Coronary thrombosis or embolism may cause MINOCA if the microcirculation is involved, with or without a hypercoagulable state. Diagnostic testing for inherited coagulopathies in patients with MINOCA should be performed when information from the patient’s personal history and family history could raise clinical concern. Coronary emboli may occur in the context of the above thrombophilic disorders or other predisposing hypercoagulable states such as atrial fibrillation and valvular heart disease. Emboli may arise from non-thrombotic sources also including valvular vegetations or calcifications, iatrogenic air emboli or cardiac tumors (e.g., papillary fibroelastoma or myxoma) [13, 23]. These different etiologies recognize the same pathogenetic mechanism, that is blockage of the microcirculation, which in turn leads to a pro-inflammatory state and to platelet activation by reiterating the pro-thrombotic stimulus, and additionally, a component of reactive vasoconstriction can be added [13, 23].

Coronary artery spasm is a prevalent cause of MINOCA, according to recent literature data it represents about 30% of cases of MINOCA. It is characterized by an intense vasoconstriction of an artery within the coronary epicardial arterial circulation. This constriction can be either focal or diffuse, involving more than 90% of the artery’s diameter, leading to compromised myocardial blood flow [24]. The underlying mechanism of this spasm involves hyperactivity of smooth muscle cells in the vascular wall, which can be triggered by various endogenous or exogenous stimuli. For instance, substances like methamphetamine and cocaine have been known to induce spasms [25]. Coronary artery spasm commonly manifests as transient ischemia, which is the underlying cause of Prinzmetal’s angina [26]. However, in some cases, it can result in more prolonged spasms and persistent ischemia, leading to AMI [27]. It has been observed that Asian individuals have a higher risk of coronary spasm compared to individuals of white race [28]. Furthermore, recent research has demonstrated that particulate matter with a diameter of 2.5 micrometers or smaller, a component of air pollution, is an independent risk factor for the development of coronary spasm and MINOCA [29].

Microcirculatory dysfunction (CMD) is responsible for approximately 20–30% of MINOCA cases [8, 30]. The diagnosis of microcirculatory dysfunction can be made using both invasive and non-invasive methods. Non-invasive diagnostic methods include CMR and positron emission tomography (PET). CMD is characterized by homogenous circumferential inducible ischemia, localized mainly in the subendocardial layer of the myocardium well identifiable with using 3-T CMR with quantitative perfusion [31]. Through myocardial PET it is possible to study the coronary microcirculation and evaluate its functionality, specifically by quantifying reductions in hyperemic myocardial blood flow (MBF) and myocardial flow reserve (MFR) [32]. Invasive evaluation should involve assessing both microvascular vasodilatory and vasoconstrictive responses. Microvascular vasoconstrictive responses could be evaluated using a provocative stimulus, either pharmacological (acetylcholine or ergonovine) or non-pharmacological (hyperventilation $\pm$ tris(hydroxymethyl)aminomethane (TRIS) buffer infusion or cold pressor testing). The vasodilatory capacity can be estimated using the coronary flow reserve (CFR), which is the ratio between the maximum hyperemic coronary blood flow velocity and the baseline flow velocity achieved through adenosine infusion [33]. Another parameter is the index of microcirculatory resistance (IMR), which is defined as the product of distal coronary pressure and the mean transit time of a saline bolus through a coronary artery during maximal hyperemia [34]. Under physiological conditions the IMR is 25. An IMR $\ge$25 indicates increased resistance to microvascular and microcirculatory dysfunction. An IMR value $>$40 after primary coronary angioplasty is associated with a higher incidence of major cardiovascular events at 30 days, the presence of a larger infarct area, and an increased risk of microvascular obstruction [35].

Spontaneous coronary artery dissection (SCAD) is defined as an ‘epicardial coronary artery dissection that is not associated with atherosclerosis or trauma and is not iatrogenic’. It is a common cause of AMI among women 50 years of age. SCAD is estimated to occur in 1–4% of patients with acute coronary syndromes. SCAD is caused by a separation of the media and intimal tunica with intramural hematoma protrusion into the vascular lumen [13]. It may exist as a basic intrinsic vascular disease to which precipitating factors associated with catecholamine release may be added. Extreme physical exertion, emotional stress, and sympathomimetic medications could all be triggering factors. The substantial correlation between SCAD and other vascular diseases, such as fibromuscular dysplasia, supports this notion [36]. Collagen vascular diseases like Marfan, Ehlers-Danlos and Alport syndromes, as well as inflammatory conditions like systemic lupus erythematosus, celiac disease, sarcoidosis, and inflammatory bowel disease, are also linked to SCAD. Notably, SCAD has been described in all phases of childbirth [37]. The majority of SCAD patients exhibit high serial biomarkers and electrocardiogram (ECG) results compatible with AMI as well as chest pain or similar symptoms. Sudden cardiac arrest, cardiogenic shock, and ventricular arrhythmias are further symptoms of SCAD. The final diagnosis could require intravascular imaging demonstrating the absence of significant atherosclerosis and the presence of dissection and intramural hematoma [38].

This is a broad category that encompasses different pathophysiological processes (such as coronary spasm and thrombosis) as well as additional systemic disorders that cause a mismatch between supply and demand (such as tachyarrhythmias, anemia, hypotension, and thyrotoxicosis) [1, 13]. When there is a reasonable etiology (such as tachycardia, anemia, or hypotension) and there are no clinical or diagnostic modalities that would otherwise support a different diagnosis, a type 2 myocardial infarction is diagnosed in patients with MINOCA [39]. One of the frequent causes of type-2 myocardial infarction is tachyarrhythmia-associated AMI [40]. The treatment or reversal of the initiating cause would take precedence in the management of a MINOCA event caused by a supply-demand mismatch.

In MINOCA events caused by plaque disruption cardioprotective therapies according to AMI guidelines should be prescribed [33, 34, 35], since atherothrombosis is primarily involved in pathogenesis. One of the remaining questions regarding the management of these patients is about the use of DAPT in case of a small plaque rupture in a non-significant stenosis and without overlying thrombus. The recent EROSION study was a pilot study that analyzed the role of DAPT without stenting in patients with an MI, secondary to plaque erosion documented by OCT [42]. The study showed a significant reduction in thrombus volume at one month follow-up for patients in DAPT therapy (aspirin and ticagrelor), and after 1 year 92.5% of patients in DAPT didn’t report any major adverse cardiovascular events. Therefore, this study offered encouraging data on DAPT in MINOCA with plaque disruption but further confirmation from prospective, randomized clinical trials are needed [43].

It is still debatable whether long-term anticoagulant or antiplatelet therapies are required in this group of MINOCA patients. Specific hypercoagulable states could be treated with appropriate therapies. For example, Thrombotic Thrombocytopenic Purpura (TTP) patients need plasmapheresis, with possible adjunctive treatments including steroids and rituximab [13]. Other hypercoagulable conditions require targeted therapies and a shared diagnostic and therapeutic management with a hematologist [13].

Calcium channel blockers are considered the keystone therapy for patients with coronary spasm. Indeed, calcium channel blockers have been demonstrated to improve angina symptoms and prognosis in this patient population [44]. For patients with refractory vasospastic angina, the use of two calcium channel blockers that act on different receptors has been shown to improve symptoms [26]. In addition to calcium channel blockers, other medications have demonstrated effectiveness in alleviating symptoms of coronary spasm. These include nitrates, nicorandil, cilostazol, and pioglitazone [45, 46, 47, 48, 49, 50, 51, 52, 53, 54]. On the other hand, the use of beta-blockers should be avoided as they can predispose individuals to episodes of vasospastic angina [55] and antiplatelet therapies have not been demonstrated to improve symptoms and/or prognosis [56].

The therapeutic management of patients with microvascular dysfunction is more debated compared to other forms of MINOCA. Indeed, many conventional vasodilator agents are less effective on the microvasculature than on large epicardial vessels [40]. Among conventional antianginal medications, beta-blockers and calcium channel blockers have been shown to alleviate symptoms [57]. Additionally, small studies have demonstrated the benefit of other drugs such as dipyridamole, ranolazine (due to their microvascular vasodilatory effect), imipramine, aminophylline (for their analgesic effect), L-arginine and statins (for their endothelial stabilization effect) [58]. However, further studies are needed to establish optimal management and treatment strategies for this subgroup of patients with MINOCA.

In terms of revascularization strategy, a conservative approach should be the preferred strategy, except for very high-risk patients [59]. In fact, it was observed that coronary segments with SCAD repair spontaneously, and revascularization is associated with a risk of dissection propagation.

In terms of pharmacological therapy, patients with SCAD should be treated with aspirin and beta-blockers [60]. SCAD survivors taking beta-blockers had a decreased risk of recurrences, according to data from a large cohort [61]. The use of a combination of anticoagulation and DAPT should be avoided since they might enhance the likelihood of bleeding and the spread of the hematoma/ false lumen [62]. Indeed, in large retrospective registries, DAPT has been associated with less favourable clinical outcomes as compared to aspirin alone [63].

Finally, depending on the patient’s specific risk factors (such as dyslipidaemia) and on the left ventricular ejection fraction, statins and/or heart failure drugs can be added [64].