Myocardial infarction with non-obstructive coronary arteries (MINOCA): State-of-the-Art Review

1. Introduction

Myocardial infarction with non-obstructive coronary arteries (MINOCA) refers to patients presenting with acute myocardial injury and clinical features of acute myocardial infarction (MI), but without significant obstructive coronary artery disease (CAD) on coronary angiography [1, 2]. The reported prevalence of working diagnosis of MINOCA varies, ranging from 4% to 15% [1, 3]. Compared to patients with classical MI due to obstructive CAD (MI-CAD), those with MINOCA tend to be younger, female, and less likely to have traditional cardiovascular risk factors such as dyslipidemia [3, 4].

Historically, MINOCA was often considered a false-positive diagnosis; however, advances in cardiac imaging and biomarker studies have confirmed that true myocardial injury can occur in the absence of obstructive CAD. Current guidelines now recognize MINOCA as a working diagnosis that warrants further investigation to identify the underlying etiology [1, 2]. This approach is critical, as MINOCA is associated with a significantly increased risk of adverse outcomes compared with the general population, and its prognosis is not as benign as initially believed [5]. Moreover, identifying the underlying etiology is essential, as the causes of MINOCA are heterogeneous and the appropriate management can vary substantially depending on the specific diagnosis [3, 6-8].

A large prospective cohort study of 900 patients with MINOCA demonstrated that although the risk of all-cause mortality and recurrent MI was lower than in MI-CAD patients, MINOCA patients still had a 4.6-fold higher risk of composite outcomes compared to age-matched controls without cardiovascular disease [6]. Another large cohort study showed that MINOCA has a prognosis similar to single vessel MI-CAD in terms of morbidity and cause-specific mortality in first-time MINOCA [9]. Similarly, the SWEDEHEART registry, which included 9,000 MINOCA patients, reported a 13.4% all-cause mortality and a 24% incidence of major adverse cardiovascular events (MACE) at 4 years [7]. The CathPCI registry, which included over 16,000 MINOCA patients aged ≥65 years, showed a 12.3% 1-year mortality and an 18% MACE rate [8]. More recently, a retrospective cohort study reported similar long-term all-cause mortality between patients with true MINOCA and those with MI-CAD, whereas mortality was significantly lower among patients with nonischemic MINOCA mimickers [10]. These findings underscore the need for careful diagnostic evaluation and tailored management in MINOCA patients [11]. This review aims to summarize the current understanding of the pathophysiology, diagnostic approach, and therapeutic evidence of MINOCA to guide clinical evaluation and management. By integrating the Fifth Universal Definition of MI with emerging randomized evidence, this review provides a contemporary framework for transitioning from an initial working diagnosis of MINOCA to definitive etiologic classification and mechanism-directed treatment. The search criteria with keywords of myocardial infarction with non-obstructive coronary arteries, MINOCA, coronary microvascular dysfunction, coronary vasospasm, and spontaneous coronary artery dissection were used to collect reports published in English language only in the PubMed database from its inception to August 2025. A targeted search update through October 2026 incorporated recent evidence. Studies were selected based on clinical relevance, prioritizing landmark studies, randomized trials, large observational studies, systematic reviews, and contemporary society guidance.

2. Definition of MINOCA

Traditionally, MINOCA was defined by three essential criteria: (1) fulfillment of the universal definition of acute MI; (2) absence of obstructive CAD, typically defined as no stenosis ≥50% in any major epicardial vessel on coronary angiography; and (3) no clinically overt alternative explanation for the presentation [1, 2]. Under the Fourth Universal Definition of MI, the diagnosis of MINOCA required evidence of myocardial injury accompanied by clinical signs of myocardial ischemia [12]. More recently, the Fifth Universal Definition of MI updated the definition of MINOCA to myocardial injury with non-obstructive coronary arteries, emphasizing that MINOCA represents a working rather than a final diagnosis [13]. This updated terminology recognizes that subsequent evaluation may identify either an ischemic MI mechanism or an alternative cardiac or non-cardiac cause of myocardial injury. When MI is subsequently confirmed, the final diagnosis should be classified as primary, secondary, or procedure-related MI according to the underlying clinical setting [13].

Because elevated troponin levels may result from both ischemic and non-ischemic mechanisms, distinguishing true MINOCA from other causes of myocardial injury is essential [11]. Non-ischemic conditions, such as myocarditis, Takotsubo syndrome, sepsis, pulmonary embolism, or cardiac trauma, may mimic acute MI [12]. These “MINOCA mimickers” must be systematically excluded before confirming the diagnosis [1, 2]. Therefore, MINOCA should be considered an initial working diagnosis at the time of coronary angiography, prompting further evaluation to distinguish primary MI due to acute coronary pathology, secondary MI due to another acute condition, and alternative nonischemic causes of myocardial injury [1, 2, 13].

The diagnostic process begins when a patient presents with a clinical picture consistent with acute MI but without significant obstructive CAD on angiography. At this stage, it is crucial to exclude overt non-coronary causes of myocardial injury and to ensure that subtle obstructive lesions, especially in distal vessels or complete occlusions in small segments, are not overlooked [1]. Left ventricular angiography may also be useful at the time of coronary angiography, as it can identify wall-motion abnormalities and suggest the diagnosis of Takotsubo syndrome. Cardiac magnetic resonance imaging (CMR) plays a central role in this evaluation, as it can identify non-ischemic injury patterns such as myocarditis or Takotsubo syndrome, and confirm ischemic injury when present [1, 2]. The diagnostic algorithm is presented in Figure 1.

^{Figure 1 Diagnostic algorithm for patients with suspected myocardial infarction with non-obstructive coronary arteries (MINOCA). The flowchart outlines a stepwise evaluation, beginning with the exclusion of MINOCA mimickers, differentiation between ischemic and non-ischemic etiologies, and the use of advanced non-invasive and invasive imaging modalities to identify the underlying cause. Figure created with BioRender.com. CAD coronary artery disease; CMD coronary microvascular dysfunction; CMR Cardiac magnetic resonance imaging; FFR fractional flow reserve; IVUS intravascular ultrasound; MI myocardial infarction; OCT optical coherence tomography.}

Ultimately, suspected MINOCA represents a heterogeneous clinical syndrome encompassing both ischemic and non-ischemic etiologies, whereas true MINOCA reflects confirmed ischemic mechanisms [1, 2]. The pathophysiology is summarized in Figure 2. Identifying the precise underlying mechanism is critical, as it directly informs both management strategies and long-term prognosis.

^{Figure 2 Pathophysiological mechanisms of myocardial infarction with non-obstructive coronary arteries (MINOCA), encompassing both atherosclerotic and non-atherosclerotic etiologies. The schematic illustrates key processes, including plaque rupture, plaque erosion, coronary vasospasm, coronary microvascular dysfunction, spontaneous coronary artery dissection, and coronary embolism/thrombosis. Figure created with BioRender.com.}

^{ET-1 endothelin-1; NO nitric oxide; ROS reactive oxygen species; VSMCs vascular smooth muscle cells.}

3. Atherosclerotic Causes of MINOCA

Atherosclerosis is a major underlying mechanism in a substantial proportion of MINOCA patients. Risk factors associated with different mechanisms of MINOCA are summarized in Table 1 [14-18]. The pathophysiology involves plaque disruption, which includes plaque rupture, plaque erosion, and calcified nodules [1]. These disruptions can trigger thrombus formation, leading to myocardial injury through mechanisms such as distal embolization, transient coronary occlusion, or luminal narrowing, which may be exacerbated by concurrent coronary vasospasm [1]. Spontaneous thrombolysis can result in non-obstructive findings on coronary angiography despite clear evidence of myocardial ischemia [1].

Importantly, coronary atherosclerosis contributes to MINOCA through several non-obstructive mechanisms beyond focal epicardial stenosis. Atherosclerotic plaque erosion can lead to distal coronary microembolization, resulting in patchy microinfarction, microvascular obstruction, and release of particulate debris and inflammatory mediators that impair the microcirculation despite angiographically normal-appearing arteries [19, 20]. In addition, diffuse atherosclerotic remodeling and endothelial dysfunction can reduce coronary flow reserve and contribute to microvascular dysfunction [20]. Thus, atherosclerosis in MINOCA encompasses a spectrum of epicardial and microvascular processes rather than solely obstructive disease.

Advanced intracoronary imaging modalities, including optical coherence tomography (OCT) and intravascular ultrasound (IVUS), have enhanced the detection of plaque disruption in MINOCA, especially when conventional angiography fails to identify a culprit lesion [21-24]. Among selected MINOCA patients undergoing OCT or IVUS, plaque disruption was identified in approximately 24% to 40% of cases, although definitions varied across studies [21-23]. For instance, the HARP multicenter study identified OCT-detectable atherosclerotic lesions in 43% of women with MINOCA [21]. Notably, up to 30% of patients with angiographically normal coronary arteries were found to have a clear culprit lesion on OCT, highlighting the limitations of conventional angiography and the usefulness of intracoronary imaging [21]. Similarly, plaque disruption was noted among 37% of patients on IVUS in a study from Paris that enrolled MINOCA patients [25].

Comparative studies reveal distinct differences in plaque morphology between MINOCA and MI-CAD. Plaque erosion, characterized by thrombus formation on an irregular endothelial surface with an intact fibrous cap, is more frequently observed in MINOCA compared to MI-CAD. The MINOCA characteristics of OCT features of erosions are a thick intima and a small or absent lipid core. If the lipid core is present, it does not communicate with luminal thrombi [26]. Calcified nodules, although less common, can also lead to thrombotic events [27]. Vulnerable plaques with thin-cap fibroatheromas are significantly less common in MINOCA (3%) compared to MI-CAD (35%). In contrast, intraplaque hemorrhage (47% in MINOCA vs. 2% in MI-CAD) and layered plaques (31% in MINOCA vs. 12% in MI-CAD) are more frequently observed in MINOCA [27]. An OCT study of 99 MINOCA patients reported plaque erosion in 65%, plaque rupture in 33%, and calcified nodules in 2% [24]. Among women presenting with MINOCA, Iqbal and colleagues found that plaque disruption occurred in fibrous or fibrofatty plaques and, contrary to expectations, was not typically seen in eccentric, outwardly remodeled, or soft plaques [28].

Collectively, these findings suggest that plaque erosion is more common in MINOCA, while plaque rupture predominates in MI-CAD. When plaque rupture does occur, its characteristics differ from those noted in MI-CAD. The use of intracoronary imaging is critical in detecting subtle atherosclerotic lesions that may be missed by angiography. Identifying plaque disruption in MINOCA supports the use of secondary prevention strategies similar to those for MI-CAD.

Based on current evidence, several limitations should be acknowledged. Most studies investigating plaque morphology in MINOCA rely on small OCT or IVUS cohorts, often conducted at tertiary centers with inherent selection bias. Comparator groups, such as chest pain patients without myocardial injury, are rarely included, making it difficult to determine the true prevalence of plaque disruption in MINOCA. Furthermore, many studies do not systematically exclude mimickers with CMR or fully assess non-atherosclerotic etiologies, contributing to the variation in reported prevalence of plaque morphology across studies.

4. Non-atherosclerotic Causes of MINOCA

In addition to atherosclerotic mechanisms, several non-atherosclerotic conditions have been identified as causes of definitive MINOCA. Recognizing these mechanisms is clinically significant, as cohort studies have shown that patients with MINOCA due to non-atherosclerotic etiologies experience similar risks of composite outcomes, including all-cause mortality and recurrent MI, over two years, compared to those with mild CAD [6].

4.1 Epicardial Coronary Vasospasm

Coronary vasospasm is a common non-atherosclerotic cause of MINOCA, with prevalence estimates ranging widely from 4% to 65%, depending on the population, diagnostic protocols, and use of provocative testing [29]. Importantly, vasospasm often occurs concomitantly with underlying atherosclerotic disease [30]. A meta-analysis reported a pooled prevalence of approximately 40%, though true prevalence remains uncertain, as provocation testing is not routinely performed and is typically reserved for selected patients [31].

Epicardial vasospasm can cause transient near-complete coronary occlusion, resulting in ischemia despite the absence of obstructive CAD. It may also exacerbate ischemia in the presence of pre-existing, non-severe plaque disruption [1]. Coronary vasospasm is defined as transient ≥90% coronary constriction, accompanied by angina and ischemic ECG changes, either spontaneously or after pharmacologic provocation [32]. Invasive provocation testing with intracoronary acetylcholine or ergonovine is the diagnostic gold standard, with inducible spasm observed in 28% to 65% of tested MINOCA patients [3, 32-34].

Vasospasm is more prevalent in females and in Asian populations. Japanese studies report inducible spasm in up to 81% of MINOCA cases, compared to lower rates in Europe and the United States [3, 35]. Moreover, in patients with MI-CAD, Japanese individuals were found to have a threefold higher incidence of inducible vasospasm compared with Caucasians [36]. Recurrent or rest angina, typically occurring in the early morning, may suggest vasospastic angina [37, 38]. Importantly, many patients with inducible vasospasm also show evidence of non-obstructive CAD on angiography [34]. Predictors of coronary spasm include younger age, typical chest pain, prior angina, ST-segment elevation, and lower left ventricular ejection fraction (LVEF) [39].

The timing of provocation testing can influence detection rates. In MI-CAD populations, testing within six weeks of MI increases the likelihood of inducible spasm compared to testing later [30]. An earlier systematic review in MINOCA patients demonstrated that inducible spasm is present in approximately 28% of those tested within six weeks after an MI, comparable to the 34% observed when testing is performed beyond six weeks [3]. However, more recent studies that performed early provocation testing, often immediately after coronary angiography, reported higher rates of inducible spasm in MINOCA, ranging from 46% to 58% [33, 34]. These findings suggest that the timing of provocation testing may significantly affect detection rates in MINOCA, as previously observed in MI-CAD; however, they may also merely reflect differences in cohort compositions. Nevertheless, direct evidence comparing early versus late testing remains limited, and further controlled studies are needed to clarify the impact of timing.

Overall, the evidence for vasospasm in MINOCA remains limited by methodological challenges. Most data are derived from highly selected cohorts, and findings vary depending on the heterogeneity of MINOCA populations, the timing of evaluation, and the provocation testing protocols used. The absence of standardized testing approaches and suitable control groups further contributes to uncertainty in defining its true prevalence and clinical impact.

4.2 Coronary Microvascular Dysfunction (CMD)

A meta-analysis reported a pooled prevalence of CMD in approximately 41% of MINOCA patients [31]. When combined with epicardial coronary vasospasm, coronary vasomotor dysfunction was present in up to 49% of cases, highlighting its substantial role in MINOCA [31]. Similar to epicardial coronary spasm, CMD is more prevalent in females [31].

CMD arises from structural and functional abnormalities in the coronary microcirculation, resulting in impaired coronary blood flow and subsequent myocardial ischemia [40]. The coronary microvasculature, which contributes up to 60% of total coronary vascular resistance, plays a critical role in regulating blood flow to meet myocardial oxygen demand, particularly since myocardial oxygen extraction is already near maximal at rest [40].

CMD results from endothelial dysfunction or vascular smooth muscle hyperreactivity, resulting in reduced vasodilation and enhanced vasoconstriction [40]. Additional mechanisms include extrinsic compression of intramural vessels, microvascular spasm and inflammation [1]. Microvascular spasm is characterized by angina and ischemic ECG changes during provocative testing without epicardial spasm, whereas impaired microvascular vasodilator capacity is reflected by reduced coronary flow reserve (CFR) and/or elevated index of microvascular resistance (IMR).

4.3 Coronary Embolism, Thrombosis, and Thrombophilia

Coronary embolism or thrombosis may cause MINOCA by occluding microvasculature or epicardial arteries, often with partial thrombus lysis. These mechanisms occur independently of atherosclerotic plaque or obstructive CAD and are often associated with underlying hypercoagulable states [1]. Other acquired thromboembolic causes include left ventricular thrombus, valvular heart disease, prosthetic heart valves, infective endocarditis, atrial fibrillation, pulmonary embolism, cardiac myxoma, papillary fibroelastoma, and cancer-associated thrombophilia. The estimated prevalence of MI due to coronary embolism is approximately 2.9% [41].

Coronary embolism can be diagnosed using the proposed Shibata criteria, which categorize findings into major and minor components [41]. These criteria integrate angiographic features and clinical clues suggestive of an embolic rather than plaque-mediated mechanism. Major criteria include angiographic evidence of embolism without significant atherosclerosis, coronary embolization at multiple sites, and concomitant systemic embolism. Minor criteria include the absence of diffuse coronary artery disease, identification of an embolic source, and the presence of embolic risk factors. Definite coronary embolism is diagnosed when ≥2 major criteria, or 1 major plus ≥2 minor criteria, or ≥3 minor criteria are met [41].

A meta-analysis of 378 MINOCA patients undergoing partial thrombophilia screening showed that approximately 14% had inherited thrombotic disorders [3]. The most common abnormalities included Factor V Leiden mutation, present in about 12% of MINOCA patients, which is higher than the 3% to 7% prevalence reported in the general population. Protein C and protein S deficiencies were also observed in 2.6% of MINOCA patients, compared to 0.1% to 1% in the general population [3, 42].

The prevalence of thrombophilia appears higher in MINOCA than in MI-CAD. One study reported Factor V Leiden mutation in 5% of patients with MI-CAD [43]. Similarly, a study of 84 MINOCA patients undergoing comprehensive testing reported abnormalities in 24%, a prevalence comparable to that of patients with cryptogenic stroke [44]. In this cohort, Factor V Leiden mutation was found in 14%, antiphospholipid syndrome in 15.5%, and activated protein C resistance in 2.4% [44]. Importantly, the majority of studies reporting a higher prevalence of Factor V Leiden were conducted in European cohorts, where the background prevalence of this mutation is known to be higher. Antiphospholipid syndrome prevalence in the general population ranges from 1% to 5%, reaching up to 11% in MI patients [45]. Furthermore, among MI patients who tested positive for antiphospholipid antibodies, approximately 20% were diagnosed with MINOCA [46]. However, these estimates should be interpreted cautiously due to differences in patient selection, screening methods, and background prevalence.

These findings highlight the importance of thrombophilia evaluation in selected MINOCA populations, particularly in younger individuals without conventional cardiovascular risk factors.

Criteria for the diagnosis of coronary embolism by Shibata et al [41].

Major criteria

• Angiographic evidence of coronary artery embolism and thrombosis without atherosclerotic components.

• Concomitant coronary artery embolization at multiple sites*.

• Concomitant systemic embolization without left ventricular thrombus attributable to acute myocardial infarction.

Minor criteria

• <25% stenosis on coronary angiography, except for the culprit lesion.

• Evidence of an embolic source based on transthoracic echocardiography, transesophageal echocardiography, computed tomography, or MRI.

• Presence of embolic risk factors: atrial fibrillation, cardiomyopathy, rheumatic valve disease, prosthetic heart valve, patent foramen ovale, atrial septal defect, history of cardiac surgery, infective endocarditis, or hypercoagulable state.

Definite CE

 Two or more major criteria, or

 One major criterion plus ≥2 minor criteria, or

 Three minor criteria

Probable CE

 One major criterion plus 1 minor criterion, or

 Two minor criteria

A diagnosis of CE should not be made if there is

 Pathological evidence of atherosclerotic thrombus

 History of coronary revascularization

 Coronary artery ectasia

 Plaque disruption or erosion detected by intravascular ultrasound or optic coherence tomography in the proximal part of the culprit lesion

CE: Coronary artery Embolism, MRI: Magnetic Resonance Imaging.

*indicates multiple vessels within 1 coronary artery territory or multiple vessels in the coronary tree.

4.4 Spontaneous Coronary Artery Dissection (SCAD)

SCAD is an uncommon but increasingly recognized cause of MI, particularly among younger women without traditional cardiovascular risk factors [1, 18]. SCAD is defined as a spontaneous dissection of the epicardial coronary artery unrelated to atherosclerosis, trauma, or iatrogenic injury [18]. Myocardial injury results from coronary obstruction caused by intramural hematoma or intimal disruption, causing significant narrowing, although some cases with less severe narrowing fall within the MINOCA spectrum [18].

The true prevalence of SCAD remains uncertain due to underdiagnosis and challenges in recognition. SCAD accounts for approximately 1% to 4% of all ACS, but up to 35% in women under 50 years old presenting with ACS [18]. Coronary angiography is the initial diagnostic modality, with three angiographic types including type 1 (double lumen with contrast staining), type 2 (long diffuse narrowing), and type 3 (focal narrowing resembling atherosclerosis) [18, 47]. In the SCAD registry, type 2 lesions are the most common (67%), followed by type 1 (29%) and type 3 (4%) [47]. Notably, no significant differences in outcomes exist between these subtypes [47].

Because SCAD may be missed or misinterpreted on angiography, particularly in cases of type 2 or type 3 patterns, intravascular imaging with IVUS or OCT may be required to confirm the diagnosis. These imaging modalities can demonstrate the absence of atherosclerotic plaque and confirm the presence of dissection and intramural hematoma. In MINOCA patients, 4% to 7% of cases diagnosed by IVUS or OCT revealed SCAD with <50% luminal stenosis [24, 48, 49]. However, both IVUS and OCT carry procedural risks, as wire passage may propagate dissection and OCT contrast injection may extend intramural hematoma. Current guidelines therefore recommend their use selectively, only when the diagnosis is uncertain and the results are expected to alter management [18, 50]. In one study of 63 SCAD patients who underwent OCT, 7.9% experienced OCT-related complications, although none resulted in MACE [51]. Overall, intravascular imaging is considered safe and can be valuable in cases of diagnostic uncertainty. There are increasing data on the use of coronary computed tomography angiography (CCTA) in SCAD [18, 50]. As a non-invasive tool, CCTA can visualize coronary anatomy, but evidence supporting its role in acute diagnosis remains limited. Current guidelines recommend its use mainly for longitudinal monitoring or when angiographic findings are inconclusive, rather than as a first-line modality in the acute setting [18, 50].

4.5 Oxygen Supply-Demand Mismatch

An imbalance between myocardial oxygen supply and demand can lead to myocardial ischemia and, when diagnostic criteria are fulfilled, infarction, historically classified as type 2 MI [12]. This mismatch may result from increased oxygen demand (e.g., tachyarrhythmias, severe hypertension) or reduced oxygen supply (e.g., hypoxia, anemia, hypotension) [52].

While various mechanisms contribute to supply-demand mismatch, most cases are triggered by non-coronary etiologies that affect systemic oxygen delivery or myocardial demand. The presence and severity of concomitant CAD may modulate the ischemic threshold. Under the previous Universal Definition of MI classification, type 2 MI could also result from direct impairment of coronary blood flow, such as in vasospasm, coronary embolism, or SCAD [52]. Notably, the Fifth Universal Definition of MI replaces the previous numerical MI classification with primary, secondary, and procedure-related MI; acute coronary pathologies such as vasospasm, coronary embolism, and SCAD are now classified as causes of primary MI, whereas secondary MI refers to myocardial oxygen supply-demand imbalance resulting from another acute condition [13]. Intravascular imaging (IVUS, OCT) can detect subtle or diffuse coronary abnormalities not visible on angiography, including non-obstructive plaques that may contribute to ischemia under increased demand [1]. Therefore, systemic causes of supply-demand mismatch identified during the evaluation of suspected MINOCA should be considered alternative diagnoses rather than primary coronary mechanisms of MINOCA. Recognizing this distinction is essential, as management should focus on treating the underlying precipitating condition.

5. Sex Differences in MINOCA

Relative to obstructive CAD, which is more common in men, the prevalence of suspected MINOCA is disproportionately higher in women [53-55]. Data from large registries report that in STEMI patients, 4% to 9% of women have non-obstructive CAD compared to 2% to 8% of men [56, 57]. In NSTEMI, 10% to 15% of women compared with 4% to 5% of men have non-obstructive CAD [56, 57]. Although fewer than half of MI-CAD patients are women, they represent 37% to 77% of MINOCA cases [53, 54]. In a cohort study of MI patients, women had five times higher odds of having MINOCA compared with men [58]. Similarly, in NSTEMI patients undergoing coronary angiography, female sex was identified as an independent predictor of MINOCA [59]. Among women with MINOCA, only about 14% present with STEMI, but this subgroup has a higher risk of adverse outcomes [53].

For non-atherosclerotic causes of MINOCA, women are more susceptible to CMD [54]. SCAD shows a marked female predominance, with only 8% to 10% of cases occurring in men. SCAD may be responsible for up to 35% of younger women presenting with ACS, compared to 1% to 4% of all overall ACS cases [18]. Pregnancy-associated SCAD is the leading cause of MI during pregnancy or the postpartum period and is associated with a poorer prognosis compared with non-pregnancy-related SCAD [60].

Preliminary molecular studies suggest a potential role of estrogen signaling in sex differences in MINOCA. In a transcriptomic study of 11 women with MINOCA, estrogen receptor signaling emerged as the most differentially regulated pathway compared to MI-CAD patients and controls [61]. G-protein-coupled estrogen receptor (GPER), the most abundant estrogen receptor transcript, along with several other estrogen-related genes, showed reduced expression in MINOCA, suggesting impaired estrogen-mediated cardioprotective effects [61]. These observations underscore the potential influence of hormonal pathways, although larger studies including male patients are needed to clarify the underlying mechanisms.

However, the influence of estrogen alone is unlikely to fully explain the female predominance of MINOCA, particularly given that the established cardiovascular effects of estrogen primarily modulate atherosclerotic rather than non-atherosclerotic processes.

Beyond hormonal influences, sex-specific differences in coronary anatomy and physiology also contribute to the higher prevalence of MINOCA observed in women. Women tend to have smaller epicardial coronary arteries, higher resting and hyperemic myocardial blood flow, and greater endothelial shear stress compared with men, features that promote diffuse epicardial atherosclerosis and microvascular dysfunction rather than focal obstructive plaque formation [53, 62]. These observations support a pathophysiologic framework in which sex-related variations in coronary size, flow dynamics, and vascular reactivity predispose women to non-obstructive ischemic mechanisms characteristic of MINOCA

The effect of sex on long-term MINOCA outcomes remains unclear. Data from large registries have shown that sex is not an independent predictor of adverse outcomes [7, 8]. Similarly, a meta-analysis found no significant differences in all-cause mortality or MACE between sexes [63]. However, a recent retrospective study of 6,000 MINOCA patients reported lower mortality and MI rates in women compared to men at 3-year follow-up [64]. Evidence on sex-specific treatment effects is limited. In a propensity-matched analysis, statins and ACEI/ARBs were associated with reduced MACE in both sexes [7]. Beta-blockers showed a trend toward benefit, while dual antiplatelet therapy (DAPT) showed no clear advantage, with findings consistent across both sexes [7].

6. Biomarkers in MINOCA

The identification and interpretation of circulating biomarkers play a crucial role in the evaluation of patients hospitalized with acute MI. Although MINOCA shares some clinical and biochemical features with MI-CAD, emerging evidence suggests distinct pathophysiological mechanisms that may be reflected in differing biomarker profiles [65]. However, a comprehensive and specific biochemical signature for MINOCA remains to be clearly defined.

6.1 Cardiac Troponins

Cardiac troponins (cTnI and cTnT), particularly measured with high-sensitivity assays (hs-cTn), are the cornerstone biomarkers for myocardial injury, with levels exceeding the 99th percentile diagnostic threshold [12]. In MINOCA, elevated troponin concentrations are a requisite criterion; however, clinical interpretation demands exclusion of alternative diagnoses such as myocarditis, Takotsubo cardiomyopathy, or renal impairment [1]. Compared to MI-CAD, hs-cTn release in MINOCA typically exhibits a less pronounced and more protracted elevation, reflecting distinct injury patterns [66, 67]. Despite these kinetic differences, troponin dynamics alone do not reliably discriminate underlying mechanisms, underscoring the necessity for comprehensive multimodal evaluation.

6.2 Inflammatory Biomarkers

Inflammation is increasingly recognized as a pivotal component of MINOCA pathogenesis. Elevated C-reactive protein (CRP), including high-sensitivity CRP (hs-CRP), is frequently documented during the acute phase and correlates with adverse outcomes such as all-cause mortality and MACE [68]. However, comparative studies frequently report overlapping CRP levels between MINOCA and MI-CAD populations, limiting its discriminative power [67, 69]. More specific inflammatory mediators, such as interleukin-6 (IL-6), P-selectin glycoprotein ligand-1 (PSGL-1), and NF-κB essential modulator (NEMO), are elevated in MINOCA patients, indicating amplified inflammatory signaling [65, 70]. Longitudinal studies reveal persistent elevation of vascular injury markers including soluble vascular cell adhesion molecule-1 (sVCAM-1), CCL-21, and placental growth factor (PlGF) up to one year post-infarction, suggesting ongoing endothelial dysfunction and microvascular injury [71, 72]. Notably, adipokines like visfatin, secreted by visceral adipose tissue, have emerged as potential mediators of endothelial impairment and inflammatory-metabolic dysregulation [73]. Despite accumulating evidence, inflammatory biomarker profiling remains investigational and is not yet integrated into routine clinical risk stratification or management algorithms for MINOCA.

6.3 Natriuretic Peptides

N-terminal pro-B-type natriuretic peptide (NT-proBNP), reflecting myocardial wall stress and ventricular dysfunction, is commonly elevated in both MINOCA and MI-CAD cohorts compared to healthy controls [67]. However, studies have not consistently demonstrated significant differences in NT-proBNP levels between these groups, limiting its discriminatory or prognostic value in MINOCA [67]. The precise role of natriuretic peptides in the pathophysiology or risk stratification of MINOCA remains largely unexplored.

6.4 Metabolic Biomarkers

Metabolic abnormalities, including hyperuricemia, hyperglycemia, and dyslipidemia, are associated with poorer prognosis in MINOCA patients [74-76]. Elevated lipoprotein(a) (Lp(a)) is independently linked with increased cardiovascular risk, potentially through mechanisms involving microvascular dysfunction and promotion of systemic inflammation, evidenced by concomitant increases in CRP and IL-6 [65, 77, 78]. However, therapeutic strategies targeting these metabolic derangements have yet to be validated in this context, necessitating further investigation.

6.5 Vasoactive and Thrombotic Mediators

Vasoactive peptides such as endothelin-1 (ET-1) and neuropeptide Y (NPY), potent regulators of coronary vasomotion, are elevated in MINOCA patients with coronary microvascular dysfunction and epicardial vasospasm, underscoring their mechanistic relevance [79, 80]. Additionally, elevated plasma levels of soluble CD40 ligand (sCD40L), often accompanied by high CRP, implicate thrombo-inflammatory processes, particularly in MI subtypes involving plaque disruption or erosion [81].

6.6 MicroRNAs (miRNAs)

Emerging evidence identifies circulating microRNAs (miRNAs) as promising biomarkers that may reflect specific pathophysiological mechanisms in MINOCA. Differential expression of miRNAs such as miR-16 and miR-26a (upregulated) and miR-1 and miR-133 (downregulated) correlates with coronary microvascular spasm, while miR-145 and miR-222 are linked to epicardial vasospasm [82]. Other candidates, including miR-155-5p, miR-483-5p, and miR-451a, show potential as early markers of plaque rupture [83]. Despite their promise, these miRNAs remain investigational and are not validated for routine MINOCA diagnosis, prognostic assessment, or treatment selection.

Although MINOCA and MI-CAD share overlapping acute-phase biomarker profiles, differences in inflammatory response resolution, metabolic derangements, and vasoactive mediator levels highlight distinct underlying pathophysiological pathways. To date, no specific, validated biomarker panel exists for unequivocal diagnosis or prognosis of MINOCA. Further well-designed studies are imperative to elucidate whether biomarker-driven strategies can refine etiological classification and enable personalized therapeutic approaches in this heterogeneous syndrome.

7. Noninvasive Imaging Evaluation

7.1 ECG

ECG is a fundamental diagnostic tool in patients presenting with acute MI. MINOCA patients can be classified as having STEMI or NSTEMI; however, the majority (approximately 70% to 80%) present as NSTEMI [1]. In non-atherosclerotic causes of MINOCA, such as epicardial coronary vasospasm, the ECG may show dynamic ST-segment elevation [1]. MINOCA mimickers, such as Takotsubo syndrome, can also cause ECG changes, most commonly ST-segment elevation, T-wave inversion, QT prolongation, or left bundle-branch block [84, 85]. These changes are often widespread and may not localize to a specific coronary territory. Given its accessibility and diagnostic value, ECG remains an essential first-line investigation in the evaluation of suspected MINOCA.

7.2 Echocardiogram

Echocardiography, like ECG, is a first-line imaging modality for assessing patients presenting with acute MI to assess LVEF and regional wall motion abnormalities [12]. According to the universal definition of MI, echocardiography can provide evidence of myocardial ischemia and is useful in diagnosing MINOCA [12]. When an embolic cause of MINOCA is suspected, echocardiography is essential to identify potential sources of embolism, such as intracardiac thrombi, valvular abnormalities, or a patent foramen ovale or atrial septal defect. In cases with multiple microinfarctions, transesophageal echocardiography (TEE) or a bubble contrast study can be particularly valuable for detecting cardiac shunts or other embolic sources.

Echocardiography is also valuable in identifying potential MINOCA mimickers. In Takotsubo syndrome, echocardiography is highly specific for identifying characteristic wall motion abnormalities, most commonly apical ballooning with basal hyperkinesis, although mid-ventricular or basal variants can also occur [84]. Additionally, echocardiography provides prognostic information in MINOCA, as studies have shown that a lower LVEF is associated with worse clinical outcomes [7, 8].

7.3 Strain imaging

Myocardial strain imaging, assessed by echocardiography or CMR, quantifies myocardial deformation as the relative change in length. Global longitudinal strain (GLS), reflecting subendocardial longitudinal fiber function, is particularly sensitive to ischemic injury, as the subendocardium is the most vulnerable myocardial layer [86].

In MINOCA, strain imaging can detect subtle regional dysfunction even when LVEF is preserved [86]. This is clinically important as many MINOCA patients present with preserved LVEF, and GLS provides incremental diagnostic information beyond conventional echocardiography. A reduced GLS despite preserved LVEF should raise suspicion for ischemic myocardial damage and prompt further evaluation for underlying atherosclerotic or non-atherosclerotic causes. Strain imaging can also help differentiate MINOCA from mimickers, such as Takotsubo syndrome, which typically shows marked regional strain abnormalities with apical dysfunction in the classic phenotype, although other variants may demonstrate different patterns, while myocarditis often exhibits patchy or non-territorial strain reduction [86].

Strain imaging also has prognostic implications in MINOCA. GLS has been shown to predict adverse cardiovascular outcomes in ACS [87]. In patients with NSTEMI and LVEF >35%, both mechanical dispersion and GLS independent predictors of ventricular arrhythmias, whereas LVEF itself was not, highlighting the added prognostic value of strain imaging [87]. A study in MINOCA patients using strain assessed by CMR demonstrated that lower GLS and left atrial reservoir strains independently predict MACE risk [88]. These findings support the role of strain imaging not only in diagnosis but also in risk stratification of MINOCA patients.

7.4 Coronary Computed Tomography Angiography (CCTA)

CCTA is a non-invasive technique used to assess coronary anatomy, myocardial bridging, and coronary stenosis [89]. Current guidelines recommend CCTA as an alternative to invasive coronary angiography to rule out ACS in patients with a low-to-intermediate likelihood of CAD [90]. In MINOCA, CCTA can detect features of plaque disruption or SCAD, although its accuracy and resolution is lower than invasive angiography, especially in distal vessels [18, 89]. CCTA is also valuable for longitudinal follow-up in SCAD, reducing the risk of dissection extension associated with repeated invasive angiography [18]. Patients with SCAD frequently present with coronary tortuosity and myocardial bridging, both of which can be visualized by CCTA. Importantly, the ongoing MINOCA-GR study is evaluating the role of CCTA in characterizing atherosclerotic plaque burden, high-risk features, and pericoronary fat attenuation, aiming to refine diagnostic and prognostic assessment in this population [91]. However, CCTA is limited by exposure to ionizing radiation and the potential adverse effects of iodinated contrast agents [89].

7.5 Cardiac Magnetic Resonance (CMR)

Given that multiple conditions can mimic MINOCA, current guidelines recommend performing CMR in all patients initially diagnosed with MINOCA [1, 90]. CMR provides high diagnostic accuracy by characterizing myocardial tissue, localizing injury, and distinguishing ischemic from non-ischemic causes. Late gadolinium enhancement (LGE) enables assessment of possible necrosis, alternative diagnoses, infarct size and distribution. In true MI, LGE typically presents in a subendocardial or transmural pattern. However, some patients with confirmed MI may exhibit absent LGE, potentially due to small infarct size, limited spatial resolution, or transient vascular occlusion [92]. Additionally, regional myocardial edema detectable by T2-weighted imaging can serve as an early marker of injury [92]. Importantly, there is no clear troponin threshold below which an abnormal CMR is unlikely among MINOCA patients [21].

CMR is particularly valuable in identifying MINOCA mimickers. Myocarditis, present in approximately one-third of patients initially diagnosed with MINOCA, is characterized by non-ischemic LGE with matching edema [93-95]. Previous meta-analyses have shown that male sex, younger age, and angiographically normal coronaries are independent predictors of CMR-confirmed myocarditis [93]. Recognizing myocarditis is important, as its treatment is generally supportive and does not require ischemic secondary prevention such as antiplatelet or statin therapy [1].

Takotsubo syndrome is another important differential diagnosis. CMR reveals characteristic wall motion abnormalities that may mimic left anterior descending artery or left main lesion, but lack the ischemic LGE distribution [84, 96]. Diagnosis is clinically relevant, as Takotsubo syndrome and cardiomyopathies in suspected MINOCA patients are associated with higher mortality. In a 3.5-year follow-up, overall all-cause mortality was 5.7%, with the highest mortality in the cardiomyopathy group (15%) compared to the MI (4%), myocarditis (2%), and normal CMR findings (2%) [97].

CMR can also guide accurate diagnosis in patients with obstructive CAD. In an NSTEMI cohort with angiographically identified infarct-related arteries (IRAs), CMR reclassified the diagnosis in 12.5% of cases, most often to myocarditis, and identified a different infarct-related arteries in 14%, with some cases ultimately meeting MINOCA criteria [98]. Another study found that CMR changed the diagnosis in 54% and management in 41% of MINOCA patients [99]. More recently, a prospective multicenter study of 320 patients with suspected MINOCA demonstrated that CMR was associated with changes in clinical diagnosis and/or management in 63% of patients, including deprescription of DAPT in 38% of patients initially prescribed DAPT [100].

The timing of CMR significantly affects diagnostic yield [99]. Early imaging, performed within 7 to 14 days post-MI, maximizes detection of myocardial injury before acute changes resolve, reducing the rate of inconclusive scans from 43% when performed after 2 weeks to 16% when performed within 2 weeks. This is particularly important for reversible conditions such as myocarditis and Takotsubo syndrome [99]. A large prospective study demonstrated that higher peak troponin levels and shorter intervals between MI onset and CMR independently increased the likelihood of a definitive diagnosis [101]. Patients with peak troponin T ≥211 ng/L scanned within 14 days achieved a 94% diagnostic yield, compared with 53% when troponin was <211 ng/L and imaging was delayed beyond 14 days [101]. Even in the lowest troponin decile (15-38 ng/L), the diagnostic yield remained 62%. No troponin threshold reliably excludes the utility of CMR, supporting its routine use in all suspected MINOCA patients [101]. Furthermore, a study of MINOCA patients who underwent early CMR within 7 days showed that both %LGE and T2 mapping values were independent predictors of MACE at 3 years [102]. Overall, variations in CMR diagnostic yield across studies may reflect differences in imaging timing, peak troponin concentrations, and patient selection. In summary, early routine CMR is a cornerstone in MINOCA evaluation, enhancing diagnostic accuracy, guiding targeted therapy, and improving prognostic assessment. However, although CMR is strongly recommended by international guidelines and its use is improving in recent years, often it is still limited by local availability and expertise [103].

Advanced imaging enhances diagnostic yield; however, most studies have been conducted in highly selected patients at specialized centers, raising concerns of selection bias. Availability and operator expertise vary widely, limiting external validity. Over-diagnosis is also possible, particularly in CMD and vasospasm, when comparator populations without myocardial injury are not included. In addition, differences in the timing of imaging may significantly influence diagnostic outcomes.

8. Invasive Imaging evaluation

8.1 Coronary angiography

Coronary angiography is fundamental in diagnosing MINOCA, as it confirms the absence of significant obstructive CAD, a key diagnostic criterion. However, coronary angiography has limitations, as plaque rupture or plaque erosion may not always be visible, and subtle lesions can be overlooked [1, 21].

Intravascular imaging modalities, including IVUS and OCT, have shown that atherosclerotic plaque disruption is more prevalent in MINOCA than angiography suggests [21]. Previous studies using IVUS or OCT have identified plaque rupture or erosion in 29 to 38% of MINOCA patients [22]. Notably, one study that excluded myocarditis by CMR prior to OCT reported plaque rupture in up to 80% of cases [48]. These wide variations in reported prevalence reflect methodological differences and selection bias. Together, the findings highlight the limitations of angiography and emphasize the crucial role of intravascular imaging in identifying the underlying mechanisms of MINOCA.

8.2 Intravascular Ultrasound (IVUS)

IVUS has greater tissue penetration (6-10 mm) compared to OCT (1-2 mm), allowing visualization of deeper vessel wall structures and assessment of calcium burden and plaque remodeling patterns. It is useful for evaluating dissections and ostial lesions [104]. However, its lower axial resolution (100-200 μm) relative to OCT (10-20 μm) limits its ability to detect microstructural features such as thin-cap fibroatheromas, small thrombi, or subtle intimal disruption [104]. A previous study using IVUS reported plaque disruption in approximately one-third of MINOCA patients [22]. While IVUS can detect plaque rupture, its lower spatial resolution limits the ability to identify plaque erosion, a common atherosclerotic cause of MINOCA [1, 27].

8.3 Optical Coherence Tomography (OCT)

OCT provides substantially higher spatial resolution than IVUS, enabling detailed characterization of plaque morphology and other coronary pathologies. With an axial resolution of 10-20 μm and transverse resolution of 20-40 μm, OCT can differentiate tissue characteristics (fibrous, lipid-rich, or calcified plaques), detect unstable plaques, and distinguish between plaque rupture and erosion [104]. OCT is particularly useful for detecting plaque erosion, which is typically invisible to IVUS [104]. Studies combining CMR and OCT have shown complementary diagnostic value, achieving diagnostic yields of up to 85%, higher than either modality alone [21].

Clinical data indicate that OCT-identified culprit lesions correlate with older age, diabetes, and angiographic abnormalities, but not with peak troponin levels or vessel stenosis severity [21]. However, the identification of plaque disruption does not necessarily establish it as the cause of the acute MI and should be interpreted in the context of clinical presentation, ECG findings, and complementary imaging results. Notably, 34% of women with an OCT-identified culprit lesion had normal angiography, compared to 69% without a culprit lesion, emphasizing the incremental value of OCT in MINOCA evaluation [21]. In vasospastic angina, OCT performed at the spasm site demonstrated plaque rupture in 12.5% and plaque erosion in 25% of cases, supporting a multifactorial pathophysiology in MINOCA [105]. OCT can also characterize SCAD, including visualization of true and false lumens [18].

Overall, OCT is preferred over IVUS in MINOCA due to its superior spatial resolution, enhanced ability to characterize plaque morphology, and greater sensitivity for detecting subtle lesions such as plaque erosion, thrombi, and dissections that may be missed by IVUS.

8.4 Fractional Flow Reserve (FFR), Coronary Flow Reserve (CFR), and Index of Microvascular Resistance IMR

Fractional flow reserve (FFR) is an invasive index used to assess the physiological significance of coronary artery lesions. It is defined as the ratio of mean distal coronary pressure to mean aortic pressure during maximal hyperemia. An FFR value ≤0.80 is generally accepted as the threshold for functionally significant CAD. However, evidence supporting the role of FFR in MINOCA remained limited [1].

Previous studies have demonstrated that a greater angiographic atherosclerotic burden correlates with poorer outcomes [106]. Although data specifically evaluating FFR in MINOCA are limited, evidence from stable CAD populations suggests that up to 25% of patients with 30-50% stenosis have functionally significant lesions when assessed by FFR [107]. Therefore, FFR may be considered in selected MINOCA patients with borderline obstructive lesions to identify ischemia-causing stenoses that may not be evident on angiography alone. The 2019 AHA scientific statement proposed that, when FFR is performed, only patients with FFR values >0.80 should be included under the working diagnosis of MINOCA [1]. However, FFR findings should be interpreted cautiously during acute MI, as microvascular dysfunction may affect physiological measurements.

Despite its potential utility, the application of FFR in MINOCA is limited by procedural complexity, the need for hyperemic agents, increased cost, and prolonged procedural time. Coronary CT-derived FFR has emerged as a non-invasive alternative, providing both anatomic and physiological assessment with diagnostic performance comparable to invasive FFR [108].

CFR is another invasive physiological index, defined as the ratio of maximal hyperemic to resting coronary blood flow. Unlike FFR, CFR reflects the combined effects of both epicardial stenosis and microvascular function [40, 109]. A CFR <2.0 is generally considered abnormal and is associated with adverse outcomes in various patient groups, including MI patients [40, 110]. In MINOCA, a reduced CFR in the absence of epicardial stenosis suggests CMD as a potential underlying mechanism.

The IMR is a pressure- and thermodilution-derived invasive parameter that specifically quantifies microvascular resistance during maximal hyperemia, independent of epicardial artery status [40, 109]. An IMR ≥25 units is considered abnormal and indicative of CMD [40]. Compared with CFR, IMR is less influenced by hemodynamic variations, making it a more reproducible measure of microvascular function [111]. In MINOCA, an elevated IMR may be consistent with CMD; however, abnormalities in CFR or IMR measured during or soon after acute MI may reflect myocardial injury, edema, microvascular obstruction, or preexisting microvascular dysfunction rather than the primary mechanism of the ischemic event. Therefore, microvascular testing is generally selective and may be deferred until after the acute phase. In contrast, the role of microvascular testing among stable outpatients with chronic stable angina (ANOCA/INOCA) is more clearly defined and endorsed by guideline documents [112-114].

In addition to these microvascular indices, provocative testing for coronary vasospasm has gained increasing importance in recent years. Coronary vasospasm represents a frequent cause of MINOCA [3]. A definitive diagnosis generally requires provocative testing, as spontaneous vasospasm during angiography is uncommon [1, 115-117]. The 2023 ESC guidelines endorse intracoronary acetylcholine testing in patients with acute MI and suspected vasospasm [1]. Although earlier reports raised concerns regarding safety due to fatal complications with intravenous ergonovine [118], contemporary intracoronary protocols using short-acting agents such as acetylcholine, performed under strict monitoring in the catheterization laboratory, have proven to be safe [116, 119]. The incidence of serious complications is comparable to that of spontaneous vasospasm or diagnostic angiography, with most adverse reactions limited to transient brady- or tachyarrhythmias, occurring in 5-9% of cases [119-121].

Recent data underscore the prognostic implications of vasospasm testing. In a prospective study of 80 MINOCA patients, intracoronary acetylcholine testing within 48 hours of admission was positive in 46.2% without major complications; however, test positivity was associated with a significantly worse long-term prognosis, including higher rates of recurrent ACS and cardiac mortality at 36 months [121]. Overall, provocative testing for vasospasm now has an established safety profile and diagnostic yield that justify its use as part of the interventional cardiologist’s routine toolkit, particularly in MINOCA, with the potential to integrate microcirculatory assessment in selected cases [122, 123].

9. Management

The management of MINOCA remains challenging due to its heterogeneous etiologies and the lack of randomized trials dedicated to this population. For patients with acute MI, secondary prevention therapies, including antiplatelets, statins, as well as, ACEI/ARBs, and possibly beta-blockers, particularly in patients with reduced LVEF, are essential to improve cardiovascular outcomes [115]. However, since MINOCA patients generally have a lower atherosclerotic burden compared to those with MI-CAD, clinical management is often less aggressive [124]. Data from the SWEDEHEART registry showed that nearly half of patients who experienced recurrent MI after an initial MINOCA event had obstructive CAD at the time of the second event [125]. Mortality at 38 months was similar between patients with recurrent MINOCA and those with recurrent MI due to obstructive CAD, suggesting comparable long-term risk profiles [125]. Despite this, observational data from the ACTION-GWTG and SWEDEHEART registries indicated that patients with MINOCA are less frequently prescribed secondary prevention therapies such as aspirin, P2Y12 inhibitors, statins, ACEI/ARBs, and beta-blockers compared to patients with MI-CAD [57, 126].

An analysis of 9,466 MINOCA patients from the SWEDEHEART registry, with a mean follow-up of 4.1 years, showed that statins and ACEI/ARB use were associated with significant reductions in MACE, defined as all-cause mortality, MI, stroke, and heart failure [7]. Beta-blockers showed a trend toward lower all-cause mortality, though not statistically significant. DAPT did not show clear benefit in this cohort [7]. However, the observational design and lack of stratification by underlying MINOCA mechanisms limit causal interpretation of these findings.

The CURRENT OASIS 7 trial included a post-hoc analysis of a MINOCA subgroup (6.7% of the total cohort) comparing high versus low doses of clopidogrel and aspirin [127]. In MINOCA patients, higher-dose clopidogrel (600 mg on day 1, followed by 150 mg daily on days 2-7, then 75 mg/day) was associated with worse outcomes compared to the standard dose (300 mg on day 1, then 75 mg/day), with a composite endpoint of cardiovascular death, MI, or stroke occurring in 2.1% versus 0.6% at 30 days [127]. These findings emphasize the need for cautious use of intensified antiplatelet therapy in MINOCA and highlight the importance of tailoring treatment based on underlying pathophysiology.

For MINOCA patients with plaque disruption, secondary prevention should follow protocols similar to those for MI-CAD, including antiplatelet therapy and statins, as supported by evidence from the SWEDEHEART registry [7]. The addition of a second antiplatelet agent may be reasonable in patients with confirmed plaque disruption, although its clinical benefit remains uncertain, as prior studies of DAPT in MINOCA populations did not consistently stratify patients by the underlying etiology.

For epicardial coronary spasm, calcium channel blockers (CCBs) are the cornerstone therapy, with non-dihydropyridine agents preferred initially. Combination therapy with dihydropyridines may be considered for persistent symptoms [1, 29]. The EDIT-CMD randomized trial in patients with ANOCA demonstrated that diltiazem significantly increased the transition from epicardial spasm to microvascular or no spasm compared with placebo. However, the primary endpoint was not met, and these findings may not be directly applicable to patients with acute MINOCA [128]. Short-acting nitrates are first-line for acute symptom relief, whereas long-acting nitrates are generally reserved for refractory cases due to the risk of tolerance [1, 29]. In patients with concomitant myocardial bridging and coronary spasm, CCBs can reduce contractility, and surgical unroofing may be considered if symptoms persist despite optimal medical therapy [29].

The management of CMD remains limited, as antianginal vasodilators are generally less effective on the microvasculature than on epicardial vessels. Most studies have excluded acute MI patients, and clinical trials specifically addressing CMD in MINOCA are lacking [40]. Symptom improvement has been reported with beta-blockers, CCBs, and, to a lesser extent, nitrates [1, 40]. A randomized study of 151 patients with anginal symptoms but no obstructive CAD demonstrated that tailored medical therapy based on CMD and provocative testing improved angina and quality of life, although it did not reduce MACE at 6 months [114].

The evidence of management in SCAD remains limited and is largely based on expert consensus. The use of anticoagulation and DAPT is controversial due to bleeding risks and the potential for hematoma propagation, despite the prothrombotic risk associated with intimal tears [18]. While antiplatelet therapy generally follows standard ACS guidelines, the duration of DAPT in conservatively managed SCAD varies and remains uncertain, with some experts recommending up to one year, whereas others limit DAPT to 1-3 months [18]. Beta-blockers should be considered for patients with reduced LVEF, arrhythmias, or hypertension and may reduce the risk of recurrence [18]. Notably, a prospective observational study of 327 SCAD patients over a median follow-up of 3.1 years showed that beta-blocker use was associated with a 64% reduction in recurrent SCAD risk, although randomized evidence confirming this benefit is lacking [129].

Based on current evidence, treatment generally includes antiplatelet therapy and statins unless advanced imaging definitively excludes atherosclerosis [1, 7]. ACEI/ARBs are recommended in patients with decreased EF and based on observational data demonstrating reduced MACE [7]. Beta-blockers are considered, particularly in patients with evidence of MI on CMR, reduced LVEF, or SCAD [1, 90]. CCBs are indicated for coronary vasospasm [1]. A recent American Heart Association scientific statement further emphasized the importance of tailoring MINOCA treatment to the underlying mechanism [130]. Mechanism-specific pharmacological strategies for MINOCA are summarized in Table 2.

The majority of available results are derived from observational registries and post-hoc analyses of heterogeneous populations. Studies on therapeutic strategies in MINOCA are limited by this heterogeneity, and both selection bias and confounding further reduce the reliability of observed treatment effects. Moreover, randomized evidence is lacking, underscoring the need for mechanism-specific clinical trials. Importantly, MI therapies should not be overgeneralized to all MINOCA cases; treatment must be tailored to the underlying mechanism.

The PROMISE trial, the first randomized study of a stratified, mechanism-guided diagnostic and therapeutic approach in MINOCA, highlighted the impact of individualized management [131]. In this multicenter study open-label trial, 101 patients with suspected MINOCA were randomized, of whom 92 had confirmed MINOCA and were included in the final analysis. Participants were randomized to stratified care involving a comprehensive diagnostic workup using OCT, intracoronary acetylcholine testing, cardiac MRI, and transesophageal echocardiography to identify the underlying mechanism, or to standard post-MI care without advanced testing. A specific mechanism was identified in 80% of patients in the stratified arm, and the initial clinical diagnosis changed in more than 75%, underscoring frequent misclassification with routine care. The stratified approach significantly improved angina-related quality of life, with a 9.38-point greater improvement in the Seattle Angina Questionnaire Summary Score at 1 year compared with standard care (P<0.001). Although rates of major adverse cardiovascular events were numerically lower (2.2% vs 8.5%), the difference was not statistically significant (P = 0.18) [131]. The study demonstrated that a comprehensive mechanism-guided diagnostic and therapeutic strategy improved angina-related patient-reported outcomes, supporting the use of an etiology-guided management strategy in MINOCA. However, the trial evaluated a combined diagnostic-and-treatment strategy rather than the independent clinical efficacy of individual diagnostic modalities. Moreover, its modest sample size, open-label design, and early termination limited its statistical power for hard clinical endpoints, including mortality and recurrent MI. Larger studies with longer follow-up are needed to confirm these findings. Current and ongoing large observational studies and randomized clinical trials evaluating treatment strategies in MINOCA are summarized in Table 3.

The MINOCA-BAT trial, designed to evaluate the efficacy of beta-blockers and ACEI/ARBs in patients with MINOCA and LVEF ≥40%, was prematurely terminated due to slow recruitment after enrolling only 192 of the planned 3,500 patients [132, 133]. A subsequent post-hoc analysis reported low cardiovascular event rates at 1 year, with no significant differences in residual symptoms or health-related quality of life between the randomized treatment groups [133]. However, the limited sample size and low event rates preclude definitive conclusions regarding the effectiveness of routine beta-blocker and ACEI/ARB therapy in this population.

For nonpharmacologic treatment, comprehensive cardiac rehabilitation is recommended for all patients with ACS [115]. Cardiac rehabilitation consistently reduces cardiovascular hospitalizations, recurrent MI, cardiovascular mortality, and, in some studies, all-cause mortality [115]. In MINOCA, a single-center prospective randomized trial of 524 patients demonstrated that exercise-based cardiac rehabilitation was associated with lower all-cause mortality and MACE over three years. However, the relatively small sample size, participant attrition, and potential selection bias warrant cautious interpretation of these findings [134].

10. Current challenges

The diagnosis and management of MINOCA remain challenging due to its heterogeneous etiologies and overlapping clinical presentations with MINOCA mimickers. Although advanced imaging modalities, such as CMR and intracoronary imaging, improve diagnostic accuracy, their use is often limited by availability, institutional protocol variability, and cost considerations, contributing to underdiagnosis or misclassification. Furthermore, a significant proportion of MINOCA patients do not undergo comprehensive evaluations to determine the underlying mechanism, resulting in suboptimal therapeutic strategies. In practice, CMR is recommended in most patients to exclude mimickers and characterize myocardial injury, while further investigations such as intracoronary imaging, vasospasm provocation, or thrombophilia testing should be individualized based on the clinical context, angiographic findings, and pre-test probability. A comprehensive diagnostic approach for MINOCA must consider cost, feasibility, and variability in healthcare resources. Current evidence on cost-effectiveness in MINOCA management remains limited. A retrospective study showed that CMR increases early costs modestly but becomes cost-neutral by 7 years and cost-saving by 10 years, largely by improving etiologic classification and reducing unnecessary exposure to DAPT [135]. Provocative spasm testing is diagnostically informative and safe in experienced centers, though implementation depends on local expertise [34]. Future studies are needed to determine risk-stratification tools to identify patients at highest risk who would benefit from more advanced investigation, especially in resource-limited settings. Evidence-based treatment approaches for MINOCA are still limited. As a result, current treatment strategies are largely extrapolated from studies in MI-CAD populations or observational registries, which may be confounded and may not fully address the diverse pathophysiological mechanisms underlying MINOCA.

11. Future direction

Advancement in the understanding and management of MINOCA requires large multicenter randomized clinical trials that evaluate therapeutic strategies tailored to specific MINOCA subgroups based on etiology. There is ongoing debate among experts as to whether confirmed myocardial infarction without obstructive CAD should continue to be categorized as ‘MINOCA’ or simply as MI, given the current ≥50% stenosis threshold. The role of emerging biomarkers such as microRNAs and the utility of physiologic coronary assessments in MINOCA remain limited, and further studies are needed to clarify their diagnostic and prognostic value. The development and validation of standardized diagnostic pathways, integrating early CMR, intracoronary imaging, and coronary physiological assessments, are essential to improve diagnostic yield and promote mechanism-directed management, while also assessing cost-effectiveness. The application of machine learning and artificial intelligence to multimodal datasets, including imaging results, biomarker profiles, and clinical parameters, may facilitate more precise risk stratification, identify patients most likely to benefit from advanced diagnostic testing, and guide mechanism-specific treatment strategies while maintaining cost-effectiveness.

12. Conclusion

MINOCA represents a heterogeneous subset of acute MI, encompassing a wide spectrum of etiologies ranging from atherosclerotic plaque disruption to non-atherosclerotic mechanisms. Despite the absence of obstructive CAD, MINOCA is associated with significant morbidity and mortality, highlighting the importance of early recognition and thorough evaluation. Advanced imaging modalities, including early CMR and intracoronary imaging, have significantly improved diagnostic accuracy, allowing for better differentiation between ischemic and non-ischemic causes. Therapeutic strategies remain largely extrapolated from MI-CAD populations and observational evidence, which may not fully address the diverse pathophysiological processes underlying MINOCA. Statins, ACEI/ARBs, and antiplatelet therapy remain the cornerstone of secondary prevention in patients with evidence of atherosclerotic involvement, while management of non-atherosclerotic causes requires a tailored, mechanism-specific approach. Recent randomized data have demonstrated that a mechanism-guided diagnostic and therapeutic strategy improves anginal symptoms and quality of life at 1 year compared with standard post-MI care without advanced testing. Future efforts should focus on large-scale randomized trials to define evidence-based treatments for distinct MINOCA subtypes, validate standardized diagnostic algorithms, and assess long-term clinical outcomes with extended follow-up.

AI Disclosure: All authors wrote, reviewed, and critically edited the article, including its ideas and conclusions. No AI model was used at any stage of manuscript preparation. Accordingly, based on the Clinical AI Score (CAIS) scoring framework, the manuscript receives a CAIS of 0 points, reflecting no use of AI for content generation, analysis, interpretation, or editing.

References

1. Tamis-Holland JE, Jneid H, Reynolds HR, Agewall S, Brilakis ES, Brown TM, et al. Contemporary Diagnosis and Management of Patients With Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation. 2019;139(18):e891-e908.

2. Agewall S, Beltrame JF, Reynolds HR, Niessner A, Rosano G, Caforio AL, et al. ESC working group position paper on myocardial infarction with non-obstructive coronary arteries. Eur Heart J. 2017;38(3):143-53.

3. Pasupathy S, Air T, Dreyer RP, Tavella R, Beltrame JF. Systematic review of patients presenting with suspected myocardial infarction and nonobstructive coronary arteries. Circulation. 2015;131(10):861-70.

4. Ciliberti G, Verdoia M, Musella F, Ceriello L, Scicchitano P, Fortuni F, Zilio F. MINOCA in Men and Women: Different Conditions and a Single Destiny? Int J Cardiol. 2023;374:6-7.

5. Ciliberti G, Coiro S, Tritto I, Benedetti M, Guerra F, Del Pinto M, et al. Predictors of poor clinical outcomes in patients with acute myocardial infarction and non-obstructed coronary arteries (MINOCA). Int J Cardiol. 2018;267:41-5.

6. Williams MJA, Barr PR, Lee M, Poppe KK, Kerr AJ. Outcome after myocardial infarction without obstructive coronary artery disease. Heart. 2019;105(7):524-30.

7. Lindahl B, Baron T, Erlinge D, Hadziosmanovic N, Nordenskjöld A, Gard A, Jernberg T. Medical Therapy for Secondary Prevention and Long-Term Outcome in Patients With Myocardial Infarction With Nonobstructive Coronary Artery Disease. Circulation. 2017;135(16):1481-9.

8. Dreyer RP, Tavella R, Curtis JP, Wang Y, Pauspathy S, Messenger J, et al. Myocardial infarction with non-obstructive coronary arteries as compared with myocardial infarction and obstructive coronary disease: outcomes in a Medicare population. Eur Heart J. 2020;41(7):870-8.

9. Eggers KM, Hjort M, Baron T, Jernberg T, Nordenskjöld AM, Tornvall P, Lindahl B. Morbidity and cause-specific mortality in first-time myocardial infarction with nonobstructive coronary arteries. J Intern Med. 2019;285(4):419-28.

10. Samaras A, Moysidis DV, Papazoglou AS, Rampidis GP, Barmpagiannos K, Barmpagiannos A, et al. Myocardial Infarction with Obstructive, Non-Obstructive, and Mimicking Conditions: Clinical Phenotypes, Diagnostic Imaging, Management, and Prognosis. J Clin Med. 2025;14(9).

11. Ciliberti G, Compagnucci P, Urbinati A, Bianco F, Stronati G, Lattanzi S, et al. Myocardial Infarction Without Obstructive Coronary Artery Disease (MINOCA): A Practical Guide for Clinicians. Curr Probl Cardiol. 2021;46(3):100761.

12. Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD. Fourth Universal Definition of Myocardial Infarction (2018). Circulation. 2018;138(20):e618-e51.

13. Mills NL, Newby LK, Zaman S, Almahmeed WA, Bucciarelli-Ducci C, Colvin MM, et al. Fifth Universal Definition of Myocardial Infarction (2026): On behalf of the Joint European Society of Cardiology (ESC)/American College of Cardiology (ACC)/American Heart Association (AHA)/World Heart Federation (WHF) Task Force for the Universal Definition of Myocardial InfarctionEndorsed by the European Association for Cardio-Thoracic Surgery (EACTS) and the Society of Thoracic Surgeons (STS)Affirmation of Value by the Society for Cardiovascular Angiography and Interventions (SCAI). European Heart Journal. 2026.

14. Yasue H, Nakagawa H, Itoh T, Harada E, Mizuno Y. Coronary artery spasm--clinical features, diagnosis, pathogenesis, and treatment. J Cardiol. 2008;51(1):2-17.

15. Lin Z, Lin X, Zhao X, Xu C, Yu B, Shen Y, Li L. Coronary Artery Spasm: Risk Factors, Pathophysiological Mechanisms and Novel Diagnostic Approaches. Rev Cardiovasc Med. 2022;23(5):175.

16. Rehan R, Yong A, Ng M, Weaver J, Puranik R. Coronary microvascular dysfunction: A review of recent progress and clinical implications. Front Cardiovasc Med. 2023;10:1111721.

17. Raphael CE, Heit JA, Reeder GS, Bois MC, Maleszewski JJ, Tilbury RT, Holmes DR, Jr. Coronary Embolus: An Underappreciated Cause of Acute Coronary Syndromes. JACC Cardiovasc Interv. 2018;11(2):172-80.

18. Hayes SN, Kim ESH, Saw J, Adlam D, Arslanian-Engoren C, Economy KE, et al. Spontaneous Coronary Artery Dissection: Current State of the Science: A Scientific Statement From the American Heart Association. Circulation. 2018;137(19):e523-e57.

19. Ma L, Cai L, Pan J, Cheng Z, Lv Y, Zheng J, et al. The immunopathology of coronary microembolization and the underlying inflammopathophysiological mechanisms. Allergol Immunopathol (Madr). 2024;52(6):137-46.

20. Heusch G. Myocardial ischemia/reperfusion: Translational pathophysiology of ischemic heart disease. Med. 2024;5(1):10-31.

21. Reynolds HR, Maehara A, Kwong RY, Sedlak T, Saw J, Smilowitz NR, et al. Coronary Optical Coherence Tomography and Cardiac Magnetic Resonance Imaging to Determine Underlying Causes of Myocardial Infarction With Nonobstructive Coronary Arteries in Women. Circulation. 2021;143(7):624-40.

22. Reynolds HR, Srichai MB, Iqbal SN, Slater JN, Mancini GB, Feit F, et al. Mechanisms of myocardial infarction in women without angiographically obstructive coronary artery disease. Circulation. 2011;124(13):1414-25.

23. Opolski MP, Spiewak M, Marczak M, Debski A, Knaapen P, Schumacher SP, et al. Mechanisms of Myocardial Infarction in Patients With Nonobstructive Coronary Artery Disease: Results From the Optical Coherence Tomography Study. JACC Cardiovasc Imaging. 2019;12(11 Pt 1):2210-21.

24. Zeng M, Zhao C, Bao X, Liu M, He L, Xu Y, et al. Clinical Characteristics and Prognosis of MINOCA Caused by Atherosclerotic and Nonatherosclerotic Mechanisms Assessed by OCT. JACC Cardiovasc Imaging. 2023;16(4):521-32.

25. Ouldzein H, Elbaz M, Roncalli J, Cagnac R, Carrié D, Puel J, Alibelli-Chemarin MJ. Plaque rupture and morphological characteristics of the culprit lesion in acute coronary syndromes without significant angiographic lesion: analysis by intravascular ultrasound. Ann Cardiol Angeiol (Paris). 2012;61(1):20-6.

26. Kubo T, Ino Y, Tanimoto T, Kitabata H, Tanaka A, Akasaka T. Optical coherence tomography imaging in acute coronary syndromes. Cardiol Res Pract. 2011;2011:312978.

27. Usui E, Matsumura M, Smilowitz NR, Mintz GS, Saw J, Kwong RY, et al. Coronary morphological features in women with non-ST-segment elevation MINOCA and MI-CAD as assessed by optical coherence tomography. Eur Heart J Open. 2022;2(5):oeac058.

28. Iqbal SN, Feit F, Mancini GB, Wood D, Patel R, Pena-Sing I, et al. Characteristics of plaque disruption by intravascular ultrasound in women presenting with myocardial infarction without obstructive coronary artery disease. Am Heart J. 2014;167(5):715-22.

29. Yaker ZS, Lincoff AM, Cho L, Ellis SG, Ziada KM, Zieminski JJ, et al. Coronary spasm and vasomotor dysfunction as a cause of MINOCA. EuroIntervention. 2024;20(2):e123-e34.

30. 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(7):1299-306.

31. Mileva N, Nagumo S, Mizukami T, Sonck J, Berry C, Gallinoro E, et al. Prevalence of Coronary Microvascular Disease and Coronary Vasospasm in Patients With Nonobstructive Coronary Artery Disease: Systematic Review and Meta-Analysis. J Am Heart Assoc. 2022;11(7):e023207.

32. Beltrame JF, Crea F, Kaski JC, Ogawa H, Ong P, Sechtem U, et al. International standardization of diagnostic criteria for vasospastic angina. Eur Heart J. 2017;38(33):2565-8.

33. Pirozzolo G, Seitz A, Athanasiadis A, Bekeredjian R, Sechtem U, Ong P. Microvascular spasm in non-ST-segment elevation myocardial infarction without culprit lesion (MINOCA). Clin Res Cardiol. 2020;109(2):246-54.

34. Montone RA, Niccoli G, Fracassi F, Russo M, Gurgoglione F, Cammà G, et al. Patients with acute myocardial infarction and non-obstructive coronary arteries: safety and prognostic relevance of invasive coronary provocative tests. Eur Heart J. 2018;39(2):91-8.

35. Fukai T, Koyanagi S, Takeshita A. Role of coronary vasospasm in the pathogenesis of myocardial infarction: study in patients with no significant coronary stenosis. Am Heart J. 1993;126(6):1305-11.

36. Pristipino C, Beltrame JF, Finocchiaro ML, Hattori R, Fujita M, Mongiardo R, et al. Major racial differences in coronary constrictor response between japanese and caucasians with recent myocardial infarction. Circulation. 2000;101(10):1102-8.

37. Prinzmetal M, Kennamer R, Merliss R, Wada T, Bor N. Angina pectoris. I. A variant form of angina pectoris; preliminary report. Am J Med. 1959;27:375-88.

38. Waters DD, Miller DD, Bouchard A, Bosch X, Theroux P. Circadian variation in variant angina. Am J Cardiol. 1984;54(1):61-4.

39. Choo EH, Chang K, Lee KY, Lee D, Kim JG, Ahn Y, et al. Prognosis and Predictors of Mortality in Patients Suffering Myocardial Infarction With Non-Obstructive Coronary Arteries. J Am Heart Assoc. 2019;8(14):e011990.

40. Del Buono MG, Montone RA, Camilli M, Carbone S, Narula J, Lavie CJ, et al. Coronary Microvascular Dysfunction Across the Spectrum of Cardiovascular Diseases: JACC State-of-the-Art Review. J Am Coll Cardiol. 2021;78(13):1352-71.

41. Shibata T, Kawakami S, Noguchi T, Tanaka T, Asaumi Y, Kanaya T, et al. Prevalence, Clinical Features, and Prognosis of Acute Myocardial Infarction Attributable to Coronary Artery Embolism. Circulation. 2015;132(4):241-50.

42. Khan S, Dickerman JD. Hereditary thrombophilia. Thromb J. 2006;4:15.

43. Mansourati J, Da Costa A, Munier S, Mercier B, Tardy B, Ferec C, et al. Prevalence of factor V Leiden in patients with myocardial infarction and normal coronary angiography. Thromb Haemost. 2000;83(6):822-5.

44. Stepien K, Nowak K, Wypasek E, Zalewski J, Undas A. High prevalence of inherited thrombophilia and antiphospholipid syndrome in myocardial infarction with non-obstructive coronary arteries: Comparison with cryptogenic stroke. Int J Cardiol. 2019;290:1-6.

45. Petri M. Epidemiology of the antiphospholipid antibody syndrome. J Autoimmun. 2000;15(2):145-51.

46. Gandhi H, Ahmed N, Spevack DM. Prevalence of myocardial infarction with non-obstructive coronary arteries (MINOCA) amongst acute coronary syndrome in patients with antiphospholipid syndrome. Int J Cardiol Heart Vasc. 2019;22:148-9.

47. Saw J, Aymong E, Sedlak T, Buller CE, Starovoytov A, Ricci D, et al. Spontaneous coronary artery dissection: association with predisposing arteriopathies and precipitating stressors and cardiovascular outcomes. Circ Cardiovasc Interv. 2014;7(5):645-55.

48. Gerbaud E, Arabucki F, Nivet H, Barbey C, Cetran L, Chassaing S, et al. OCT and CMR for the Diagnosis of Patients Presenting With MINOCA and Suspected Epicardial Causes. JACC Cardiovasc Imaging. 2020;13(12):2619-31.

49. Raparelli V, Elharram M, Shimony A, Eisenberg MJ, Cheema AN, Pilote L. Myocardial Infarction With No Obstructive Coronary Artery Disease: Angiographic and Clinical Insights in Patients With Premature Presentation. Can J Cardiol. 2018;34(4):468-76.

50. Adlam D, Alfonso F, Maas A, Vrints C. European Society of Cardiology, acute cardiovascular care association, SCAD study group: a position paper on spontaneous coronary artery dissection. Eur Heart J. 2018;39(36):3353-68.

51. Jackson R, Al-Hussaini A, Joseph S, van Soest G, Wood A, Macaya F, et al. Spontaneous Coronary Artery Dissection: Pathophysiological Insights From Optical Coherence Tomography. JACC Cardiovasc Imaging. 2019;12(12):2475-88.

52. Sandoval Y, Jaffe AS. Type 2 Myocardial Infarction: JACC Review Topic of the Week. J Am Coll Cardiol. 2019;73(14):1846-60.

53. Reynolds HR, Bairey Merz CN, Berry C, Samuel R, Saw J, Smilowitz NR, et al. Coronary Arterial Function and Disease in Women With No Obstructive Coronary Arteries. Circ Res. 2022;130(4):529-51.

54. La S, Beltrame J, Tavella R. Sex-specific and ethnicity-specific differences in MINOCA. Nat Rev Cardiol. 2024;21(3):192-202.

55. Lawless M, Appelman Y, Beltrame JF, Navarese EP, Ratcovich H, Wilkinson C, Kunadian V. Sex differences in treatment and outcomes amongst myocardial infarction patients presenting with and without obstructive coronary arteries: a prospective multicentre study. Eur Heart J Open. 2023;3(2):oead033.

56. Hochman JS, Sleeper LA, Webb JG, Sanborn TA, White HD, Talley JD, et al. Early revascularization in acute myocardial infarction complicated by cardiogenic shock. SHOCK Investigators. Should We Emergently Revascularize Occluded Coronaries for Cardiogenic Shock. N Engl J Med. 1999;341(9):625-34.

57. Smilowitz NR, Mahajan AM, Roe MT, Hellkamp AS, Chiswell K, Gulati M, Reynolds HR. Mortality of Myocardial Infarction by Sex, Age, and Obstructive Coronary Artery Disease Status in the ACTION Registry-GWTG (Acute Coronary Treatment and Intervention Outcomes Network Registry-Get With the Guidelines). Circ Cardiovasc Qual Outcomes. 2017;10(12):e003443.

58. Safdar B, Spatz ES, Dreyer RP, Beltrame JF, Lichtman JH, Spertus JA, et al. Presentation, Clinical Profile, and Prognosis of Young Patients With Myocardial Infarction With Nonobstructive Coronary Arteries (MINOCA): Results From the VIRGO Study. J Am Heart Assoc. 2018;7(13).

59. Patel MR, Chen AY, Peterson ED, Newby LK, Pollack CV, Jr., Brindis RG, et al. Prevalence, predictors, and outcomes of patients with non-ST-segment elevation myocardial infarction and insignificant coronary artery disease: results from the Can Rapid risk stratification of Unstable angina patients Suppress ADverse outcomes with Early implementation of the ACC/AHA Guidelines (CRUSADE) initiative. Am Heart J. 2006;152(4):641-7.

60. Faden MS, Bottega N, Benjamin A, Brown RN. A nationwide evaluation of spontaneous coronary artery dissection in pregnancy and the puerperium. Heart. 2016;102(24):1974-9.

61. Barrett TJ, Lee AH, Smilowitz NR, Hausvater A, Fishman GI, Hochman JS, et al. Whole-Blood Transcriptome Profiling Identifies Women With Myocardial Infarction With Nonobstructive Coronary Artery Disease. Circ Genom Precis Med. 2018;11(12):e002387.

62. Patel MB, Bui LP, Kirkeeide RL, Gould KL. Imaging Microvascular Dysfunction and Mechanisms for Female-Male Differences in CAD. JACC Cardiovasc Imaging. 2016;9(4):465-82.

63. Ang SP, Chia JE, Krittanawong C, Lee K, Iglesias J, Misra K, Mukherjee D. Sex Differences and Clinical Outcomes in Patients With Myocardial Infarction With Nonobstructive Coronary Arteries: A Meta-Analysis. J Am Heart Assoc. 2024;13(15):e035329.

64. Milewski M, Desperak A, Koźlik M, Bujak M, Gierlotka M, Milewski K, et al. Sex differences in patients with working diagnosis of myocardial infarction with nonobstructive coronary arteries (MINOCA). Sci Rep. 2025;15(1):2764.

65. Xu X, Zhang G, Li Z, Li D, Chen R, Huang C, et al. MINOCA biomarkers: Non-atherosclerotic aspects. Clin Chim Acta. 2023;551:117613.

66. Rao K, De Silva K, Sood A, Denniss AR, Hsu CJ. Predicting Patients With Troponin Positive Chest Pain and Unobstructed Coronary Arteries With Electrocardiogram, Troponin Kinetics and GRACE Score. Heart Lung Circ. 2022;31(9):1219-27.

67. Hjort M, Eggers KM, Lakic TG, