for VSA. By blocking voltage-dependent L-type calcium channels in vascular smooth muscle cells, CCBs inhibit calcium influx, leading to coronary vasodilation and a reduction in coronary vasoreactivity[64]. A large prospective, multicenter cohort study from South Korea involving 1586 patients with confirmed VSA demonstrated comparable efficacy in long-term clinical outcomes between first-generation (diltiazem, nifedipine) and second-generation (amlodipine, benidipine) CCBs, although second-generation CCBs were associated with a lower incidence of acute coronary syndrome[65]. In patients with severe VSA, high dosages of CCBs or a combination of both non-dihydropyridine with a dihydropyridine agent may be considered[66]. Both the 2024 ESC Guidelines for Chronic Coronary Syndrome and the 2023 JCS guidelines recommend CCBs as the cornerstone of pharmacotherapy for vasospastic angina[8,63].

Nitrates

Nitrates are effective vasodilators that act by increasing NO bioavailability, counteracting the endothelial dysfunction central to vasospastic angina pathophysiology. It also reduces ventricular filling pressures decreasing myocardial oxygen demand[29].

In a Japanese study of 1429 patients with confirmed VSA, the addition of long-acting nitrates to CCBs provided additional benefit in reducing symptom frequency in approximately 40% of subjects. However, it appears to be more effective in epicardial spasm rather than microvascular spasm[67]. Nitrate tolerance can develop with continuous use, potentially limiting long-term efficacy[68]. A randomized crossover study demonstrated that an eccentric dosing schedule (nitrate-free interval of 10-12 hours) helped prevent tolerance development while maintaining therapeutic efficacy[69].

Short-acting nitrates (sublingual nitroglycerin) provide rapid relief during acute attacks, while long-acting formulations (isosorbide mononitrate/dinitrate) are used for prevention. Despite their efficacy, nitrates alone are generally considered insufficient as monotherapy and are typically used in combination with CCBs. The ESC 2024 chronic coronary syndrome guidelines recommend nitrates as second-line therapy for vasospastic angina when CCBs provide inadequate symptom control (Class IIa, Level B evidence). Similarly, 2023 JCS Guidelines on Vasospastic Angina recommend that long-acting nitrates be considered as an adjunct therapy to CCBs in cases where symptom control is suboptimal. However, the JCS guidelines caution against the continuous use of nitrates without a nitrate-free interval due to the risk of tolerance and emphasize the importance of individualized dosing strategies to optimize efficacy[8,63,70,71].

Nicorandil

Nicorandil offers a dual mechanism of action: Increasing cyclic guanosine monophosphate and opening of adenosine triphosphate (ATP)-sensitive potassium channels. These hyperpolarize vascular smooth muscles, increases nitric oxide, and decreases Rho-kinase activity[66]. The 2023 JCS guidelines provide a Class IIa level B recommendation for nicorandil as add-on therapy for patients with insufficient response to CCBs and nitrates[63].

EMERGING/NOVEL THERAPIES

Statins

Although not traditionally classified as anti-anginal agents, statins may have a role in vasospastic angina (VSA) given the central role of endothelial dysfunction in its pathogenesis—paralleling their established benefits in atherosclerotic coronary disease. This shared mechanism provides a pathophysiologic rationale for statin therapy in VSA, as statins enhance endothelial function and reduce vascular inflammation[72]. A prospective randomized trial of 64 patients with confirmed coronary vasospasm demonstrated that adding fluvastatin 30 mg daily to CCB therapy significantly reduced the incidence of acetylcholine-provoked spasm at 6 months (52% vs 21%, P = 0.231)[72]. A meta-analysis of 10 cohort studies involving a total of 9333 patients found 30% relative risk reduction in MACE on patients on statin (RR: 0.70, 95%CI: 0.49-0.99)[73].

Cyproheptadine

Cyproheptadine is an antihistamine with strong 5-HT2 serotoninergic blocking activity and has been reported to abort refractory coronary vasospasm. A classic report from 1994 described cyproheptadine successfully treating a patient with refractory Prinzmetal’s angina[74]. Since then, multiple case reports have documented its use in refractory VSA (including post-PCI spasm)[75,76]. Cyproheptadine is usually started at 4 mg three times daily and titrated as tolerated (common side effect is sedation, as it crosses blood-brain barrier). While no large clinical trials have been done, it is sometimes anecdotally recommended by some experts for refractory VSA[76].

Cilostazol

Cilostazol, a selective phosphodiesterase-3 inhibitor, increases intracellular cyclic adenosine monophosphate, promoting vasodilation and inhibiting platelet aggregation. Although primarily indicated for the treatment of intermittent claudication, growing evidence—particularly from East Asia—suggests that cilostazol may benefit patients with microvascular spasm/VSA, potentially by improving endothelial function and promoting vascular smooth muscle relaxation. In patients with variant angina and coexistent coronary artery disease, cilostazol added to CCB therapy has been associated with reduced angina frequency and ischemic episodes. The STELLA trial, a multicenter, randomized, double-blind, placebo-controlled study, demonstrated that cilostazol significantly reduced weekly chest pain frequency (66.5% vs 17.6%, P = 0.009) and improved symptom-free rates (76% vs 33%) compared with placebo in patients with VSA refractory to amlodipine. The typical dose used is 100 mg twice daily. While not yet incorporated into major clinical guidelines, cilostazol may be a useful adjunct in refractory VSA[77,78].

