Coronary plaque disruption represents a relevant cause of MINOCA, involving 40% of total cases. In this critical context, acute thrombosis usually develops as a consequence of different pathophysiological processes, leading to a subcritical coronary stenosis rate ($\le$50%) [7]. The term ‘vulnerable plaque’ is usually used to define three main pathogenic lesions responsible for acute coronary thrombosis: plaque rupture, erosion, and eruptive calcified nodules [8]. Plaque rupture is the most frequent histopathological lesion leading to acute coronary syndrome. Ruptured atherosclerotic plaques are characterized by a discontinuity of their thin fibrous cap and a discontinuous intimal layer, together with a large necrotic core including lipids and inflammatory cells [9]. On the contrary, eroded plaques, which account for nearly 25% of ST-segment elevation MI, exhibit a thick, intact fibrous cap, with missing local endothelial cells, a smaller lipid core and a larger lumen area. Plaque erosions are characterized by apoptosis of the endothelium, with ensuing intimal denudation and exposure of pro-thrombotic agents. However, they typically maintain intact internal and external elastic laminas and have a well-represented tunica media with contractile smooth muscle cells; unlike ruptured plaques, which are characterized by a discontinuous internal lamina, together with a thin and less-developed tunica media [10]. Intracoronary imaging, particularly with high-resolution optical coherence tomography (OCT), plays a pivotal role in order to diagnose plaque rupture and to better characterize plaque morphology. In this regard, Dai and coworkers [11] described three different subsets of eroded plaques, based on plaque morphology: (i) fibrous plaque (defined as a lesion with a high backscattering and a homogeneous region); (ii) thick-cap fibroatheroma (characterized by a minimal fibrous cap thickness $\ge$65 $\mu$m); (iii) thin-cap fibroatheroma (defined by a minimal fibrous cap 65 $\mu$m). Finally, in 2–7% of overall acute coronary syndromes, eruptive calcified nodules are identified as a subset of MINOCA. They are characterized by a disruption of luminal surface by nodules of dense calcium with overlying thrombotic material, with no underlying necrotic core; they usually involve the intimal layer, the mid-right coronary artery and, most frequently, the left anterior descending coronary artery, at the sites of maximal torsion [12, 13]. Although the precise mechanism responsible for the formation of eruptive calcified nodules is still under investigation, a plausible hypothesis takes into account the increase in phosphate concentration in vascular smooth muscle cells and macrophage, which induces a shift towards a osteoblast-like-phenotype and promotes mineralization through the secretion of bone-associated proteins [14]. Although both ruptured and eroded plaques, as well as eruptive calcified nodules may give rise to potential acute thrombosis, the thrombus formed by plaque rupture generally consists of red thrombi, mainly formed by red blood cells and fibrin, while the surface of eroded plaques and eruptive calcified nodules is covered with white thrombi, mainly characterized by platelet and fibrinogen [9].

Epicardial coronary spasm has been found in a wide range of patients with MINOCA, particularly in subjects under 50 years of age, with a prevalence rate of 16–74% of total cases, thus suggesting its pivotal role in the pathogenesis of acute myocardial ischemia in this subset population [5, 15]. An increasing prevalence of cases has been reported in women, particularly East Asians, especially from Korea and Japan [16, 17]. These demographic variations are partially related to genetic factors, such as the deficiency of the aldehyde dehydrogenase 2 genotipe variant, with consequent increase of toxic aldheyde levels in this subset of patients [18]. Several endogenous or exogenous vasoconstrictive triggers have been numbered in the literature, including smoking habits, cold exposure, psychological stress, hyperventilation, alcohol intake and stimulant agents (i.e., cocaine consumption) [19]. Chemotherapeutic agents (particularly belonging to the class of fluoropyrimidines) have been shown to induce endothelial injury and smooth muscle cell activation, with consequent myocardial ischemia secondary to epicardial coronary spasm [20, 21]. Furthermore, coronary vasospasm has been reported as a pivotal pathogenic mechanism involved in the Kounis syndrome, described as the occurrence of acute coronary syndrome triggered by an anaphylactic or anaphylactoid reaction [22, 23]. Finally, several studies have pointed out the occurrence of epicardial coronary spasm at segments with myocardial bridges, for which several pathogenic mechanisms have been hypothesized including myogenic myocardial mechanisms, abnormal coronary vasomotor mechanisms and impaired coronary adventitial vasa vasorum at the segments of the myocardial bridge [24]. Besides all the heterogeneous potential leading mechanisms, epicardial coronary spasm can be diagnosed in case of documented reduction of blood vessel diameter $\ge$75%, either occurring spontaneously or induced by pharmacological provocative testing with intracoronary acetylcholine (Ach), ergonovine or methylergonovine, together with clinical symptoms or instrumental findings of myocardial ischemia [5, 15].

