IMR Press / RCM / Volume 23 / Issue 5 / DOI: 10.31083/j.rcm2305175
Open Access Review
Coronary Artery Spasm: Risk Factors, Pathophysiological Mechanisms and Novel Diagnostic Approaches
Show Less
1 Department of Forensic Medicine, School of Basic Medical Sciences, Fudan University, 200032 Shanghai, China
2 Department of Cardiology, Shanghai Institute of Cardiovascular Diseases, Zhongshan Hospital, Fudan University, 200032 Shanghai, China
*Correspondence: shenyiwen@fudan.edu.cn (Yiwen Shen); liliangli11@fudan.edu.cn (Liliang Li)
These authors contributed equally.
Academic Editors: Brian Tomlinson and Takatoshi Kasai
Rev. Cardiovasc. Med. 2022, 23(5), 175; https://doi.org/10.31083/j.rcm2305175
Submitted: 28 December 2021 | Revised: 19 January 2022 | Accepted: 27 January 2022 | Published: 16 May 2022
(This article belongs to the Special Issue State-of-the-Art Cardiovascular Medicine in Asia 2021)
Copyright: © 2022 The Author(s). Published by IMR Press.
This is an open access article under the CC BY 4.0 license.
Abstract

Coronary artery spasm (CAS) is a transient reversible subtotal or complete occlusion induced by coronary hypercontraction and the critical cause of myocardial ischaemia with non-obstructive coronary arteries. During the past decades, our knowledge of the risk factors and pathophysiological mechanisms of CAS have been increasingly progressed, and various diagnostic approaches, including imaging technologies and novel biomarkers, have been proposed to serve well to diagnose CAS clinically. This review aims to summarize these research progresses on the risk factors of CAS and introduce current knowledge about the mechanisms accounting for CAS, including endothelial dysfunction, vascular smooth muscle cell hyperreactivity, and adventitial and perivascular adipose tissue inflammation. We also gathered the recently evolved diagnostic approaches and analyzed their advantages/disadvantages, in purpose of enhancing the diagnostic yield on the basis of ensuring accuracy.

Keywords
coronary artery spasm
risk factors
endothelial dysfunction
vascular smooth muscle cell hyperreactivity
adventitial inflammation
diagnostic approaches
1. Introduction

In 1959, Prinzmetal et al. [1] first proposed the term “variant angina” which is later evolved and re-named as coronary artery spasm (CAS). CAS is generally considered as abnormal contraction of epicardial coronary arteries causing myocardial ischemia and includes microvascular CAS in a broad sense. Clinically, CAS is defined as a transient reversible subtotal or complete occlusion of coronary arteries with >90% vasoconstriction on angiography using spasm provocation test (SPT) known as the gold standard approach, accompanied by angina pectoris and ischaemic electrocardiogram (ECG) changes [2]. CAS could also appear in common ischemic heart disease, including stable angina, unstable angina, and acute myocardial infarction (AMI), coupled with a variety of pathophysiological alterations, such as coronary atherosclerosis and thrombosis. The current European Society of Cardiology (ESC) guideline further emphasizes the concept that vasospastic angina (VSA) and microvascular angina are also components of chronic coronary syndrome (CCS) [3]. Moreover, coronary angiography (CAG) revealed that the degree of stenosis due to mere atheromatosis was less than 50% in a large angina patient cohort [4], suggesting the additional involvement of CAS in coronary stenosis and the importance of assessing CAS in patients with CCS.

CAS is not a benign disease. Approximately 1–14% of AMIs are considered to occur in CAS patients, which could further lead to fatal arrhythmia, and even sudden cardiac death [5]. Thrombosis secondary to CAS may be another important cause of myocardial infarction [6]. Despite the area of CAS-induced myocardial infarction is small in general, spontaneous reperfusion after CAS subsiding also increases the risk of fatal arrhythmia [7]. VSA is the major clinical manifestation of CAS-induced myocardial ischemia. It is usually independent of effort occurring at rest with obvious circadian rhythm, namely more occurrences in the period from midnight to dawn [2]. ST-segment elevation or depression on ECG is one of the clinical features [2]. Compared with coronary atherosclerotic diseases (CAD), CAS is more prevalent in women, younger people and Asian populations, such as Japanese and South Koreans. With the utilization of invasive SPT, it is also not uncommon for VSA in some Western countries such as Germany and Australia [8, 9]. However, true prevalence needs further investigation due to the rare utilization of SPT in most countries, such as China, where SPT is cautiously performed only for clinical diagnosis in specialized medical centers.

Recent years have witnessed increasing advances towards our understanding of CAS. This review aims to introduce the recent knowledge on the risk factor, pathophysiological mechanisms of CAS and also highlights the latest advancements in clinical diagnosis of CAS, aiming at providing effective alternatives for invasive methods, especially for the countries where SPT is not performed routinely in the clinic.

2. Precipitating Factors and Clinical Risk Factors

There are a vast number of precipitating factors for CAS (Fig. 1), which can be divided as physiological and pharmacological categories. The former includes emotional stress, cold stimulation, hyperventilation, valsalva maneuver, and exercise etc., while the latter contains psychoactive drugs (such as cocaine, marijuana, and amphetamine), sympathomimetic agents (such as epinephrine, norepinephrine), parasympathomimetic agents (such as acetylcholine (Ach), pilocarpine), vasoconstrictors (such as thromboxane, ergonovine), alcohol consumption, and magnesium deficiency etc. [10, 11]. In addition, there have been reports about CAS induced by traditional Chinese medicine, including Di-Long (dried earthworm), Ma-Huang (plant of ephedra), and cucumis polypeptide (the combined extracts from deer horn and sweet melon seeds) [12].

Fig. 1.

Precipitating factors (grey ellipses) and clinical risk factors (white ellipses) of CAS. CAS, coronary artery spasm; hs-CRP, high-sensitivity C-reactive protein.

Unlike CAD, CAS patients seem to be more common among young people and women [7, 13]. However, male patients still account for the majority of CAS patients, and high prevalence is in the age range of 40–70 years [4]. As mentioned above, CAS is a highly prevalent disease in East Asia with ethnic and genetic diversity. It is worth noting that East Asian patients tend to present diffuse and multi-vascular CAS, while Caucasians tend to present focal CAS [14]. Smoking is an unequivocal risk factor for CAS and about 75% of CAS patients are smokers [15]. It was also reported that the proportion of smokers in CAS patients was 42.6%, but it still surpassed that in CAD patients [16]. The substances in cigarettes, such as carbon monoxide and nicotine, are able to damage blood vessels by increasing inflammation and oxidative stress, which explains why smoking is a high risk factor for CAS [17]. Although hyperlipidemia, hyperglycemia, and hypertension in CAS patients are less common than those in CAD patients [16], these metabolic disorders also contribute to the development of CAS. Serum high-sensitivity C-reactive protein (hs-CRP) is higher in CAS patients than that among healthy individuals, implicating the potential of hs-CRP to be a predictor of CAS [18]. Moreover, alcohol consumption [19] and chemotherapeutics [20] that destruct blood vessels through independent mechanisms have also been found to relate to CAS.

3. Pathophysiological Mechanisms of CAS

The pathogenesis of CAS is complicated and could be categorized as endothelial dysfunction (ED) in the intima, vascular smooth muscle cell (VSMC) hyperreactivity in the media, and adventitial and perivascular adipose tissue (PVAT) inflammation (Fig. 2).

Fig. 2.

A schematic illustration of CAS pathogenesis including endothelial dysfunction, VSMC hyperreactivity, and adventitial/perivascular adipose tissue inflammation. CaM, calmodulin; EC, endothelial cell; ERS, endoplasmic reticulum stress; ET-1, endothelin-1; MLC, myosin light chain; MLCK, MLC kinase; NO, nitric oxide; ox-LDL, oxidized low-density lipoprotein; PKC, protein kinase C; PLC, phospholipase C; RhoA, Ras homolog gene member A; RhoGEF, Rho guanine nucleotide exchange factors; RhoK, Rho kinase; ROS, reactive oxygen species; VSMC, vascular smooth muscle cell.

3.1 Endothelial Dysfunction in the Intima

ED is defined as a series of phenotypes related to pathophysiological heterogeneous changes in vascular tone, permeability, inflammation, and de-differentiation by the ESC [21]. Clinical observations have shown that ED is associated with the pathogenesis of CAS. Nitroglycerin and isosorbide dinitrate, two endothelial-independent vasodilators, are highly efficient to relieve vasospasm angina during CAS [22, 23]. Nitrates are even prescribed as vasodilator agents after SPT [24]. In clinical angiography, it has been found that most of the spastic sites were in parallel to atherosclerotic plaque [25], and the coronary intima of CAS patients was remarkably thickened [26]. Immunohistological analysis of endomyocardial biopsy samples further showed that most CAS patients had endothelial cells (ECs) activation [27]. After removal of the endothelium, porcine coronary arteries successfully developed CAS with high cholesterol feeding [28].

At the molecular level, ED refers to disruption of homeostasis for endothelial regulation of vascular tension, and defines the abnormal function of synthesis and release of vasoactive substances such as nitric oxide (NO) and endothelin-1 (ET-1). Endothelial NO synthase (eNOS) dimer is the pivotal molecule for ECs to physiologically produce NO. When high-risk factors are present, reactive oxygen species (ROS) is increased in ECs due to stimulation by reduced nicotinamide adenine dinucleotide phosphate (NADPH) oxidase [21, 29]. The increased ROS then clears NO in ECs and converts it into peroxynitrite (ONOO-) with strong oxidizing property. Increased ROS also oxidizes tetrahydrobiopterin (BH4), an important co-factor of eNOS that maintains its dimerization, to be dihydrobiopterin (BH2), leading to eNOS uncoupling and attenuation of NO synthesis. Furthermore, production of the eNOS monomer can in turn prevent O2 from converting into superoxide anion (O2-), which further augments ROS and exacerbates the failure of eNOS dimerization. In addition, increased ROS also mediates the development of inflammation and ECs damage, which ultimately leads to ED. ET-1 is a powerful vasoconstrictor, and the increase of its synthesis and release is also one of the components of ED. Toyo-oka et al. [30] presented that plasma ET-1 level of CAS patients was significantly higher than that of non-CAS patients. Increased ET-1 then activated protein kinase C (PKC) and thereby enhancing coronary contraction induced by prostaglandin F2α (PGF2α) and 5-hydroxytryptamine (5-HT; also named as serotonin) [31, 32]. High levels of ET-1 also repressed the NO synthesis in a PKC-dependent manner [33]. Studies have shown that cigarette smoking increased the vascular ET-1 receptors by activating mitogen-activated protein kinase (MAPK) [34]. In addition, cocaine may promote the release of ET-1 to elicit CAS [35], and a few hours after drinking, CAS was observed to be caused by an obvious elevation of ET-1 level [36]. These studies might explain the association between common risk factors and the development of ED-related CAS.

The ED in association with CAS is further supported by genetic evidence. The polymorphisms of NOS gene [37], aldehyde dehydrogenase 2 (ALDH2) gene [38], paraoxonase I gene [39], p22 phox gene in male [40], manganese superoxide dismutase (MnSOD) gene [41], and inflammatory factor interleukin-6 (IL-6) gene [40] all influence the NO synthesis, oxidative stress and inflammation. The polymorphisms of ET-1 gene are also related to CAS. Lee et al. [42] showed that CAS is related to the + 138delA, G8002A and Lys198Asn polymorphisms of the ET-1 gene. Ford et al. [43] observed that patients with coronary microvascular dysfunction have a higher frequency of the rs9349379-G allele and are associated with higher serum ET-1 levels.