Alpha-adrenergic blockade

The potential role of alpha-adrenergic stimulation in coronary vasomotor tone has led to investigation of alpha-adrenergic antagonists in the treatment of vasospastic angina. Early anecdotal reports suggested clinical benefit with agents such as prazosin and phenoxybenzamine; however, subsequent controlled studies failed to demonstrate significant reductions in anginal episodes, nitroglycerin use, or ischemic burden with alpha-1 blockade. Randomized trials, including those employing continuous electrocardiographic monitoring, found no therapeutic advantage of prazosin over placebo, and side effects such as orthostatic hypotension were frequently reported. Given the lack of robust efficacy data and potential for adverse effects, alpha-adrenergic antagonists are not recommended as first-line therapy and are generally reserved for refractory cases. It should be noted that much of the available evidence derives from older studies, underscoring the need for updated clinical investigation in this area[79-83].

Magnesium

Magnesium is a physiological calcium antagonist with vasodilatory effects, likely mediated by inhibition of calcium influx into vascular smooth muscle. In a small prospective trial, intravenous magnesium sulfate reduced acetylcholine-induced coronary spasm, ischemic ECG changes, and chest pain in patients with vasospastic angina. Although there are no guidelines for its routine use in VSA, IV magnesium may be considered an adjunct in refractory cases. Oral supplementation may be considered for chronic management due to its low risk, but robust evidence for long-term benefit is lacking[84].

Rho-kinase inhibitors

Fasudil is an intravenous Rho-kinase (ROCK) inhibitor available in Japan, has demonstrated notable efficacy in suppressing coronary artery spasm. Small clinical studies have shown that intracoronary fasudil significantly reduces acetylcholine-induced vasospasm and myocardial ischemia in patients with VSA and improves ischemic parameters in a majority of those with coronary microvascular spasm. Its mechanism involves inhibition of ROCK-mediated calcium sensitization in vascular smooth muscle. However, fasudil is not widely available outside East Asia, and no Rho-kinase inhibitor is currently approved for chronic treatment of VSA. There is also no oral formulation in clinical use. While fasudil has been used under compassionate protocols in refractory cases in Japan, broader application awaits further clinical evidence. Nevertheless, Rho-kinase inhibition remains a promising therapeutic strategy[46,47,85].

Endothelin receptor antagonists

Another promising pharmacological target is ET-1, a potent vasoconstrictor implicated in coronary vasospasm. ET-1 acts via two receptor subtypes: ETA, which mediates vasoconstriction in vascular smooth muscle, and ETB, which has both vasoconstrictive and vasodilatory effects depending on its location in smooth muscle or endothelium[82]. Bosentan (a dual endothelin-A/B receptor blocker) has shown some benefit in case reports of refractory VSA at a dose of 125 mg twice a day[86]. Given the risks of hepatotoxicity, teratogenicity, peripheral edema, and hematologic changes, bosentan should be used with caution for vasospastic angina and reserved as a last-line option when other treatments have failed[82].

REFRACTORY VASOSPASM

Refractory VSA is defined by the JCS as unresponsive to two types of coronary vasodilators (usually a CCB and a nitrate) and affects about 10% of patients with VSA. It is a challenging condition that can lead to sudden cardiac death[87]. Uptitrating doses, starting one or more of the novel therapies mentioned in this paper, or an interventional approach may be considered.

Levosimendan

Levosimendan is a unique inodilator that enhances contractility by increasing the sensitivity of cardiac myofilaments to calcium and opens ATP-sensitive potassium channels in VSMCs leading to vasodilation approved for the treatment of acute heart failure and has an off-label use for managing refractory cerebral vasospasm following atraumatic subarachnoid hemorrhage[88,89]. A case report of a patient with recurrent vasospastic angina complicated by acute pulmonary edema and cardiogenic shock, unresponsive to standard therapy, was successfully stabilized with levosimendan, suggesting its potential benefit in refractory life-threatening cases[90].

Coronary artery stenting

Coronary artery stenting may be considered in selected cases of refractory VSA, particularly when vasospasm occurs at sites of significant fixed stenosis unresponsive to optimal pharmacological therapy. While stenting can alleviate anginal symptoms and reduce the risk of acute coronary events in some patients, it is not routinely recommended due to the potential for complications and limited supporting evidence. Importantly, vasospasm tends to recur in segments proximal or distal to the stented area rather than within the stented segment itself, highlighting the diffuse and dynamic nature of the disease. This phenomenon underscores the limitations of stenting in addressing the underlying pathophysiology of VSA. Consequently, stenting should be reserved for highly selected patients, particularly those at high risk or with focal, angiographically confirmed spasm refractory to maximal medical treatment[29,87,91].

It is also worthwhile to note that stent-induced spasm has been described particularly for first generation drug-eluting stents with endothelial dysfunction thought of as a major process involved[92-94]. Interestingly, a recently published retrospective study of 1039 patients who underwent ACh-provocation testing found that prior coronary stenting is associated with higher rates of epicardial spasm at both the patient and vessel levels with no statistically significant difference between bare metal stents and drug-eluting stents, however likely underpowered for this subgroup comparison[95].

Sympathectomy

Sympathectomy for refractory vasospastic angina includes several methods aimed at reducing sympathetic nervous system activity to alleviate coronary spasms. Stellate ganglion block, especially left-sided, temporarily interrupts sympathetic signals and can be repeated to achieve long-term symptom relief. Surgical endoscopic thoracic sympathectomy involves cardiac sympathetic denervation (plexectomy) and has shown effectiveness in reducing angina episodes and ST changes on monitoring. Renal sympathetic denervation, although primarily used for hypertension, may help in refractory cases by reducing intracardiac sympathetic tone. These procedures are considered in extreme cases when pharmacological therapies fail to control symptoms[87].

Implantable cardioverter defibrillator

While Implantable cardioverter-defibrillators (ICDs) do not suppress coronary artery spasm and no recommendation exists for primary preventions for patients with VSA. ICDs should be considered for secondary prevention of sudden cardiac death in patients with VSA who experience life-threatening ventricular arrhythmias refractory to optimal medical therapy[29,87,96,97].

EXPANDING THE VSA TREATMENT TOOLBOX: NEW TRIALS AND OTHER EMERGING THERAPIES

Drug repurposing initiatives are looking at finding new therapeutic uses for existing approved drugs for novel applications in VSA[98]. Vericiguat, a soluble guanylate cyclase stimulator approved for patients with refractory heart failure with reduced ejection fraction, is undergoing Phase II clinical trial for patients with VSA (Vericiguat in Vasospastic Angina [ViVA] trial; NCT06415227) with the trial set to end in September 2026. A prospective pilot study which involves implanting spinal cord stimulator device in patients with refractory VSA is also underway (NCT06176391).

The role of inflammation in the pathogenesis of VSA could promote additional therapeutic targets. An observational prospective cohort trial recently completed recruitment of 71 patients and investigated outcomes of patients with VSA who received immunomodulatory therapy (methylprednisolone and/or intravenous immunoglobulin) vs traditional therapy (NCT06696807). Targeted therapy on interleukin-6 such as tocilizumab and/or other cytokines may be explored in the future[48].

Future research on N-acetylcysteine (NAC), a glutathione precursor with antioxidant properties that may enhance nitric oxide bioavailability and improve endothelial function. Its use alongside nitrates has been shown to mitigate nitrate tolerance and augment vasodilation. While clinical evidence is limited, NAC’s mechanistic profile supports its potential as an adjunctive therapy in refractory coronary vasospasm[99,100].

Traditional Chinese medication formulations have also been explored only as adjuncts in refractory VSA, with low-certainty evidence. In small-animal models, Tongxinluo attenuated 5-HT-induced coronary spasm and intimal hyperplasia, partly via downregulating Rho-kinase signaling[101]. A recent preclinical study reported that Xiao-Xu-Ming decoction components reduce coronary artery spasm by inhibiting CaM-mediated MLCK/MLC pathway in rat models[102]. Limited Japanese kampo case reports also exist, but robust controlled human data are lacking; if considered, these therapies should be framed explicitly as last-resort, adjunctive options after standard care and ideally within research settings[103].

CONCLUSION

Coronary vasospasm is now recognized as a significant and complex contributor to myocardial ischemia. Over the years, our understanding of this phenomenon has greatly evolved. This evolving knowledge has highlighted that coronary vasomotor dysfunction is far from benign – it can precipitate acute coronary syndromes, serious arrhythmias, and even sudden cardiac death. Consequently, there is a growing emphasis on recognizing vasospastic angina in clinical practice and treating it proactively. In summary, coronary vasospasm represents a distinct pathophysiological entity in ischemic heart disease, one driven by a dynamic interplay between endothelial dysfunction, hyperreactive vascular smooth muscle, autonomic influences, and possibly inflammation. Effective management requires a personalized strategy that addresses this multifaceted nature. Calcium-channel blockers and nitrates remain the cornerstone of treatment, providing symptomatic relief for most patients. Beyond these, emerging therapies and tailored interventions – guided by individual patient profiles and risk factors – are on the horizon to improve outcomes. As the field advances, the hope is that integrating novel research findings into clinical care and individualized treatment approaches will translate into better symptom control, fewer cardiac events, and improved quality of life for patients suffering from coronary vasospasm.