SCAD represents another leading epicardial cause of MINOCA, with a mean prevalence rate of 4% among patients presenting with acute coronary syndrome, reaching a percentage of 35% in women under 50 years of age. Mechanisms of acute myocardial ischemia in SCAD refer to the development of an intramural hematoma within the tunica media, which predisposes to the separation from the underlying intimal layer and the compression of the true lumen [25, 26]. In accordance with the Yip-Saw angiographic classification, type 2 SCAD is the most common variant, and is characterized by a diffuse long smooth tubular lesion (typically $>$20 mm) because of a compressing intramural hematoma, with an abrupt change of the vessel caliper between normal and diseased segments. Specifically, type 2A SCAD has a normal vascular segment at its extremities, while type 2B SCAD prolongs up to the distal part of the vessel, and may appear as a ‘normal tapering’ vessel [27]. Type 1 SCAD consists of a longitudinal filling defect with contrast staining of the vessel wall and the appearance of double or multiple radiolucent lumens of different opacities [28]. Finally, type 3 SCAD is less frequent, due to multiple focal stenosis mimicking atherosclerosis. It is similar to type 2 SCAD, albeit shorter (usually 20 mm) and often requires intravascular imaging for the diagnosis [25] (Fig. 4, Ref. [25]). Several overlapping conditions may favor SCAD, including arterial hypertension, fibromuscular dysplasia, connective tissue diseases, inherited arteriopathies, systemic inflammatory conditions, as well as pregnancy. The latter takes a pivotal role in developing SCAD, particularly in the first weeks after delivery due to the hormonal and hemodynamic changes involved [29]. Changes in estrogen and progesterone levels drive structural changes in the tunica media, predisposing to coronary dissection (including impairment of connective tissue synthesis, increase in muchopolysaccharide content and fragmentation of elastic fibers) [25, 29]. On the other hand, anatomical factors, such as the presence of coronary tortuosity and the lack of intraluminal thrombus, predispose to SCAD recurrence and have a huge impact on prognostic outcomes [30]. Among diagnostic tools, OCT is the most accurate imaging technique in detecting SCAD and guiding coronary intervention, as it allows a better detection of both dissection length and changes in lumen diameter and because it is less affected by coronary calcifications than intravascular ultrasound (IVUS) [31].

Fig. 4.

Yip-Saw angiographic spontaneous coronary artery dissection. Adapted from Teruzzi et al. [25].

Coronary microvascular dysfunction represents another leading cause of MINOCA, with a mean prevalence rate of 30% of patients with angina symptoms, particularly women with cardiovascular risk factors [32]. A standardized definition of coronary microvascular angina includes subjects with chest pain, together with the angiographic finding of non-obstructive epicardial coronary arteries, and an impaired coronary blood flow. The latter can be defined either as values of coronary flow reserve 2.0 or index of microcirculatory resistance $\ge$25 units after intracoronary vasodilator injection, or as the presence of coronary microvascular spasm diagnosed during intracoronary functional provocative test, or else as impaired coronary blood flow measured with a corrected Thrombolysis in Myocardial Infarction (TIMI) frame count [26, 33]. Endothelium has been shown to play a pivotal role in modulating vascular tone, due to its synthesis of endothelium-derived relaxing factors, including nitric oxide and vascular prostaglandins (which act mainly on epicardial coronary vasculature), and endothelium-dependent hyperpolarization factors, particularly hydrogen peroxide (which predominantly provokes vasodilatation of small resistance vasculature, such as coronary microvessels) [34]. As a result of this fine-tuned mechanism, increased myocardial metabolic activity promotes vasodilatation of the smallest arterioles (40 $\mu$m), leading to the reduction of intraluminal pressure in medium-size arterioles (40–100 $\mu$m), which results in vasodilatation regulated by a myogenic response. This in turn increases flow upstream in the large arterioles (100–200 $\mu$m) through endothelium-dependent vasodilatation, in response to the wall share stress. Through these mechanisms, microcirculation regulates myocardial perfusion both at rest and at different levels of myocardial metabolic demands [35] (Fig. 5, Ref. [35]). Therefore, in this clinical setting endothelial-dependent microvascular dysfunction has been thought to be related to a reduced production of the aforementioned relaxing agents and their effects on coronary microcirculation. Furthermore, endothelium-dependent disfunction also involves microvascular inflammation and platelet activation, which in turn lead to vessel obstruction due to microvascular spasm, smooth cells proliferation and intimal thickening [32]. Endothelial cell dysfunction is also the pathophysiological key of coronary microvascular impairment detected in thrombotic microangiopathies. The latter include two typical phenotypes (thrombotic thrombocytopenic purpura and hemolytic uremic syndrome) and a spectrum of life-threatening clinical conditions, in which cardiovascular involvement is linked by a common pathophysiological basis, including endothelial damage of terminal arterioles and capillaries, with complete or partial microvascular occlusion caused by platelet and hyaline thrombi, and schistocyte formation due to the increased shear stress which impairs the membrane of red blood cells [36, 37]. Coronary microvascular spasm is defined as the concurrence of angina symptoms together with ECG abnormalities, without induction of coronary epicardial spasm during intracoronary pharmacologic provocative tests. Different pathogenic mechanisms of coronary microvascular spasm have been reported, including myosin light-chain phosporylation induced by Rho kinase and systemic inflammation leading to increased production of vasoconstrictive agents (i.e., serotonin or endothelin-1) and microvascular vasoconstriction [26, 38]. Additionally, also endothelium-independent vascular reactivity, unresponsive to intracoronary administration of adenosine, has been reported as the potential leading cause of myocardial ischemia due to coronary microvascular dysfunction, either related to atherosclerotic or non-atherosclerotic etiology [38]. Finally, intramural or extramural structural changes in the vascular wall (including luminal narrowing, vascular rarefaction, as well as extraluminal compression consequent to systemic disease) also contribute to coronary microvascular ischemia [39]. Specifically, a greater prevalence of cardiovascular risk factors (including diabetes mellitus, body overweight, dyslipidemia and older age) together with the presence of chronic inflammatory disorders, have been shown to promote inflammatory perivascular adipose tissue, which contributes to both epicardial and coronary microvascular flow disruption [40].

Fig. 5.

Macro and micro coronary circulation and mechanisms inducing vasodilatation. Adapted from Vancheri et al. [33].

Albeit commonly reported in case series, coronary embolisms represent an infrequent and often unrecognized cause of acute coronary syndromes, affecting near 3% of patients with MINOCA, with a higher embolism recurrence and 10-year mortality rate, compared to non-embolic acute coronary syndromes [41]. Coronary arteries seem to be relatively protected from embolic sources, due to their acute angle takeoff from the aortic bulb, as compared to the aortic or distal systemic circulation. Three different types of embolic sources have been described: direct; paradoxical and iatrogenic, with potential overlap among them. Direct coronary emboli may originate from left sided thrombotic material. Left ventricular thrombotic material is usually reported as a consequence of coronary heart disease, while atrial fibrillation or mitral stenosis are common predisposing factors for thrombi located at the left atrium or left atrial appendage [42]. Infective endocarditic vegetations represent another underestimated cause of coronary embolism, which has been reported as embolic source in up to 60% of post-mortem assessments. Several risk factors for systemic embolization of infective vegetations have been proposed, including: (i) echocardiographic diameter greater than 10 mm); (ii) involvement of the mitral valve; (iii) staphylococcal or fungal infections [43]. Finally, albeit uncommon, cardiac tumors represent a predisposing source of coronary embolism, particularly villiform mixomas and papillary fibroelastomas [41, 44]. Furthermore, coronary embolism also includes the paradoxical migration of thrombotic material coming from the deep venous system and reaching the systemic circulation through a patent foramen ovale or atrial septal defect [45]. Finally, the presence of embolic material in the coronary circulation may be the consequence of interventional procedures (such as cardiac surgery or percutaneous interventions at the time of coronary or valvuloplasty procedure), particularly when systemic heparinization is not adequately maintained and catheters are not adequately flushed [46, 47]. Despite different causes, the common mechanism predisposing to coronary embolism is related to microvascular obstruction, leading to platelet cell activation and vasospasm, together with mechanical plugging of the microcirculation [32, 48].

Cardiac ultrasound is a first-level technique for assessing the causes of MINOCA. It should be performed in the acute onset, in order to identify ‘epicardial’ or ‘microvascular’ patterns by detecting regional wall motion abnormalities either involving a single epicardial coronary artery or extending beyond the myocardial wall region of a single epicardial coronary artery [2, 5]. Transthoracic and transoesophageal echocardiography also play a pivotal role in detecting sources of coronary embolism, such as ventricular thrombi, myxomas and papillary fibroelastomas and other cardiac tumors; valvular heart disease, endocarditis and unstable plaques in the ascending aorta. Furthermore, cardiac ultrasound may assess right-to-left interatrial shunts (demonstrated by i.v. microbubble infusion), thereby revealing the presence of patent foramen ovale, atrial septal defects or other intracardiac shunts [45].

CMR imaging is a useful tool with patients with MINOCA, in order to confirm the diagnosis of MI and provide insights for detecting potential underlying causes. A prospective analysis by Pathik and co-workers [55] showed that CMR identified the underlying cause in 87% of patients with MINOCA. Particularly, CMR should be performed within 2 weeks after the onset of symptoms, in order to increase the diagnostic accuracy of the test in identifying the causes of MINOCA. Even very small necrotic areas can be detected, as the spatial resolution of CMR allows to detect even a mass as small as 0.16 g [56]. In subjects with MINOCA CMR may sometimes show large areas of myocardial oedema with or without small areas of necrosis, thus suggesting that coronary flow has been compromised transiently in a large vessel. This event may be attributed to a spontaneous coronary thrombolysis or to the occurrence of vasospasm. Finally, it allows LGE to be detected. CMR that reveals LGE allows to locate the area of myocardial damage and provides insight into the mechanisms of injury. For instance, an area of LGE in the subendocardium suggests an ischemic cause, though it cannot identify the cause of the ischemia (plaque disruption, vasospasm, thromboembolism, or dissection), while a sub-epicardial localization suggests cardiomyopathy. A non-ischemic appearance of LGE may suggest either myocarditis or an infiltrative disorder. CMR may be useful in the diagnostic work-up of MINOCA resulting from epicardial plaque disruption; in such cases, it enables the assessment of large areas of myocardial oedema and can detect transient flow compromission in a large vessel. It can also identify small well-defined areas of LGE, which suggests that atherothrombotic small vessel embolization from the site of disruption may be the main cause of myocardial necrosis in MINOCA patients [55]. Finally, in a subgroup of MINOCA patients, CMR is normal. This may be due to the fact that myocardial necrosis in these patients is too small to be detected. Alternatively, the normal CMR appearance may result from a wider spatial distribution of necrosis, i.e. necrotic myocytes may be scattered over a large area with no contiguous island of cell death of sufficient size to be detected by LGE imaging. Patients whose CMR is normal tend to display lower peak troponin values, though peak troponin values 100 times higher than the normal upper limit may occur even in patients who do not present LGE [56]. Furthermore, in patients with MINOCA and normal CMR, myocardial oedema imaging, which provides evidence of myocardial injury, is also absent. In the initial CMR studies, the finding of normality may be due to the fact that T2 imaging is undertaken late in the clinical course or that the CMR sequences utilized are not sufficiently sensitive [54, 56]. Developments in CMR techniques for imaging myocardial oedema and the routine application of CMR in MINOCA patients will provide further insights (Table 1).

Studies on MINOCA patients have revealed that as many as 15% may have an abnormality that is detected on thrombophilia screening [57]. Several hypercoagulable disorders, including inherited or acquired causes, may predispose to a higher risk of coronary thromboembolic events. The main inherited causes of thrombophilia include factor V Leiden and increased levels of factor VIII, as well as protein C, protein S and factor XII deficiency, while acquired etiology may include antiphospholipid syndrome, heparin-induced thrombocytopenia, thrombotic thrombocytopenic purpura, autoimmune disorders and myeloproliferative tumors [58]. Although inherited thrombophilia may significantly impact on the increased risk for venous thromboembolism, no evidence of increased risk for arterial thromboembolism has been shown in long-term cohort trials of subjects with inherited thrombophilia. Furthermore, in patients with no known environmental and acquired thrombogenic factors and without long-term oral anticoagulation, the recurrence rate of thromboembolic events was near 10% on follow-up, thus suggesting a false reassurance for negative thrombophilia screening tests, because only a limited subset of thrombophilia mutations were taken into account [42].