Of note, Shimokawa [44] and Lanza et al. [45] presented evidence such as successful establishment of CAS animal models with normal endothelial function to show that ED might not be the key mechanism of CAS pathogenesis. Moreover, some CAS patients were resistant to nitrate treatment, which means supplementing NO cannot always mitigate CAS [46]. In addition, not all CAS patients have ED, and ED or inhibition of NO synthesis alone may be insufficient to cause CAS [45, 47], implicating that ED is an important yet unnecessary pathophysiological change of CAS.

3.2 VSMC Hyperreactivity in the Media

While VSMC hyperreactivity is dependent on the cytoplasm Ca2+ sensitivity or the [Ca2+]i quantity, multiple pathways such as RhoGEF/RhoA/RhoK pathway, PLC/PKC pathway, Ca2+-CaM/MLCK/MLC pathway, and endoplasmic reticulum stress have been suggested to regulate the VSMC hyperreactivity and induce CAS.

3.2.1 RhoGEF/RhoA/RhoK Pathway

The Ras homolog family (Rho) pathway activity has been observed to have circadian rhythm, showing higher activity particularly at midnight and early morning [48, 49], a time window that conforms to the circadian rhythm of CAS. Also in CAS patients, intervention by Rho kinase (RhoK) inhibitors remarkably reduced Ach-induced coronary contraction [50, 51], as well as the degree of myocardial ischemia [52, 53], and further improve coronary artery relaxation combined with nitroglycerin [54]. These data suggested that the Rho pathway plays a pivotal role in the pathogenesis of CAS in human. Indeed, Rho guanine nucleotide exchange factors (RhoGEFs) are a class of molecules with abundant subtypes, which can activate Rho protein by converting GDP into GTP [55]. In VSMCs, RhoGEFs are mainly regulated by G protein-coupled receptors (GPCRs) and the activated RhoGEFs then transduce signals to the downstream Rho family member A (RhoA), thereby modulating the Ca2+ sensitivity [55, 56, 57].

Many etiologies can induce VSMC hyperreactivity by activating the RhoA/RhoK pathway, such as oxidized low-density lipoprotein (oxLDL) [58, 59], chronic hypoxia and ROS [60, 61, 62], inflammation [63, 64], hemorrhagic shock [65], and chronic stress [66]. Galle et al. [58] observed that oxLDL augmented the activity of RhoA in rabbit aorta, and thereby potentiating the contractile responsiveness of aorta to Angiotensin (Ang) II. Bolz et al. [59] proved that oxLDL increased the [Ca2+]i and RhoK-mediated Ca2+ sensitization in isolated small resistance arteries, which reduced the response to vasodilators and provoked vascular hyperreactivity to norepinephrine and Ach. Maruko et al. [60] showed that chronic hypoxia attenuated [Ca2+]i in coronary artery of fetal sheep, but enhanced Ca2+ sensitivity, and thromboxane A2 (TXA2) receptor-mediated contraction could be inhibited by Rho inhibitors rather than PKC inhibitors. Gao et al. [61] further showed that hypoxic stimulus increased the levels of intracellular inosine 5’-triphosphate (ITP) and inosine 3’,5’-cyclic monophosphate (cIMP), which promoted the elevation of RhoK activity. Knock et al. [62] showed that ROS mediated Ca2+ sensitization through the RhoK pathway in VSMCs. Inflammatory factors could also enhance the expression and activation of RhoK as well as its downstream molecules in human coronary VSMCs [64]. Corticosteroids play significant roles in the treatment of refractory CAS patients, and researchers believed that it might be attributed to the inhibition of inflammation and alleviation of the coronary VSMC hyperreactivity [67, 68]. In COVID-19 patients with cytokine storms, several cases of severe CAS have also been reported [69, 70], but it is unknown whether these patients suffered from CAS before infection of SARS-CoV-2. It should be noted that chronic inflammation and oxidative stress are extremely common in cardiovascular diseases, especially CAD, but not all patients will develop CAS. We believe that these factors are in association with but rather independent causes of VSMC hyperreactivity.

Polymorphisms of RhoK gene also link with CAS. Kamiunten et al. [71] found that the missense mutation G930T resulted in the enhancement of RhoK activity in CAS patients and Yoo et al. [72] found that the GTCTG haplotype in 5 interesting single nucleotide polymorphisms (SNPs) might play a protective role in non-CAS patients.

Myosin light chain (MLC) phosphatase (MLCP) is one of the most important downstream molecules of RhoK and its inactivation by RhoK enhances the phosphorylation of MLC. Phosphorylated MLC (pMLC) was found at the spastic sites and positively correlated with the degree of contraction in interleukin 1β (IL-1β)-induced porcine CAS model [73], further supporting the involvement of Rho pathway in the development of CAS.

3.2.2 PLC/PKC Pathway

Okumura et al. [74] cultivated the skin fibroblasts from CAS patients and found that the phospholipase C (PLC) activity was enhanced and positively correlated with the contractile hyperresponsiveness of coronary arteries, proposing that the increased PLC activity may be involved in the pathogenesis of CAS. The p122 protein, an agonist of PLC, was up-regulated in skin fibroblasts of CAS patients [75]. Increased p122 protein promoted the basal and peak [Ca2+]i to Ach in human coronary VSMCs [75]. Also, in p122 transgenic mice, ergonovine could successfully induce the occurrence of CAS [76]. Nakano et al. [77] further found that the R257H mutation in the PLC-δ1 gene was higher in CAS patients, though the incidence was overall less than 10%. In the R257H homozygous knock-in mice, 3 in 5 (60%) developed CAS using the microvascular filling technology [78].

In addition, downstream PKC is also critically involved in the development of CAS [79, 80]. Giardina et al. [81] proved that oxLDL enhanced the Ca2+ sensitivity of VSMCs by activating PKC-α and PKC-ϵ. Allahdadi et al. [82] treated rats with eucapnic intermittent hypoxia, leading to contractile hyperresponsiveness to ET-1 via PKCδ in the small mesenteric arteries. In support of this, the downstream signals of PKC such as C-kinase potentiated protein phosphatase-1 inhibitor of 17 kDa (CPI-17), calponin (CaP), MAPKs were also revealed to regulate VSMC hyperreactivity. CPI-17, upon phosphorylation by PKC, inhibits the activity of the catalytic subunit PP1cδ of MLCP, leading to inactivation of MLCP. In CPI-17 knockout mice, the systolic blood pressure and average blood pressure decreased apparently, and vascular contraction induced by various agonists was significantly weakened [83, 84]. These results indicate that CPI-17 might be one of the most important downstream factors boosting vasoconstriction. A study also showed that inhibition of CaP binding to actin would augment Ca2+ sensitivity of vascular smooth muscle in isolated mesenteric artery [85]. However, this was challenged by follow-up studies that showed knockout of CaP gene did not affect the Ca2+ sensitivity in mice [86]. p38 MAPK might also be involved in PKC-regulated contractile responsiveness since adenosine increased pMLC level through the p38 MAPK/MK2 pathway, leading to enhancement of VSMC responsiveness to AngII [87].

Interestingly, in the porcine CAS model induced by IL-1β, RhoK inhibitor was capable of repressing the effect of PKC agonist, but the effect of RhoK could not be blocked by PKC inhibitors [88], implying that the RhoK may also be downstream of PKC signaling in the development of CAS.

3.2.3 Calcium and Ca2+-CaM/MLCK/MLC Pathway

Calcium channel blockers (CCBs) have been well established as therapeutic agents for CAS in clinic, suggesting that Ca2+ is the core element of CAS. Indeed, the up-regulation of voltage-dependent Ca2+ channels and enhanced Ca2+ influx are major features of hypertension [89]. Smith et al. [90] observed that the V734I mutation of ABCC9 gene (encoding Sur2 subunit of the KATP channel) was associated with CAS. When Sur2 subunit of the KATP channel was knocked out, the function of Ca2+ channels was perturbed, leading to spontaneous CAS episodes [91].

Calcium functions via binding with Calmodulin (CaM). The Ca2+-CaM complex then directly activates the MLC kinase (MLCK). Decreased MLCK activity attenuated Ca2+ sensitivity and contractile responsiveness in carotid arteries [92]. Kim [93] observed that CPI-17 and MLCK were up-regulated in obese Sprague-Dawley rats fed with high-fat, which collectively mediated the vascular hyperreactivity. Ca2+/CaM-dependent protein kinase II (CaMKII) activated by Ca2+-CaM also promotes the activation of MLCK through the extracellular signal-regulated kinase 1 and 2 (ERK1/2) at a slow rate, but it phosphorylates a specific serine residue in the CaM-binding domain of MLCK, which reduces the Ca2+ sensitivity of MLC phosphorylation [94]. Moreover, autophosphorylation on CaMKII Thr286 greatly enhances its affinity with CaM, which is involved in maintaining vasoconstriction [95]. It is suggested that the abnormal activity of CaMKII may also be involved in the VSMC hyperreactivity. Furthermore, we also performed immunohistochemistry analysis of death cases from CAS and confirmed that pMLC2 might serve as a tissue marker of antemortem CAS [96].

3.2.4 Endoplasmic Reticulum Stress

Endoplasmic reticulum stress (ERS) is defined as the accumulation of unfolded and/or misfolded proteins in the endoplasmic reticulum (ER) that breaks the ER homeostasis, and thereby activating the unfolded protein response (UPR) to restore and maintain the ER homeostasis [97]. The causes of ERS encompass various physiological or pathological stimuli such as hypoxia, starvation, oxidative stress, imbalance of Ca2+ homeostasis, etc. [97]. The UPR proceeds through three signaling pathways to resist the cellular stress, including transcription factor 6 (ATF6) pathway, inositol-requiring enzyme 1 (IRE1) pathway, and protein kinase R-like ER kinase (PERK) pathway [97].

Choi et al. [98] found that hyperglycemia led to enhanced coronary myogenic response and ED via triggering ERS in mice. Liang et al. [99] showed that ERS inducers, such as tunicamycin (Tm), increased the phosphorylation of MLC in VSMCs and enhanced the contractile responsiveness to phenylephrine in aorta independent of endothelium. Zhang et al. [100] observed that ceramide resulted in the VSMC hyperreactivity to phenylephrine through ERS/COX-2/PGE2 pathway. We observed that an ERS inhibitor significantly prevented VSMC contraction, whereas Tm aggravated the CAS-induced myocardial ischemia in mice, and ERS regulated CAS possibly through the MLCK/MLC pathway [101]. Ziomek et al. [102] also pointed out that Tm did not activate Ca2+ channels, but altered the Ca2+ permeability of plasma membrane and ER, leading to an increase in [Ca2+]i and initiating the VSMC contraction. Meanwhile, Tm also caused a decrease of Ca2+ concentration in ER [99, 102]. The above studies have shed novel insights into the pathogenesis of CAS. However, the detailed mechanisms of how ERS regulated CAS remain largely unknown and merit future investigation.

3.3 Adventitial and PVAT Inflammation

Shimokawa and colleagues utilized IL-1β and other inflammatory factors to mediate coronary adventitial inflammation and established a porcine CAS model [63, 103], indicating that adventitial inflammation is able to induce CAS. Coronary adventitial infiltration of mast cells and/or eosinophils in some CAS autopsy reports also suggested the influence of adventitial inflammation on the pathogenesis of CAS [104, 105], but mast cells are likely to provoke CAS by releasing histamine and other vasoconstrictors [106]. In recent years, PVAT inflammation in the pathogenesis of CAS has been brought to the forefront of research interest. Ohyama et al. [107] observed an increased coronary PVAT volume of CAS patients using CTA technique, which was in general consistent with Ito et al. [108]. The increased PVAT inflammation was further evidenced by remarkable 18F-fluorodeoxyglucose (FDG) uptake via positron emission tomography/computed tomography (PET/CT) scanning in CAS patients [109]. Nishimiya et al. [110] also noticed an enhanced formation of adventitial vasa vasorum in CAS patients using optical frequency domain imaging, and the extent of adventitial vasa vasorum positively correlated with RhoK activity of circulatory leukocytes. Moreover, drug-eluting stent-induced CAS was also observed at the presence of PVAT inflammation in a porcine model [111].

Of note, the vasoconstriction effect of PVAT inflammation seems to be VSMCs-dependent [112]. For instance, Lynch et al. [113] revealed that PVAT activated the BKCa channels on VSMCs by releasing adiponectin, thereby resisting vasoconstriction. Saxton et al. [114] found that sympathetic excitation triggered the release of adiponectin from PVAT viaβ3-adrenergic receptors, and PVAT took up norepinephrine, which prevented its interaction with VSMCs. Aalbaek et al. [115] proved that PVAT inhibited the Ca2+ sensitivity mediated by the RhoK pathway in the coronary artery of rats, further validating that PVAT is capable of regulating the Ca2+ sensitivity of coronary VSMCs.

4. Novel Diagnostic Approaches

In the clinic, CAS may present in a variety of ways and is often asymptomatic, which causes CAS remaining a quite underdiagnosed and underreported disease with an average estimated delay of 3 months from presentation to diagnosis [7]. Currently, it is an urgency to develop accessible and practical diagnosis approaches for the disease. This section will introduce state-of-the-art diagnostic approaches (Tables 1,2) that might aid in clinical diagnosis of CAS.

Table 1.A summary of the imaging approaches for diagnosis of CAS.
Imaging approaches Advantages Disadvantages References
Coronary angiography (CAG) Gold standard when performed under provocation testing Confusion between CAD and CAS [2, 116, 117, 118]
Omission in conditions of severe stenosis
Electrocardiogram (ECG) Convenience, safety, availability, acceptability Low specificity [119, 120, 121, 122, 123]
Omission in resting intervals
Intracoronary imaging approaches Exhibition of morphological and functional changes despite complex conditions In theoretical stage [117, 119, 124, 125, 126, 127, 128]
High requirements for equipment and operators
OCT Better image quality and resolution to estimate intima Interruption of the blood flow [126, 128]
Tissue penetration: 2 mm
Safety worries
IVUS Deeper penetration (4–8 mm) for accessing perivascular injury without interrupting the blood flow Less resolution [126, 129]
Positron emission tomography (PET) Revelation of coronary vasomotor function and tissue image Expensive [109, 130]
High requirements for equipment
18F-PET Evaluation of inflammation of coronary perivascular adipose tissue Expensive [109]
High requirements for equipment
Myocardial contrast echocardiography (MCE) Microvascular evaluation Indirect functional information [131, 132, 133]
Ignorance of minor systolic wall move
Low resolution
OCT, optical coherence tomography; IVUS, intravascular ultrasound.
Table 2.A summary of the novel diagnostic biomarkers in CAS.
Markers Category References
cystatin C Endothelial dysfunction [141, 142, 143, 144, 145]
xanthine oxidoreductase (XOR) Endothelial dysfunction [29, 146, 147, 148]
hs-CRP Inflammation [18, 148, 149, 150]
sCD40L Inflammation [18]
peripheral monocyte counts Inflammation [151]
Endothelin-1 (ET-1) Vasomotor [30, 152]
Serotonin (5-HT) Vasomotor [153, 154]
Neuropeptide Y Vasomotor [141, 155]
Lipoprotein(a) perivascular adipose tissue metabolism [148, 156, 157, 158, 159]
RhoK activity in circulating neutrophils RhoK pathway [49, 50, 66, 160, 161, 162, 163, 164, 165]
pMLC2 Vascular smooth muscle cell hypersensitivity [96, 101]
ox-LDL Oxidative stress [166, 167]
MDA-LDL Oxidative stress [166, 168, 169]
miR-17-5p, miR-92a-3p, miR-126-3 MicroRNAs [170, 171, 172, 173]
4.1 Imaging Approaches (Table 1, Ref. [2, 109, 116, 117, 118, 119, 120, 121, 122, 123, 124, 125, 126, 127, 128, 129, 130, 131, 132, 133])
4.1.1 Spasm Provocation Test (SPT)

Since the spontaneous coronary vasospasm at the time of angiography is only occasionally observed [134], the current gold-standard diagnosis of CAS is documentation by angiography with pharmacological provocative testing via high-dose intracoronary administration of Ach, ergonovine, or methylergonovine [2]. The typical positive response should include a transient >90% vasoconstriction (Fig. 3A, Ref. [109, 128, 131, 135]) with reproduction of the usual chest pain and ischemic ECG changes at the meantime [2]. Abnormalities of ventricular wall motion on echocardiogram is considered to be equivocal for CAS as well [119]. To distinguish from obstructive arthrosclerosis and other underlying acute coronary syndrome [136], standard 12-lead ECG during an attack, ambulatory cardiac monitoring, or exercise stress testing should be initially performed in a standard cardiac workup [11]. Although coronary artery SPT has been clinically practiced for 40 years [2], complications by invasive operations like arrhythmias (6.8%) [137], hypertension, hypotension, and nausea [138] should also be noteworthy. Therefore, the procedure is suggested to be performed in a specialized center after careful evaluation of the risks and benefits [2], which limits the accessibility and restricts progress of CAS for decades.

Fig. 3.

Representative images of novel diagnostic approaches for CAS. (A) Coronary angiograms of epicardial and microvascular CAS after spasm provocation test (SPT) using intracoronary perfusion of Ach. Images from Arrebola-Moreno et al. [131]. (B) Optical coherence tomography (OCT) image of a spasm lesion after provocation. Medial thickening led to luminal narrowing with intimal gathering. Image from Tanaka et al. [128]. (C) 18F-fluorodeoxyglucose (FDG) positron emission tomography/computed tomography (PET/CT) image of a CAS patients. FDG uptake of coronary PVAT was significantly increased. Image from Ohyama et al. [109]. (D) Myocardial contrast echocardiography (MCE) was carried out with intravenous injection of ergonovine. Apparent regional wall motion abnormalities (arrows) of the interventricular septum and left ventricular (LV) apex, compared with the resting state (left image). Images from Om et al. [135].

4.1.2 Coronary Angiography (CAG)

CAG remains the gold standard for CAD [117]. However, except from the occasional attacks, the coronary artery shows normal appearance on resting CAG [116]. Therefore, if a patient is suspected with CAS, the angiography always accompanies with provocation testing to document the coronary spasm [134]. However, it is challenging to evaluate the interplay of the functional aspects and structural ones in patients with coronary artery atherosclerosis and the provocation testing is usually not performed in the presence of a significant epicardial stenosis. But studies approve that spontaneous attacks of coronary spasm can be superimposed on a relevant stenosis, illustrating the missing part in present clinical practice [118].

4.1.3 Electrocardiogram (ECG)

An ECG of CAS diversifies from completely normal to ST deviation, T, U, R wave abnormality and arrythmia, depending on the severity, duration of episodes and distribution of the spasm artery [119, 120]. Mild seizures could appear just normal in ECG, while total or subtotal spasm of a major coronary artery tend to cause a ST-segment elevation in the leads [120]. However, ST-segment depression also occurs when a less severe, subendocardial myocardial ischemia occurs, when a major artery receiving collaterals or a small artery is completely occluded [122]. These situations include most part of unstable angina/non–ST-elevation myocardial infarction (NSTEMI) cases, thus making ST-segment depression more frequent in CAS [14]. A previous study has shown that 45% of patients with angina at rest and ST-segment depression alone had CAS [123].

In addition to ST-segment changes, a peaked and symmetrical T wave appears in around 50% of cases during a focal proximal coronary spasm [119]. And other wave changes can occur including a delay in the peak and an increase in the height and width of R wave, a decrease in magnitude of S wave and negative U wave may also appear [22]. Various forms of arrhythmia including ventricular premature complex, ventricular tachycardia and/or fibrillation (mostly in case of anterior ischaemia), atrioventricular block (mostly in case of inferior ischaemia), asystole and supraventricular tachyarrhythmias may also be present [121]. In conclusion, ECG takes its advantage in convenience, safety, availability and high-acceptability.

However, even with ambulatory ECG monitoring, the attack may not appear during the monitoring periods, especially when the attack is not frequent [139]. Moreover, ECG does not provide direct or specific evidence of CAS [22]. Thus ECG monitoring is an auxiliary detection in clinic.

4.1.4 Intracoronary Imaging

Intracoronary imaging, such as optical coherence tomography (OCT) and intravascular ultrasound (IVUS) [117], is capable of addressing not only the morphological changes of intima and media during vasospasm, but also providing information regarding the association of vasospasm with underlying atherosclerotic plaque, fibrous cap disruption, enhanced adventitial vasa vasorum [125, 127, 140], increased PVAT volume [109], inflammation, erosion or thrombus formation [119]. OCT analysis during CAS reveals a typical image of intimal bumps deforming the lumen, combining with intimal gathering (Fig. 3B), without alteration of the intimal area. Medial contraction is presented by an increment in medial thickness [124]. However, intracoronary imaging does not wildly spread in clinical practice due to the complex procedure and low specificity, and each approach has its advantages and disadvantages. OCT has better image quality and resolution, which enables estimations of intima [125, 126]. IVUS has a deeper penetration (4–8 mm versus 2 mm of OCT), which assists accessing perivascular injury. In addition, it is safer and easier to perform IVUS since there is no need to cut off the blood flow, rather than OCT which still needs an interruption [126].

4.1.5 Positron Emission Tomography (PET)

PET is a well-validated technique that can not only help assess coronary vasomotor function by providing non-invasive, accurate, and reproducible quantification of myocardial blood flow and coronary flow reserve (CFR) in humans, but also assist in revelation of coronary spasm tissue image [130]. Intriguingly, inflammatory changes of coronary PVAT assessed by 18F-FDG PET imaging (Fig. 3C) were more extensive at the spastic segments of CAS patients as compared to control subjects, which showed significantly suppression after CCBs treatment [109]. Hence, aside from the high price, PET/CT might be useful to assess coronary artery function and the perivascular tissue inflammation surrounding the coronary arteries.

4.1.6 Myocardial Contrast Echocardiography (MCE)

This non-invasive technique is able to provide indirect functional information about micro vessels and thus assists in diagnosing CAS (Fig. 3D). Ong et al. [132] documented a transient myocardial ischemia by myocardial contrast echocardiography during Ach-induced CAS. Similarly, Arrebola-Moreno et al. [131] has shown the MCE as a systematic evidence for 60% Ach-induced CAS, consistent with single photon emission computed tomography (SPECT) and ECG. However, there are still many limitations in MCE. Due to the restriction of supine position that all the transthoracic echocardiographic images are performed at, it is possible for operators to ignore the minor systolic wall motion [131]. Furthermore, MCE can only detect tissue perfusion in the addition of extra contrast because of the poor back scattering from red blood cells [130], which impairs specificity of the technique. In fact, few available studies of MCE are focused on CAS since the vast majority pay attention to the vasodilatation dysfunction [133].

4.2 Serum Biomarkers

Recently, non-invasive biochemical markers have been found to associate with the occurrence of CAS [141], including inflammatory factors, Lipoprotein a, Cystatin C, 5-HT, and ET-1 etc. (Table 2, Ref. [18, 29, 30, 49, 50, 66, 96, 101, 141, 142, 143, 144, 145, 146, 147, 148, 149, 150, 151, 152, 153, 154, 155, 156, 157, 158, 159, 160, 161, 162, 163, 164, 165, 166, 167, 168, 169, 170, 171, 172, 173]).

4.2.1 Endothelial Dysfunction Markers

As mentioned above, ED has been demonstrated an underlying mechanism of CAS [45]. Several potential biomarkers are under investigation through this pathogenesis. It has been proved that cystatin C is a reliable marker of kidney dysfunction [142], and renal failure could lead to inactivation of eNOS [145], which is supposed to be a basic pathogenesis in CAS. In fact, 2 clinical studies conducted in Japan and Korea respectively found a promising relationship between a high level of cystatin C and the prevalence of CAS [143, 144]. Nevertheless, there are still questions since renal dysfunction is also related to atherosclerosis and CAD [141], thus further investigations are still required to identify cystatin C as the unique biomarker for CAS. Additionally, xanthine oxidoreductase (XOR) is a rate-limiting enzyme of purine metabolism, catalyzing the oxidation of hypoxanthine to xanthine and of xanthine to uric acid (UA) [146]. It has been elucidated that increased serum UA produces extra ROS [148], resulting in ED [144]. Previous studies also have revealed that XOR-induced ROS can lead to arterial smooth cell proliferation and migration, up-regulate the renin-angio-tensin system to cause vasoconstriction [147]. A recent prediction model including XOR activity showed significantly improved C index (0.771 versus 0.685 of baseline model), net reclassification index (0.612; 95% confidence interval, 0.237–0.986; p = 0.001) and integrated discrimination index (0.098; 95% confidence interval, 0.040–0.156; p = 0.001), and concluded that serum XOR level might be an effective biomarker of CAS [29].

4.2.2 Inflammatory Markers

Within the belief of an association between inflammation [64], vasomotor dysfunction [45] and CAS, researchers keep finding evidence to prove inflammation markers as potential predictors for CAS, such as hs-CRP and soluble CD40 ligand (sCD40L). Hung et al. [149] showed that serum hs-CRP concentrations were correlated independently to CAS in 116 Taiwanese patients with VSA (41% with focal spasm) versus 66 control patients. Teragawa et al. [150] reported that increased serum hs-CRP levels were an independent predictor of coronary microvascular dysfunction by assessing coronary blood flow responses to Ach. Masami et al. [148] found hs-CRP were significantly increased in the VSA group (N = 441) than in the atypical chest pain group (N = 197). Ong et al. [18] found elevated hs-CRP and sCD40L concentrations were significantly (p 0.05) associated in patients with angina pectoris free from angiographically obstructed coronary arteries. However, there is no obvious correlation between neopterin and CAS since it plays a role in the presence and progression of obstructive CAD [18]. Furthermore, the clinical results about inflammatory factors remain contradictory as a Korean study turned out to show that patients with CAS had no difference in levels of serum CRP as compared to those without CAS. Meanwhile the level of peripheral monocyte counts is found as a good potential marker for CAS [151].

4.2.3 Vasoactive Markers

Except from hs-CRP and sCD40L as mentioned above, more biomarkers are found to be associated with CAS via inducing vasomotor dysfunction since decades ago. In 1990s, several laboratory teams viewed successively that the levels of ET-1 increased in blood during the episodes of CAS [30]. And bosentan, an antagonist of endothelin receptor, significantly relieved the severity and frequency of chest pain induced by CAS [152]. Until now, the relationship and pathogenesis of ET-1 in CAS almost disclose, but the clinical utility of ET-1 as a biomarker of the diseases is still on the way. In addition, 5-HT is proved to play an important role in vasocontraction and vasodilation [174]. Researchers found a high level of 5-HT in blood of patient with CAS during episodes as well as nonischemic intervals [153]. A recent study conducted showed an elevation of 5-HT in CAS patients without obstructed arteries [154]. Fortunately, no obvious contradictions occur in various studies so far. But there are still more work needing to be done about 5-HT before it gets to be applied in clinical practice because of lack of fresh evidence and clinical utility tests. Moreover, recent clinical studies found endogenous neuropeptide Y, another effective vasoactive factor, as a potential pathogenesis of CAS especially microvascular constrictions, for both patients without coronary stenosis and patients of ST-elevated myocardial infarction [155]. Intriguingly, as a co-transmitter of norepinephrine, neuropeptide Y is the only biomarker conformed to be correlated to microvascular spasm instead of epicardial ones [141], which indicates the potential differentiation between spasm in two sizes of coronary arteries and underlying different corresponding medication. Obviously, it will take a further more time from confirming the significant correlation between neuropeptide Y and CAS, to identify it as a well-qualified biomarker for clinical use.

4.2.4 Abnormal Perivascular Adipose Tissue Metabolism

Tsuchida et al. [158] have already reported that higher lipoprotein(a) level was associated with coronary vasomotion in VSA. Masami et al. [148] verified the relationship between serum lipoprotein(a) level and VSA again within 441 Japanese patients. Intriguingly, it has been suggested that the lipoprotein(a) level is related to racial and genetic backgrounds [159], which suggest it is difficult to control the lipoprotein(a) level with medications for the management of VSA in some way. However, a large-scale clinical study did not identify obvious relationship between lipoprotein(a) and the vasospastic response to the intracoronary Ach provocation test [157].

4.2.5 RhoK Activity in Circulating Neutrophils

Accumulated evidence proves that enhanced RhoK activity plays a central role in the coronary VSMC hypersensitivity, which we have demonstrated in CAS pathogenesis above [50, 162]. Further investigations suggest that RhoK activity in circulating neutrophils maybe a potential biomarker for coronary spasm both in diagnosis and assessment of disease activity and efficacy of treatment [164]. In fact, a previous study showed an immediate, temporary increase of RhoK activity in circulating neutrophils in VSA patients after the Great East Japan Earthquake due to disaster-related mental stress [160]. And the cross-link between stress and CAS is indicated by another experimental study which found excessive sensitivity of VSMC to 5-HT under exposure to sustained elevation of serum cortisol level, resulting in coronary vasoconstrictive responses in pigs in vivo [66]. Moreover, there are some interesting biological coincidence between RhoK and CAS. For example, researchers found a circadian variation of RhoK activity in circulating neutrophils with a peak in the early morning, which showed strong association with alterations in coronary basal tone and vasomotor reactivity and might explain the onset preference of CAS [49]. Furthermore, the suppression effect on RhoK by estrogen may partly account for the higher incidence of vasospastic disorders in postmenopausal women [161]. Finally, RhoK activity in circulating neutrophils combining with the Japanese Coronary Spasm Association (JCSA) risk score substantially appears to be a better prognostic choice in risk stratification of VSA patient as compared with either alone [165]. Taking these issues into consideration, it seems that RhoK activity in circulating neutrophils has a strong potential to be developed into a useful biomarker for CAS with a broad versatility. Further investigations about mechanism, stability, detection time window and simplified measurement are required before it being applied to patients.

4.2.6 Oxidative Stress

Oxidation of low density lipoprotein (LDL) produces ox-LDL, which has been proven as a well-established marker of oxidative disorder [141]. Meanwhile, oxidation of LDL is also a key factor in the process and plays a role throughout atherosclerosis as well as CAS pathogenesis [167]. Recently, malondialdehyde-modified low-density lipoprotein (MDA-LDL) is suggested as another marker of endothelial damage [168]. Observational studies reported a strong correlation between serum MDA-LDL levels and endothelial damage, assessed with flow-mediated dilatation [168]. High MDA-LDL levels harbor a predisposing atherosclerotic segment for coronary spasm to arise, which explains the higher chances of ergonovine-induced CAS [166]. MDA-LDL lowering therapy such as intensive statin treatment [169] may have the potential to treat CAS.

4.2.7 Circulating MicroRNAs

Human microRNAs (miRs) are small, single-stranded, endogenous noncoding RNAs that regulate gene expression at the post-transcriptional level by promoting the messenger RNA (mRNA) degradation or repressing certain coding mRNA translation [127]. It is recently reported that the significant higher expression levels of circulating miR-17-5p, miR-92a-3p, and miR-126-3p show discriminatory power in distinguishing patients with VSA from other CADs [170]. MiRs above are indicated to inhibit eNOS expression directly or via KLF2 gene [170, 171], resulting in impaired NO production and thus leaving the coronary arteries in risk of vasoconstriction, platelet aggregation, low-density lipoprotein metabolic abnormalities and VSMC proliferation disorder [172, 173].

5. Conclusions

During the last decades, our knowledge of CAS has been increasingly progressed due to advances in the research strategy and diagnostic approaches. This review summarized the clinical risk factors and molecular mechanisms of CAS pathogenesis, and introduce state-of-the-art diagnostic strategies including both clinical imaging approaches and currently under laboratory-testing biomarkers. More mechanistic studies are mandated to further uncover the development of CAS. The seemingly promising biomarkers exist contradictory results, which suggests a long way off from reaching the clinical practice. More rigorous studies are required for further improvement.

Author Contributions

ZL and XL searched literatures and completed the original draft. XZ provided clinical comments on this review and provided meaningful discussion on the novel diagnostic approaches. CX and BY drew the figures and provided writing assistance. YS and LL conceived and designed the study, and revised the manuscript. All authors read and approved the final manuscript.

Ethics Approval and Consent to Participate

Not applicable.

Acknowledgment

We would like to express our gratitude to all those who helped us during the writing of this manuscript. Thanks to all the peer reviewers for their opinions and constructive suggestions.

Funding

This work was financially supported by the National Natural Science Foundation of China (No. 81871527 and 82070285), the Shanghai Health Committee Research Foundation (20194Y0066), the Zhengyi Scholar Foundation of School of Basic Medical Sciences, Fudan University (No. S25-15), and the Fudan Junzheng Scholar Foundation (No. 2193101011003).

Conflict of Interest

The authors declare no conflict of interest.

References
[1]
Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris. I. A variant form of angina pectoris; preliminary report. American Journal of Medicine. 1959; 27: 375–388.
[2]
Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, et al. International standardization of diagnostic criteria for vasospastic angina. European Heart Journal. 2017; 38: 2565–2568.
[3]
Knuuti J, Wijns W, Saraste A, Capodanno D, Barbato E, Funck-Brentano C, et al. 2019 ESC Guidelines for the diagnosis and management of chronic coronary syndromes. European Heart Journal. 2020; 41: 407–477.
[4]
Kunadian V, Chieffo A, Camici PG, Berry C, Escaned J, Maas A, et al. An EAPCI Expert Consensus Document on Ischaemia with Non-Obstructive Coronary Arteries in Collaboration with European Society of Cardiology Working Group on Coronary Pathophysiology & Microcirculation Endorsed by Coronary Vasomotor Disorders International Study Group. European Heart Journal. 2020; 41: 3504–3520.
[5]
Ibanez B, James S, Agewall S, Antunes MJ, Bucciarelli-Ducci C, Bueno H, et al. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: The Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). European Heart Journal. 2018; 39: 119–177.
[6]
Maseri A, L’Abbate A, Baroldi G, Chierchia S, Marzilli M, Ballestra AM, et al. Coronary vasospasm as a possible cause of myocardial infarction. A conclusion derived from the study of “preinfarction” angina. New England Journal of Medicine. 1978; 299: 1271–1277.
[7]
Slavich M, Patel RS. Coronary artery spasm: Current knowledge and residual uncertainties. International Journal of Cardiology. Heart & Vasculature. 2016; 10: 47–53.
[8]
Ong P, Athanasiadis A, Borgulya G, Vokshi I, Bastiaenen R, Kubik S, et al. Clinical usefulness, angiographic characteristics, and safety evaluation of intracoronary acetylcholine provocation testing among 921 consecutive white patients with unobstructed coronary arteries. Circulation. 2014; 129: 1723–1730.
[9]
Di Fiore DP, Zeitz CJ, Arstall MA, Rajendran S, Sheikh AR, Beltrame JF. Clinical determinants of acetylcholine-induced coronary artery spasm in Australian patients. International Journal of Cardiology. 2015; 193: 59–61.
[10]
Matta A, Bouisset F, Lhermusier T, Campelo-Parada F, Elbaz M, Carrie D, et al. Coronary Artery Spasm: New Insights. Journal of Interventional Cardiology. 2020; 2020: 5894586.
[11]
Beijk MA, Vlastra WV, Delewi R, van de Hoef TP, Boekholdt SM, Sjauw KD, et al. Myocardial infarction with non-obstructive coronary arteries: a focus on vasospastic angina. Netherlands Heart Journal. 2019; 27: 237–245.
[12]
Li J, Zheng J, Zhou Y, Liu X, Peng W. Acute coronary syndrome secondary to allergic coronary vasospasm (Kounis Syndrome): a case series, follow-up and literature review. BMC Cardiovascular Disorders. 2018; 18: 42.
[13]
Aziz A, Hansen HS, Sechtem U, Prescott E, Ong P. Sex-Related Differences in Vasomotor Function in Patients with Angina and Unobstructed Coronary Arteries. Journal of the American College of Cardiology. 2017; 70: 2349–2358.
[14]
Beltrame JF, Sasayama S, Maseri A. Racial heterogeneity in coronary artery vasomotor reactivity: differences between Japanese and Caucasian patients. Journal of the American College of Cardiology. 1999; 33: 1442–1452.
[15]
Sugiishi M, Takatsu F. Cigarette smoking is a major risk factor for coronary spasm. Circulation. 1993; 87: 76–79.
[16]
Kawano H, Node K. The role of vascular failure in coronary artery spasm. Journal of Cardiology. 2011; 57: 2–7.
[17]
Ambrose JA, Barua RS. The pathophysiology of cigarette smoking and cardiovascular disease: an update. Journal of the American College of Cardiology. 2004; 43: 1731–1737.
[18]
Ong P, Carro A, Athanasiadis A, Borgulya G, Schaufele T, Ratge D, et al. Acetylcholine-induced coronary spasm in patients with unobstructed coronary arteries is associated with elevated concentrations of soluble CD40 ligand and high-sensitivity C-reactive protein. Coronary Artery Disease. 2015; 26: 126–132.
[19]
Sohn SM, Choi BG, Choi SY, Byun JK, Mashaly A, Park Y, et al. Impact of alcohol drinking on acetylcholine-induced coronary artery spasm in Korean populations. Atherosclerosis. 2018; 268: 163–169.
[20]
Chong JH, Ghosh AK. Coronary Artery Vasospasm Induced by 5-fluorouracil: Proposed Mechanisms, Existing Management Options and Future Directions. Interventional Cardiology. 2019; 14: 89–94.
[21]
Alexander Y, Osto E, Schmidt–Trucksass A, Shechter M, Trifunovic D, Duncker DJ, et al. Endothelial function in cardiovascular medicine: a consensus paper of the European Society of Cardiology Working Groups on Atherosclerosis and Vascular Biology, Aorta and Peripheral Vascular Diseases, Coronary Pathophysiology and Microcirculation, and Thrombosis. Cardiovascular Research. 2021; 117: 29–42.
[22]
Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y. Coronary artery spasm–clinical features, diagnosis, pathogenesis, and treatment. Journal of Cardiology. 2008; 51: 2–17.
[23]
Okumura K, Yasue H, Matsuyama K, Ogawa H, Kugiyama K, Ishizaka H, et al. Diffuse disorder of coronary artery vasomotility in patients with coronary spastic angina. Hyperreactivity to the constrictor effects of acetylcholine and the dilator effects of nitroglycerin. Journal of the American College of Cardiology. 1996; 27: 45–52.
[24]
Group JCSJW. Guidelines for diagnosis and treatment of patients with vasospastic angina (Coronary Spastic Angina) (JCS 2013). Circulation Journal. 2014; 78: 2779–2801.
[25]
MacAlpin RN. Correlation of the location of coronary arterial spasm with the lead distribution of ST segment elevation during variant angina. American Heart Journal. 1980; 99: 555–564.
[26]
Miyao Y, Kugiyama K, Kawano H, Motoyama T, Ogawa H, Yoshimura M, et al. Diffuse intimal thickening of coronary arteries in patients with coronary spastic angina. Journal of the American College of Cardiology. 2000; 36: 432–437.
[27]
Lindemann H, Petrovic I, Hill S, Athanasiadis A, Mahrholdt H, Schaufele T, et al. Biopsy-confirmed endothelial cell activation in patients with coronary microvascular dysfunction. Coronary Artery Disease. 2018; 29: 216–222.
[28]
Shimokawa H, Tomoike H, Nabeyama S, Yamamoto H, Araki H, Nakamura M, et al. Coronary artery spasm induced in atherosclerotic miniature swine. Science. 1983; 221: 560–562.
[29]
Watanabe K, Shishido T, Otaki Y, Watanabe T, Sugai T, Toshima T, et al. Increased plasma xanthine oxidoreductase activity deteriorates coronary artery spasm. Heart and Vessels. 2019; 34: 1–8.
[30]
Toyo–oka T, Aizawa T, Suzuki N, Hirata Y, Miyauchi T, Shin WS, et al. Increased plasma level of endothelin-1 and coronary spasm induction in patients with vasospastic angina pectoris. Circulation. 1991; 83: 476–483.
[31]
Sirous ZN, Fleming JB, Khalil RA. Endothelin-1 enhances eicosanoids-induced coronary smooth muscle contraction by activating specific protein kinase C isoforms. Hypertension. 2001; 37: 497–504.
[32]
Nakayama K, Ishigai Y, Uchida H, Tanaka Y. Potentiation by endothelin-1 of 5-hydroxytryptamine-induced contraction in coronary artery of the pig. British Journal of Pharmacology. 1991; 104: 978–986.
[33]
Ramzy D, Rao V, Tumiati LC, Xu N, Sheshgiri R, Miriuka S, et al. Elevated endothelin-1 levels impair nitric oxide homeostasis through a PKC-dependent pathway. Circulation. 2006; 114: I319–I326.
[34]
Zhang Y, Edvinsson L, Xu CB. Up-regulation of endothelin receptors induced by cigarette smoke–involvement of MAPK in vascular and airway hyper-reactivity. The Scientific World Journal. 2010; 10: 2157–2166.
[35]
Wilbert-Lampen U, Seliger C, Zilker T, Arendt RM. Cocaine increases the endothelial release of immunoreactive endothelin and its concentrations in human plasma and urine: reversal by coincubation with sigma-receptor antagonists. Circulation. 1998; 98: 385–390.
[36]
Kaku B, Mizuno S, Ohsato K, Murakami T, Moriuchi I, Arai Y, et al. Plasma endothelin-1 elevation associated with alcohol-induced variant angina. Japanese Circulation Journal. 1999; 63: 554–558.
[37]
Nakayama M, Yasue H, Yoshimura M, Shimasaki Y, Kugiyama K, Ogawa H, et al. T-786–>C mutation in the 5’-flanking region of the endothelial nitric oxide synthase gene is associated with coronary spasm. Circulation. 1999; 99: 2864–2870.
[38]
Mizuno Y, Harada E, Morita S, Kinoshita K, Hayashida M, Shono M, et al. East asian variant of aldehyde dehydrogenase 2 is associated with coronary spastic angina: possible roles of reactive aldehydes and implications of alcohol flushing syndrome. Circulation. 2015; 131: 1665–1673.
[39]
Ito T, Yasue H, Yoshimura M, Nakamura S, Nakayama M, Shimasaki Y, et al. Paraoxonase gene Gln192Arg (Q192R) polymorphism is associated with coronary artery spasm. Human Genetics. 2002; 110: 89–94.
[40]
Murase Y, Yamada Y, Hirashiki A, Ichihara S, Kanda H, Watarai M, et al. Genetic risk and gene–environment interaction in coronary artery spasm in Japanese men and women. European Heart Journal. 2004; 25: 970–977.
[41]
Fujimoto H, Kobayashi H, Ogasawara K, Yamakado M, Ohno M. Association of the manganese superoxide dismutase polymorphism with vasospastic angina pectoris. Journal of Cardiology. 2010; 55: 205–210.
[42]
Lee J, Cheong SS, Kim J. Association of endothelin-1 gene polymorphisms with variant angina in Korean patients. Clinical Chemistry and Laboratory Medicine. 2008; 46: 1575–1580.
[43]
Ford TJ, Corcoran D, Padmanabhan S, Aman A, Rocchiccioli P, Good R, et al. Genetic dysregulation of endothelin-1 is implicated in coronary microvascular dysfunction. European Heart Journal. 2020; 41: 3239–3252.
[44]
Shimokawa H. 2014 Williams Harvey Lecture: importance of coronary vasomotion abnormalities-from bench to bedside. European Heart Journal. 2014; 35: 3180–3193.
[45]
Lanza GA, Careri G, Crea F. Mechanisms of coronary artery spasm. Circulation. 2011; 124: 1774–1782.
[46]
Freeman WR, Peter T, Mandel WJ. Verapamil therapy in variant angina pectoris refractory to nitrates. American Heart Journal. 1981; 102: 358–362.
[47]
Hubert A, Seitz A, Pereyra VM, Bekeredjian R, Sechtem U, Ong P. Coronary Artery Spasm: The Interplay Between Endothelial Dysfunction and Vascular Smooth Muscle Cell Hyperreactivity. European Cardiology. 2020; 15: e12.
[48]
Saito T, Hirano M, Ide T, Ichiki T, Koibuchi N, Sunagawa K, et al. Pivotal role of Rho-associated kinase 2 in generating the intrinsic circadian rhythm of vascular contractility. Circulation. 2013; 127: 104–114.
[49]
Nihei T, Takahashi J, Tsuburaya R, Ito Y, Shiroto T, Hao K, et al. Circadian variation of Rho-kinase activity in circulating leukocytes of patients with vasospastic angina. Circulation Journal. 2014; 78: 1183–1190.
[50]
Masumoto A, Mohri M, Shimokawa H, Urakami L, Usui M, Takeshita A. Suppression of coronary artery spasm by the Rho-kinase inhibitor fasudil in patients with vasospastic angina. Circulation. 2002; 105: 1545–1547.
[51]
Suda A, Takahashi J, Hao K, Kikuchi Y, Shindo T, Ikeda S, et al. Coronary Functional Abnormalities in Patients with Angina and Nonobstructive Coronary Artery Disease. Journal of the American College of Cardiology. 2019; 74: 2350–2360.
[52]
Fukumoto Y, Mohri M, Inokuchi K, Ito A, Hirakawa Y, Masumoto A, et al. Anti-ischemic effects of fasudil, a specific Rho-kinase inhibitor, in patients with stable effort angina. Journal of Cardiovascular Pharmacology. 2007; 49: 117–121.
[53]
Mohri M, Shimokawa H, Hirakawa Y, Masumoto A, Takeshita A. Rho-kinase inhibition with intracoronary fasudil prevents myocardial ischemia in patients with coronary microvascular spasm. Journal of the American College of Cardiology. 2003; 41: 15–19.
[54]
Otsuka T, Ibuki C, Suzuki T, Ishii K, Yoshida H, Kodani E, et al. Administration of the Rho-kinase inhibitor, fasudil, following nitroglycerin additionally dilates the site of coronary spasm in patients with vasospastic angina. Coronary Artery Disease. 2008; 19: 105–110.
[55]
Loirand G, Scalbert E, Bril A, Pacaud P. Rho exchange factors in the cardiovascular system. Current Opinion in Pharmacology. 2008; 8: 174–180.
[56]
Carbone ML, Bregeon J, Devos N, Chadeuf G, Blanchard A, Azizi M, et al. Angiotensin II activates the RhoA exchange factor Arhgef1 in humans. Hypertension. 2015; 65: 1273–1278.
[57]
Momotani K, Artamonov MV, Utepbergenov D, Derewenda U, Derewenda ZS, Somlyo AV. p63RhoGEF couples Galpha(q/11)-mediated signaling to Ca2+ sensitization of vascular smooth muscle contractility. Circulation Research. 2011; 109: 993–1002.
[58]
Galle J, Mameghani A, Bolz SS, Gambaryan S, Gorg M, Quaschning T, et al. Oxidized LDL and its compound lysophosphatidylcholine potentiate AngII-induced vasoconstriction by stimulation of RhoA. Journal of the American Society of Nephrology. 2003; 14: 1471–1479.
[59]
Bolz SS, Galle J, Derwand R, de Wit C, Pohl U. Oxidized LDL increases the sensitivity of the contractile apparatus in isolated resistance arteries for Ca(2+) via a rho- and rho kinase-dependent mechanism. Circulation. 2000; 102: 2402–2410.
[60]
Maruko K, Stiffel VM, Gilbert RD. The effect of long-term hypoxia on tension and intracellular calcium responses following stimulation of the thromboxane A(2) receptor in the left anterior descending coronary artery of fetal sheep. Reproductive Sciences. 2009; 16: 364–372.
[61]
Gao Y, Chen Z, Leung SW, Vanhoutte PM. Hypoxic Vasospasm Mediated by cIMP: When Soluble Guanylyl Cyclase Turns Bad. Journal of Cardiovascular Pharmacology. 2015; 65: 545–548.
[62]
Knock GA, Snetkov VA, Shaifta Y, Connolly M, Drndarski S, Noah A, et al. Superoxide constricts rat pulmonary arteries via Rho-kinase-mediated Ca(2+) sensitization. Free Radical Biology and Medicine. 2009; 46: 633–642.
[63]
Shimokawa H, Ito A, Fukumoto Y, Kadokami T, Nakaike R, Sakata M, et al. Chronic treatment with interleukin-1 beta induces coronary intimal lesions and vasospastic responses in pigs in vivo. The role of platelet-derived growth factor. Journal of Clinical Investigation. 1996; 97: 769–776.
[64]
Hiroki J, Shimokawa H, Higashi M, Morikawa K, Kandabashi T, Kawamura N, et al. Inflammatory stimuli upregulate Rho-kinase in human coronary vascular smooth muscle cells. Journal of Molecular and Cellular Cardiology. 2004; 37: 537–546.
[65]
Li T, Liu L, Xu J, Yang G, Ming J. Changes of Rho kinase activity after hemorrhagic shock and its role in shock-induced biphasic response of vascular reactivity and calcium sensitivity. Shock. 2006; 26: 504–509.
[66]
Hizume T, Morikawa K, Takaki A, Abe K, Sunagawa K, Amano M, et al. Sustained elevation of serum cortisol level causes sensitization of coronary vasoconstricting responses in pigs in vivo: a possible link between stress and coronary vasospasm. Circulation Research. 2006; 99: 767–775.
[67]
Asano T, Kobayashi Y, Ohno M, Nakayama T, Kuroda N, Komuro I. Multivessel coronary artery spasm refractory to intensive medical treatment. Angiology. 2007; 58: 636–639.
[68]
Takeuchi M, Saito K, Kajimoto K, Nagatsuka K. Successful Corticosteroid Treatment of Refractory Spontaneous Vasoconstriction of Extracranial Internal Carotid and Coronary Arteries. Neurologist. 2016; 21: 55–57.
[69]
Rivero F, Antuna P, Cuesta J, Alfonso F. Severe coronary spasm in a COVID–19 patient. Catheterization and Cardiovascular Interventions. 2021; 97: E670–E672.
[70]
Saad Shaukat MH, Wilson J, Stys A. Segmental Coronary Vasospasm Mimicking ST-Elevation Myocardial Infarction in an Incidentally COVID-Positive Patient. South Dakota Medicine. 2021; 74: 248–249.
[71]
Kamiunten H, Koike J, Mashiba J, Shimokawa H, Takeshita A. A comprehensive analysis of a novel missense mutation in Rho-kinase that causes coronary vasospasm in the Japanese. Circulation Journal. 2004; 68: 211.
[72]
Yoo SY, Kim J, Cheong S, Shin DH, Jang J, Lee C, et al. Rho-associated kinase 2 polymorphism in patients with vasospastic angina. Korean Circulation Journal. 2012; 42: 406–413.
[73]
Katsumata N, Shimokawa H, Seto M, Kozai T, Yamawaki T, Kuwata K, et al. Enhanced myosin light chain phosphorylations as a central mechanism for coronary artery spasm in a swine model with interleukin-1beta. Circulation. 1997; 96: 4357–4363.
[74]
Okumura K, Osanai T, Kosugi T, Hanada H, Ishizaka H, Fukushi T, et al. Enhanced phospholipase C activity in the cultured skin fibroblast obtained from patients with coronary spastic angina: possible role for enhanced vasoconstrictor response. Journal of the American College of Cardiology. 2000; 36: 1847–1852.
[75]
Murakami R, Osanai T, Tomita H, Sasaki S, Maruyama A, Itoh K, et al. p122 protein enhances intracellular calcium increase to acetylcholine: its possible role in the pathogenesis of coronary spastic angina. Arteriosclerosis, Thrombosis, and Vascular Biology. 2010; 30: 1968–1975.
[76]
Kinjo T, Tanaka M, Osanai T, Shibutani S, Narita I, Tanno T, et al. Enhanced p122RhoGAP/DLC-1 Expression Can Be a Cause of Coronary Spasm. PloS One. 2015; 10: e0143884.
[77]
Nakano T, Osanai T, Tomita H, Sekimata M, Homma Y, Okumura K. Enhanced activity of variant phospholipase C-delta1 protein (R257H) detected in patients with coronary artery spasm. Circulation. 2002; 105: 2024–2029.
[78]
Shibutani S, Osanai T, Ashitate T, Sagara S, Izumiyama K, Yamamoto Y, et al. Coronary vasospasm induced in transgenic mouse with increased phospholipase C-delta1 activity. Circulation. 2012; 125: 1027–1036.
[79]
Ito A, Shimokawa H, Nakaike R, Fukai T, Sakata M, Takayanagi T, et al. Role of protein kinase C-mediated pathway in the pathogenesis of coronary artery spasm in a swine model. Circulation. 1994; 90: 2425–2431.
[80]
Kadokami T, Shimokawa H, Fukumoto Y, Ito A, Takayanagi T, Egashira K, et al. Coronary artery spasm does not depend on the intracellular calcium store but is substantially mediated by the protein kinase C-mediated pathway in a swine model with interleukin-1 beta in vivo. Circulation. 1996; 94: 190–196.
[81]
Giardina JB, Tanner DJ, Khalil RA. Oxidized-LDL enhances coronary vasoconstriction by increasing the activity of protein kinase C isoforms alpha and epsilon. Hypertension. 2001; 37: 561–568.
[82]
Allahdadi KJ, Duling LC, Walker BR, Kanagy NL. Eucapnic intermittent hypoxia augments endothelin-1 vasoconstriction in rats: role of PKCdelta. American Journal of Physiology: Heart and Circulatory Physiology. 2008; 294: H920–H927.
[83]
Yang Q, Fujii W, Kaji N, Kakuta S, Kada K, Kuwahara M, et al. The essential role of phospho-T38 CPI-17 in the maintenance of physiological blood pressure using genetically modified mice. FASEB Journal. 2018; 32: 2095–2109.
[84]
Sun J, Tao T, Zhao W, Wei L, She F, Wang P, et al. CPI-17-mediated contraction of vascular smooth muscle is essential for the development of hypertension in obese mice. Journal of Genetics and Genomics. 2019; 46: 109–118.
[85]
Itoh T, Suzuki A, Watanabe Y, Mino T, Naka M, Tanaka T. A calponin peptide enhances Ca2+ sensitivity of smooth muscle contraction without affecting myosin light chain phosphorylation. Journal of Biological Chemistry. 1995; 270: 20400–20403.
[86]
Matthew JD, Khromov AS, McDuffie MJ, Somlyo AV, Somlyo AP, Taniguchi S, et al. Contractile properties and proteins of smooth muscles of a calponin knockout mouse. Journal of Physiology. 2000; 529: 811–824.
[87]
Martinka P, Lai EY, Fahling M, Jankowski V, Jankowski J, Schubert R, et al. Adenosine increases calcium sensitivity via receptor-independent activation of the p38/MK2 pathway in mesenteric arteries. Acta Physiologica. 2008; 193: 37–46.
[88]
Kandabashi T, Shimokawa H, Miyata K, Kunihiro I, Eto Y, Morishige K, et al. Evidence for protein kinase C-mediated activation of Rho-kinase in a porcine model of coronary artery spasm. Arteriosclerosis, Thrombosis, and Vascular Biology. 2003; 23: 2209–2214.
[89]
Bannister JP, Bulley S, Narayanan D, Thomas-Gatewood C, Luzny P, Pachuau J, et al. Transcriptional upregulation of alpha2delta-1 elevates arterial smooth muscle cell voltage-dependent Ca2+ channel surface expression and cerebrovascular constriction in genetic hypertension. Hypertension. 2012; 60: 1006–1015.
[90]
Smith KJ, Chadburn AJ, Adomaviciene A, Minoretti P, Vignali L, Emanuele E, et al. Coronary spasm and acute myocardial infarction due to a mutation (V734I) in the nucleotide binding domain 1 of ABCC9. International Journal of Cardiology. 2013; 168: 3506–3513.
[91]
Chutkow WA, Pu J, Wheeler MT, Wada T, Makielski JC, Burant CF, et al. Episodic coronary artery vasospasm and hypertension develop in the absence of Sur2 K(ATP) channels. Journal of Clinical Investigation. 2002; 110: 203–208.
[92]
Injeti ER, Sandoval RJ, Williams JM, Smolensky AV, Ford LE, Pearce WJ. Maximal stimulation-induced in situ myosin light chain kinase activity is upregulated in fetal compared with adult ovine carotid arteries. American Journal of Physiology: Heart and Circulatory Physiology. 2008; 295: H2289–2298.
[93]
Kim JI. High fat diet confers vascular hyper-contractility against angiotensin II through upregulation of MLCK and CPI-17. Korean Journal of Physiology & Pharmacology. 2017; 21: 99–106.
[94]
Akata T. Cellular and molecular mechanisms regulating vascular tone. Part 2: regulatory mechanisms modulating Ca2+ mobilization and/or myofilament Ca2+ sensitivity in vascular smooth muscle cells. Journal of Anesthesia. 2007; 21: 232–242.
[95]
Kim HR, Appel S, Vetterkind S, Gangopadhyay SS, Morgan KG. Smooth muscle signalling pathways in health and disease. Journal of Cellular and Molecular Medicine. 2008; 12: 2165–2180.
[96]
Li L, Li Y, Lin J, Jiang J, He M, Sun D, et al. Phosphorylated Myosin Light Chain 2 (p-MLC2) as a Molecular Marker of Antemortem Coronary Artery Spasm. Medical Science Monitor. 2016; 22: 3316–3327.
[97]
Almanza A, Carlesso A, Chintha C, Creedican S, Doultsinos D, Leuzzi B, et al. Endoplasmic reticulum stress signalling - from basic mechanisms to clinical applications. The FEBS journal. 2019; 286: 241–278.
[98]
Choi SK, Lim M, Yeon SI, Lee YH. Inhibition of endoplasmic reticulum stress improves coronary artery function in type 2 diabetic mice. Experimental Physiology. 2016; 101: 768–777.
[99]
Liang B, Wang S, Wang Q, Zhang W, Viollet B, Zhu Y, et al. Aberrant endoplasmic reticulum stress in vascular smooth muscle increases vascular contractility and blood pressure in mice deficient of AMP-activated protein kinase-alpha2 in vivo. Arteriosclerosis, Thrombosis, and Vascular Biology. 2013; 33: 595–604.
[100]
Zhang H, Li J, Li L, Liu P, Wei Y, Qian Z. Ceramide enhances COX-2 expression and VSMC contractile hyperreactivity via ER stress signal activation. Vascular Pharmacology. 2017; 96–98: 26–32.
[101]
Xue A, Lin J, Que C, Yu Y, Tu C, Chen H, et al. Aberrant endoplasmic reticulum stress mediates coronary artery spasm through regulating MLCK/MLC2 pathway. Experimental Cell Research. 2018; 363: 321–331.
[102]
Ziomek G, Cheraghi Zanjani P, Arman D, van Breemen C, Esfandiarei M. Calcium regulation in aortic smooth muscle cells during the initial phase of tunicamycin-induced endo/sarcoplasmic reticulum stress. European Journal of Pharmacology. 2014; 735: 86–96.
[103]
Fukumoto Y, Shimokawa H, Ito A, Kadokami T, Yonemitsu Y, Aikawa M, et al. Inflammatory cytokines cause coronary arteriosclerosis-like changes and alterations in the smooth-muscle phenotypes in pigs. Journal of Cardiovascular Pharmacology. 1997; 29: 222–231.
[104]
Forman MB, Oates JA, Robertson D, Robertson RM, Roberts LJ 2nd, Virmani R. Increased adventitial mast cells in a patient with coronary spasm. New England Journal of Medicine. 1985; 313: 1138–1141.
[105]
Arai R, Migita S, Koyama Y, Homma T, Saigusa N, Akutsu N, et al. Imaging and Pathology of Eosinophilic Coronary Periarteritis. JACC: Cardiovascular Interventions. 2020; 13: e151–e154.
[106]
Laine P, Kaartinen M, Penttila A, Panula P, Paavonen T, Kovanen PT. Association between myocardial infarction and the mast cells in the adventitia of the infarct-related coronary artery. Circulation. 1999; 99: 361–369.
[107]
Ohyama K, Matsumoto Y, Nishimiya K, Hao K, Tsuburaya R, Ota H, et al. Increased Coronary Perivascular Adipose Tissue Volume in Patients with Vasospastic Angina. Circulation Journal. 2016; 80: 1653–1656.
[108]
Ito T, Fujita H, Ichihashi T, Ohte N. Impact of epicardial adipose tissue volume quantified by non-contrast electrocardiogram-gated computed tomography on ergonovine-induced epicardial coronary artery spasm. International Journal of Cardiology. 2016; 221: 877–880.
[109]
Ohyama K, Matsumoto Y, Takanami K, Ota H, Nishimiya K, Sugisawa J, et al. Coronary Adventitial and Perivascular Adipose Tissue Inflammation in Patients with Vasospastic Angina. Journal of the American College of Cardiology. 2018; 71: 414–425.
[110]
Nishimiya K, Matsumoto Y, Takahashi J, Uzuka H, Wang H, Tsuburaya R, et al. Enhanced Adventitial Vasa Vasorum Formation in Patients with Vasospastic Angina: Assessment with OFDI. Journal of the American College of Cardiology. 2016; 67: 598–600.
[111]
Ohyama K, Matsumoto Y, Amamizu H, Uzuka H, Nishimiya K, Morosawa S, et al. Association of Coronary Perivascular Adipose Tissue Inflammation and Drug-Eluting Stent-Induced Coronary Hyperconstricting Responses in Pigs: (18) F-Fluorodeoxyglucose Positron Emission Tomography Imaging Study. Arteriosclerosis, Thrombosis, and Vascular Biology. 2017; 37: 1757–1764.
[112]
Chang L, Garcia-Barrio MT, Chen YE. Perivascular Adipose Tissue Regulates Vascular Function by Targeting Vascular Smooth Muscle Cells. Arteriosclerosis, Thrombosis, and Vascular Biology. 2020; 40: 1094–1109.
[113]
Lynch FM, Withers SB, Yao Z, Werner ME, Edwards G, Weston AH, et al. Perivascular adipose tissue-derived adiponectin activates BK(Ca) channels to induce anticontractile responses. American Journal of Physiology: Heart and Circulatory Physiology. 2013; 304: H786–H795.
[114]
Saxton SN, Withers SB, Nyvad J, Mazur A, Matchkov V, Heagerty AM, et al. Perivascular Adipose Tissue Contributes to the Modulation of Vascular Tone in vivo. Journal of Vascular Research. 2019; 56: 320–332.
[115]
Aalbaek F, Bonde L, Kim S, Boedtkjer E. Perivascular tissue inhibits rho-kinase-dependent smooth muscle Ca(2+) sensitivity and endothelium-dependent H2 S signalling in rat coronary arteries. Journal of Physiology. 2015; 593: 4747–4764.
[116]
Song JK. Coronary Artery Vasospasm. Korean Circulation Journal. 2018; 48: 767–777.
[117]
Ong P, Aziz A, Hansen HS, Prescott E, Athanasiadis A, Sechtem U. Structural and Functional Coronary Artery Abnormalities in Patients with Vasospastic Angina Pectoris. Circulation Journal. 2015; 79: 1431–1438.
[118]
Bentz K, Ong P, Sechtem U. Unstable angina pectoris–combination of an epicardial stenosis and a Prinzmetal spasm. Deutsche Medizinische Wochenschrift. 2013; 138: 2546–2549. (In German)
[119]
Picard F, Sayah N, Spagnoli V, Adjedj J, Varenne O. Vasospastic angina: A literature review of current evidence. Archives of Cardiovascular Diseases. 2019; 112: 44–55.
[120]
Hung MJ, Hu P, Hung MY. Coronary artery spasm: review and update. International Journal of Medical Sciences. 2014; 11: 1161–1171.
[121]
Rodriguez-Manero M, Oloriz T, le Polain de Waroux JB, Burri H, Kreidieh B, de Asmundis C, et al. Long-term prognosis of patients with life-threatening ventricular arrhythmias induced by coronary artery spasm. Europace: European Pacing, Arrhythmias, and Cardiac Electrophysiology. 2018; 20: 851–858.
[122]
Yasue H, Omote S, Takizawa A, Masao N, Hyon H, Nishida S, et al. Comparison of coronary arteriographic findings during angina pectoris associated with S-T elevation or depression. American Journal of Cardiology. 1981; 47: 539–546.
[123]
Bertrand ME, LaBlanche JM, Tilmant PY, Thieuleux FA, Delforge MR, Carre AG, et al. Frequency of provoked coronary arterial spasm in 1089 consecutive patients undergoing coronary arteriography. Circulation. 1982; 65: 1299–1306.
[124]
Task Force M, Montalescot G, Sechtem U, Achenbach S, Andreotti F, Arden C, et al. 2013 ESC guidelines on the management of stable coronary artery disease: the Task Force on the management of stable coronary artery disease of the European Society of Cardiology. European Heart Journal. 2013; 34: 2949–3003.
[125]
Tanaka A, Taruya A, Shibata K, Fuse K, Katayama Y, Yokoyama M, et al. Coronary artery lumen complexity as a new marker for refractory symptoms in patients with vasospastic angina. Scientific Reports. 2021; 11: 13.
[126]
Tearney GJ, Yabushita H, Houser SL, Aretz HT, Jang IK, Schlendorf KH, et al. Quantification of macrophage content in atherosclerotic plaques by optical coherence tomography. Circulation. 2003; 107: 113–119.
[127]
van Rooij E, Olson EN. MicroRNAs: powerful new regulators of heart disease and provocative therapeutic targets. Journal of Clinical Investigation. 2007; 117: 2369–2376.
[128]
Tanaka A, Shimada K, Tearney GJ, Kitabata H, Taguchi H, Fukuda S, et al. Conformational change in coronary artery structure assessed by optical coherence tomography in patients with vasospastic angina. Journal of the American College of Cardiology. 2011; 58: 1608–1613.
[129]
Jang IK, Bouma BE, Kang DH, Park SJ, Park SW, Seung KB, et al. Visualization of coronary atherosclerotic plaques in patients using optical coherence tomography: comparison with intravascular ultrasound. Journal of the American College of Cardiology. 2002; 39: 604–609.
[130]
Camici PG, d’Amati G, Rimoldi O. Coronary microvascular dysfunction: mechanisms and functional assessment. Nature Reviews: Cardiology. 2015; 12: 48–62.
[131]
Arrebola-Moreno AL, Arrebola JP, Moral-Ruiz A, Ramirez-Hernandez JA, Melgares-Moreno R, Kaski JC. Coronary microvascular spasm triggers transient ischemic left ventricular diastolic abnormalities in patients with chest pain and angiographically normal coronary arteries. Atherosclerosis. 2014; 236: 207–214.
[132]
Ong P, Athanasiadis A, Mahrholdt H, Shah BN, Sechtem U, Senior R. Transient myocardial ischemia during acetylcholine-induced coronary microvascular dysfunction documented by myocardial contrast echocardiography. Circulation: Cardiovascular Imaging. 2013; 6: 153–155.
[133]
Gurudevan SV, Nelson MD, Rader F, Tang X, Lewis J, Johannes J, et al. Cocaine-induced vasoconstriction in the human coronary microcirculation: new evidence from myocardial contrast echocardiography. Circulation. 2013; 128: 598–604.
[134]
Waterbury TM, Tarantini G, Vogel B, Mehran R, Gersh BJ, Gulati R. Non-atherosclerotic causes of acute coronary syndromes. Nature Reviews: Cardiology. 2020; 17: 229–241.
[135]
Om SY, Yoo SY, Cho GY, Kim M, Woo Y, Lee S, et al. Diagnostic and Prognostic Value of Ergonovine Echocardiography for Noninvasive Diagnosis of Coronary Vasospasm. JACC: Cardiovascular Imaging. 2020; 13: 1875–1887.
[136]
Ford TJ, Corcoran D, Berry C. Stable coronary syndromes: pathophysiology, diagnostic advances and therapeutic need. Heart. 2018; 104: 284–292.
[137]
Ishii M, Kaikita K, Sato K, Tanaka T, Sugamura K, Sakamoto K, et al. Acetylcholine-Provoked Coronary Spasm at Site of Significant Organic Stenosis Predicts Poor Prognosis in Patients with Coronary Vasospastic Angina. Journal of the American College of Cardiology. 2015; 66: 1105–1115.
[138]
Probst S, Seitz A, Martinez Pereyra V, Hubert A, Becker A, Storm K, et al. Safety assessment and results of coronary spasm provocation testing in patients with myocardial infarction with unobstructed coronary arteries compared to patients with stable angina and unobstructed coronary arteries. European Heart Journal. Acute Cardiovascular Care. 2021; 10: 380–387.
[139]
Araki H, Koiwaya Y, Nakagaki O, Nakamura M. Diurnal distribution of ST-segment elevation and related arrhythmias in patients with variant angina: a study by ambulatory ECG monitoring. Circulation. 1983; 67: 995–1000.
[140]
Calin GA, Dumitru CD, Shimizu M, Bichi R, Zupo S, Noch E, et al. Frequent deletions and down-regulation of micro-RNA genes miR15 and miR16 at 13q14 in chronic lymphocytic leukemia. Proceedings of the National Academy of Sciences of the United States of America. 2002; 99: 15524–15529.
[141]
Li L, Jin YP, Xia SD, Feng C. The Biochemical Markers Associated with the Occurrence of Coronary Spasm. BioMed Research International. 2019; 2019: 4834202.
[142]
Lamb EJ. Cystatin C: why clinical laboratories should be measuring it. Annals of Clinical Biochemistry. 2015; 52: 709–711.
[143]
Funayama A, Watanabe T, Tamabuchi T, Otaki Y, Netsu S, Hasegawa H, et al. Elevated cystatin C levels predict the incidence of vasospastic angina. Circulation Journal. 2011; 75: 2439–2444.
[144]
Lee SN, Shin DI, Jung MH, Choi IJ, Seo SM, Her SH, et al. Impact of cystatin-C level on the prevalence and angiographic characteristics of vasospastic angina in Korean patients. International Heart Journal. 2015; 56: 49–55.
[145]
Koga S, Ikeda S, Nakata T, Yasunaga T, Takeno M, Koide Y, et al. Low glomerular filtration rate is associated with high prevalence of vasospastic angina. Circulation Journal. 2011; 75: 1691–1695.
[146]
Otaki Y, Watanabe T, Kinoshita D, Yokoyama M, Takahashi T, Toshima T, et al. Association of plasma xanthine oxidoreductase activity with severity and clinical outcome in patients with chronic heart failure. International Journal of Cardiology. 2017; 228: 151–157.
[147]
Battelli MG, Polito L, Bolognesi A. Xanthine oxidoreductase in atherosclerosis pathogenesis: not only oxidative stress. Atherosclerosis. 2014; 237: 562–567.
[148]
Nishino M, Mori N, Yoshimura T, Nakamura D, Lee Y, Taniike M, et al. Higher serum uric acid and lipoprotein(a) are correlated with coronary spasm. Heart and Vessels. 2014; 29: 186–190.
[149]
Hung MJ, Cherng WJ, Yang NI, Cheng CW, Li LF. Relation of high-sensitivity C-reactive protein level with coronary vasospastic angina pectoris in patients without hemodynamically significant coronary artery disease. American Journal of Cardiology. 2005; 96: 1484–1490.
[150]
Teragawa H, Fukuda Y, Matsuda K, Ueda K, Higashi Y, Oshima T, et al. Relation between C reactive protein concentrations and coronary microvascular endothelial function. Heart. 2004; 90: 750–754.
[151]
Yun KH, Oh SK, Park EM, Kim HJ, Shin SH, Lee EM, et al. An increased monocyte count predicts coronary artery spasm in patients with resting chest pain and insignificant coronary artery stenosis. Korean Journal of Internal Medicine. 2006; 21: 97–102.
[152]
Vermeltfoort IA, Raijmakers PG, Kamphuisen PW. Improved myocardial perfusion preceding clinical response on bosentan treatment for coronary vasospasm. Acta Cardiologica. 2009; 64: 415–417.
[153]
Murakami Y, Ishinaga Y, Sano K, Murakami R, Kinoshita Y, Kitamura J, et al. Increased serotonin release across the coronary bed during a nonischemic interval in patients with vasospastic angina. Clinical Cardiology. 1996; 19: 473–476.
[154]
Odaka Y, Takahashi J, Tsuburaya R, Nishimiya K, Hao K, Matsumoto Y, et al. Plasma concentration of serotonin is a novel biomarker for coronary microvascular dysfunction in patients with suspected angina and unobstructive coronary arteries. European Heart Journal. 2017; 38: 489–496.
[155]
Herring N, Tapoulal N, Kalla M, Ye X, Borysova L, Lee R, et al. Neuropeptide-Y causes coronary microvascular constriction and is associated with reduced ejection fraction following ST-elevation myocardial infarction. European Heart Journal. 2019; 40: 1920–1929.
[156]
Sandholzer C, Hallman DM, Saha N, Sigurdsson G, Lackner C, Csaszar A, et al. Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups. Human Genetics. 1991; 86: 607–614.
[157]
Mashaly A, Rha SW, Choi BG, Baek MJ, Ryu YG, Choi SY, et al. Impact of serum lipoprotein(a) on endothelium-dependent coronary vasomotor response assessed by intracoronary acetylcholine provocation. Coronary Artery Disease. 2018; 29: 516–525.
[158]
Tsuchida K, Hori T, Tanabe N, Makiyama Y, Ozawa T, Saigawa T, et al. Relationship between serum lipoprotein(a) concentrations and coronary vasomotion in coronary spastic angina. Circulation Journal. 2005; 69: 521–525.
[159]
Abe A, Noma A. Studies on apolipoprotein(a) phenotypes. Part 1. Phenotype frequencies in a healthy Japanese population. Atherosclerosis. 1992; 96: 1–8.
[160]
Nihei T, Takahashi J, Kikuchi Y, Takagi Y, Hao K, Tsuburaya R, et al. Enhanced Rho-kinase activity in patients with vasospastic angina after the Great East Japan Earthquake. Circulation Journal. 2012; 76: 2892–2894.
[161]
Bairey Merz CN, Pepine CJ, Walsh MN, Fleg JL. Ischemia and No Obstructive Coronary Artery Disease (INOCA): Developing Evidence-Based Therapies and Research Agenda for the Next Decade. Circulation. 2017; 135: 1075–1092.
[162]
Shimokawa H, Sunamura S, Satoh K. RhoA/Rho-Kinase in the Cardiovascular System. Circulation Research. 2016; 118: 352–366.
[163]
Takahashi J, Suda A, Nishimiya K, Godo S, Yasuda S, Shimokawa H. Pathophysiology and Diagnosis of Coronary Functional Abnormalities. European Cardiology. 2021; 16: e30.
[164]
Kikuchi Y, Yasuda S, Aizawa K, Tsuburaya R, Ito Y, Takeda M, et al. Enhanced Rho-kinase activity in circulating neutrophils of patients with vasospastic angina: a possible biomarker for diagnosis and disease activity assessment. Journal of the American College of Cardiology. 2011; 58: 1231–1237.
[165]
Nihei T, Takahashi J, Hao K, Kikuchi Y, Odaka Y, Tsuburaya R, et al. Prognostic impacts of Rho-kinase activity in circulating leucocytes in patients with vasospastic angina. European Heart Journal. 2018; 39: 952–959.
[166]
Ito T, Fujita H, Tani T, Sugiura T, Ohte N. Increased circulating malondialdehyde-modified low-density lipoprotein levels in patients with ergonovine-induced coronary artery spasm. International Journal of Cardiology. 2015; 184: 475–480.
[167]
Witztum JL. The oxidation hypothesis of atherosclerosis. The Lancet. 1994; 344: 793–795.
[168]
Sugiura T, Dohi Y, Yamashita S, Yamamoto K, Tanaka S, Wakamatsu Y, et al. Malondialdehyde-modified LDL to HDL-cholesterol ratio reflects endothelial damage. International Journal of Cardiology. 2011; 147: 461–463.
[169]
Tamura A, Watanabe T, Nasu M. Effects of atorvastatin and pravastatin on malondialdehyde-modified LDL in hypercholesterolemic patients. Circulation Journal. 2003; 67: 816–820.
[170]
Park CS, Kim I, Oh GC, Han JK, Yang HM, Park KW, et al. Diagnostic Utility and Pathogenic Role of Circulating MicroRNAs in Vasospastic Angina. Journal of Clinical Medicine Research. 2020; 9: 1313.
[171]
Moldovan L, Batte KE, Trgovcich J, Wisler J, Marsh CB, Piper M. Methodological challenges in utilizing miRNAs as circulating biomarkers. Journal of Cellular and Molecular Medicine. 2014; 18: 371–390.
[172]
Mocharla P, Briand S, Giannotti G, Dorries C, Jakob P, Paneni F, et al. AngiomiR-126 expression and secretion from circulating CD34(+) and CD14(+) PBMCs: role for proangiogenic effects and alterations in type 2 diabetics. Blood. 2013; 121: 226–236.
[173]
Treguer K, Heinrich EM, Ohtani K, Bonauer A, Dimmeler S. Role of the microRNA-17-92 cluster in the endothelial differentiation of stem cells. Journal of Vascular Research. 2012; 49: 447–460.
[174]
Watts SW. Oh, the places you’ll go! My many colored serotonin (apologies to Dr. Seuss). American Journal of Physiology: Heart and Circulatory Physiology. 2016; 311: H1225–H1233.
Share
Back to top