The most common pathophysiologic mechanism of acute myocardial infarction (AMI) is represented by atherosclerotic plaque rupture with subsequent intracoronary thrombus formation.1

However, following the increased use of coronary angiography in patients with AMI in the last two decades and the broadening of AMI diagnosis even in patients with only mild troponin increase as a marker of myocardial necrosis, myocardial infarction with nonobstructive coronary arteries (MINOCA) appears to be increasingly recognized in daily clinical practice.2

The first case of MINOCA dates back >75 years, when an autopsy revealed myocardial necrosis without significant coronary atherosclerosis. DeWood et al. reported, in their angiographic studies, an approximately 5% prevalence of nonobstructive coronary artery disease among patients with AMI.3,4 A meta-analysis, which included 28 studies from 1995 to 2013, reported an overall prevalence of 6–8% with variations depending on the proportion of patients who underwent coronary angiography and on the assay used for high-sensitivity cardiac troponin measurement.5–7 In a recent multicenter study of young patients (aged 18–55 years), MINOCA showed a prevalence of 11%.8 Compared with AMI and obstructive coronary artery disease (CAD), MINOCA presents some peculiar epidemiological features. Subjects are younger, show a predominance of women and nonwhite patients and present fewer traditional risk factors and previous or concurrent cardiovascular diseases, except for hypertension, which seems to be equally shared by MINOCA and MIOCA patients.2,9 Despite initial considerations, more extensive long-term studies have demonstrated that MINOCA prognosis is not benign, with an increased long-term risk of all-cause mortality and major adverse cardiovascular events (MACE) similar to the data observed in MI-CAD patients.10,11

However, MINOCA has heterogeneous causes which may result in different and variable prognostic implications (Fig. 1). Accordingly, to apply the most appropriate form of treatment, it is important to clarify the specific underlying pathophysiological mechanism of the syndrome in individual patients.12 In this review, we discuss the different pathophysiological pathways that lead to MINOCA and evaluate the best therapeutic approach in each scenario.

In 2016, the European Society of Cardiology proposed the following criteria for the diagnosis of MINOCA: AMI criteria, as defined by the ‘Third Universal Definition of Myocardial Infarction’; the presence of nonobstructive coronary arteries disease, that is, no stenosis ≥50% in any epicardial vessel; and no other clinically obvious specific cause that might provide an alternative diagnosis for the acute presentation.13

Importantly, although elevated troponin levels indicate myocyte damage, the process is not disease specific and can result from either ischemic or nonischemic conditions. Therefore, with the ‘Fourth Universal Definition of Myocardial Infarction’ the concept of myocardial injury was redefined and the diagnosis of MINOCA was also revised.1 Specifically, in case of suspected AMI and absence of obstructive CAD, alternative causes of elevated troponin levels, such as sepsis, pulmonary embolism, and myocarditis, should be excluded. Among the above, the most challenging confounder is represented by acute myocarditis presenting with chest pain, which is often associated with ST-segment deviation, perfectly mimicking an AMI. Therefore, the diagnosis of MINOCA should be considered as a working diagnosis until other possible causes are ruled out.12

MINOCA can present both as a type-1 or type-2 AMI. Clinical history, electrocardiogram, cardiac biomarkers, echocardiography, and coronary angiography represent the first-level diagnostic tools to confirm or exclude the diagnosis.14 Additional coronary imaging or physiologic studies may be necessary when angiography is nondiagnostic. Invasive coronary imaging with optical coherence tomography (OCT) and intravascular ultrasound (IVUS) allows a detailed examination of the vascular layers and plaque structure. Instead, the assessment of coronary physiology with pharmacologic provocation testing may identify abnormalities in epicardial and/or microvascular vasomotor function that can be responsible for myocardial ischemia when no other apparent cause of AMI is identified. Of note, a relevant role in the diagnostic workup of patients with an acute clinical presentation with suspected MINOCA is played by cardiac magnetic resonance (CMR).12

CMR is particularly helpful in cases of uncertain diagnosis, thanks to its ability to differentiate ischemic versus nonischemic myocardial damage.15–17 Late gadolinium enhancement (LGE) with sub-endocardial or transmural distribution and regional coronary injury indicates an ischemic cause, whereas nonischemic LGE patterns (sub-epicardial or intra-myocardial) suggest a cardiomyopathy or myocarditis.18,19 Finally, the absence of relevant LGE with myocardial edema associated with specific wall motion abnormalities (e.g. apical ballooning) is indicative of Takotsubo syndrome (TSS) (see thereafter).20

Disruption of noncritical atherosclerotic plaques, including plaque erosion, ulceration, and rupture, is an important cause of MINOCA and may accounts for 5–20% of cases (Fig. 1).21,22

Myonecrosis in these patients can be mediated by transient thrombosis, thromboembolism, superimposed vasospasm, or a combination of these processes. Spontaneous thrombolysis or autolysis of a coronary thrombosis has been proposed to explain the absence of subocclusive or occlusive thrombi at coronary angiography in MINOCA, especially when coronary angiography is performed late and antithrombotic as well as antiplatelet agents have been promptly administered.23

Among MINOCA patients with subcritical plaque disruption, CMR imaging may show large areas of myocardial edema with or without small areas of necrosis, suggesting that flow has been only transiently impaired in a large vessel. Alternatively, CMR may reveal a smaller, well defined LGE area, related to a smaller vessel, suggesting embolization of ather-othrombotic debris from the rupture site as the most likely mechanism of myonecrosis.21

The angiographic features that may indicate plaque rupture include mild vessel narrowing (