Coronary CT angiography has been progressively employed as a non-invasive diagnostic tool capable to provide a three-dimensional reconstruction set, allowing further geometrical characterization of cardiac chambers and epicardial coronary anatomy (albeit limited by increased heart rate, more than 70 beats per min). However, only a few data reported in the literature have investigated its systematic use in detecting underlying coronary atherosclerosis and critical coronary lesions in patients with MINOCA, also due to its low positive predictive value and diagnostic accuracy, particularly in distinguishing between coronary plaque rupture or erosion. For these reasons, the role of coronary CT angiography is still confined to excluding a low diagnostic suspicion of coronary atherosclerosis in subjects with a low pre-test probability, also because of its high specificity index [59]. Taken together, these findings suggest a still limited role of coronary CT angiography in diagnosis and therapeutic decision making for subjects with MINOCA.

The role of coronary angiography is the cornerstone for diagnosing MINOCA, as it allows to ascertain the absence of obstructive atherosclerotic lesions. However, unfortunately this procedure may sometimes result in a misleading diagnosis, owing to the fact that intravascular ultrasound studies have frequently demonstrated a significant atherosclerotic burden even in patients with “normal” coronary angiography [2]. Furthermore, the angiographic criteria for ‘non-obstructive coronary arteries’ detailed in the MINOCA definition utilize the conventional cut-off of $>$50% stenosis, which is consistent with the current angiographic guidelines. This conventional threshold is rather arbitrary and there is substantial inter- and intra-observer variability in the visual estimation of angiographic stenosis. Moreover, the dynamic pathophysiological nature of an acute coronary syndrome may result in significant angiographic changes arising from fluctuating coronary vasomotor tone and unstable coronary plaques (including a shifting thrombotic mass, plaque hemorrhage and washout of plaque contents) [5, 8]. Finally, coronary angiography cannot demonstrate, but only suggest, the presence of coronary plaque disruption in the presence of haziness or of a small filling defect; conversely, OCT or, to a lesser extent, IVUS should be used to identify plaque disruption [34]. Furthermore, coronary angiography may also play a role in the angiographic suspicion of coronary embolism, which may angiographically appear as a heavy thrombotic burden and filling defects in different coronary arteries, although bystander atherosclerotic lesions are commonly present, making angiographic diagnosis more challenging [42].

Intracoronary imaging tools play a pivotal role in confirming non-obstructive coronary lesions in patients with acute coronary syndromes and identifying the various possible causes of MINOCA. Specifically, intracoronary imaging techniques have proved capable of identifying not only coronary plaque disruption (which encompasses plaque rupture, erosion and eruptive calcified nodules), but also its underling atherogenic mechanisms and consequent therapeutic approach. While thrombi are frequently detected at the site of plaque rupture, they cannot be found at the site of old ruptured atherosclerotic plaques, nor in the case of freshly ruptured plaques that have been promptly treated with anti-thrombotic therapies [2]. Thus, if executed at the time of cardiac catheterization, intracoronary imaging with either IVUS or OCT may be useful in identifying the most important causes of MINOCA. OCT should be preferred to IVUS, as it allows the identification of ruptured atherosclerotic plaque with thrombosis [2, 9]. Taking into account the current intracoronary imaging modalities, only OCT has been demonstrated to successfully identify plaque erosions, and distinguish between ‘defined’ and ‘probable’ OCT erosions (as the former consist of an unrupted fibrous cap and overlying white thrombus, while the latter are characterized by the absence of luminal thrombus or attenuation of the atherosclerotic plaque underlying the thrombus). Finally, although eruptive calcified nodules were first described by means of IVUS, OCT has proved superior in detecting them, as it shows fibrous cap breakage and/or thrombus over a calcified plaque protruding into the coronary lumen [3, 60]. Intracoronary imaging diagnostic tools may also help to detect coronary artery dissections. IVUS is a safe, accurate and reproducible imaging tool for detecting vessel wall structure; it can help differentiate between true and false coronary aneurysms, and allows intravascular assessment of coronary mural hematoma [31, 61]. However, OCT has been reported to be superior for the detection of coronary dissection, particularly in the presence of type 1 SCAD (in which a false lumen is detected), due to its higher spatial resolution and capability of generate high-resolution cross-sectional images of coronary wall structure [62]. Moreover, it allows a better definition of intimal flaps and can aid the assessment of guidewire location prior to percutaneous intervention. Finally, because of its greater diagnostic power in detecting intima-media layers and intramural hematoma, OCT plays a role in case of diagnostic uncertainty, especially for the diagnosis of type 3 SCAD, which either mimics atherosclerotic lesions or describes an abrupt vessel occlusion [25, 63] (Table 2). On the basis of the aforementioned properties of OCT, Taruya and coworkers investigated the potential impact of lesion characteristics on prognostic outcome in subjects with MINOCA. They found that nearly half of them were characterized by the presence of hidden ‘high-risk’ vascular wall lesions (i.e. ruptured or eroded plaques, calcified nodules, SCAD or endothelial dysfunction), and resulted in poorer outcomes than those affected by functional etiologies (i.e., coronary spasm) [64]. These findings underline the need to introduce intracoronary imaging tools in diagnostic flow charts for MINOCA, in order to rule out potential underlying organic causes and perform a proper risk stratification of MINOCA patients, particularly for those with mild coronary stenosis.

In patients with MINOCA, if clinical data suggest coronary artery spasm, provocative testing by means of intra-coronary Ach or ergonovine should be performed in the diagnostic work-up. Provocative spasm testing has been seen to induce spasm in 27% of MINOCA patients, suggesting that it is a common and important pathogenic mechanism in MINOCA [3, 15]. Given that nitrates, and especially calcium channel blockers, are effective therapies for coronary artery spasm, and that the latter have been shown to prevent cardiac events in vasospastic angina, the diagnosis and treatment of coronary artery spasm need to be carefully considered [65]. Microvascular spasm is another potential cause of MINOCA, since elevated troponins have been detected via ultrasensitive assays following provocative spasm testing, despite the absence of inducible large-vessel spasm [66]. In this pathophysiologic context, further insight into the general safety and prognostic value of provocative spasm tests in MINOCA have been investigated. Data from the AChPOL Registry including patients undergoing intracoronary provocative test with Ach from December 2010 to March 2013 for a suspicion of variant angina or coronary microvascular spasm, showed a general safety and feasibility of intracoronary Ach use. Furthermore, over a median follow-up of 56 months, a significantly higher rate of recurrent chest pain requiring hospitalization has been reported in the microvascular spasm subgroup, compared to patients with negative intracoronary Ach test [67]. In a single-center analysis by Montone et al. [68] focusing on the role of abnormal coronary vasomotion as a trigger of acute coronary syndrome, the following findings were reported: (i) in MINOCA patients, provocative tests for spasm identify a large proportion of patients who would otherwise be discharged from hospital without a sure pathogenic diagnosis; (ii) provocative tests for spasm have prognostic significance; (iii) spasm can be safely elicited in the catheter laboratory even in the acute or subacute phases (i.e., within the first 48 h) of MINOCA. The safety of performing intracoronary provocative spasm tests in the acute setting of MINOCA has been confirmed in a systematic review conducted by Ciliberti et al. [69], who evaluated the safety of pharmacological provocative intracoronary tests with Ach or ergonovine in more than 9400 patients presenting with acute coronary syndrome or stable coronary artery disease. No deaths were reported and the overall occurrence of major (0.8%) and minor (4.7%) complications was low [70]. The most prevalent major complications included: ventricular tachycardia or ventricular fibrillation (0.69%), cardiogenic shock (0.03%), acute MI (0.01%), coronary dissection (0.01%), cardiac tamponade (0.01%) and prolonged spasm (0.01%). The most common minor event (2.17%) was the induction of marked bradycardia or transient second- or third-degree atrioventricular block following Ach injection into the right coronary artery, with spontaneous resolution within 3–5 s in the absence of associated symptoms [67, 68]. Taken together, these findings encourage interventional cardiologists to incorporate intracoronary provocative spasm tests in their routine clinical practice, as they may improve interventional strategies in subjects with MINOCA due to functional etiologies, and contribute to design a prompt diagnostic work-up and therapeutic approach in this subset population [71].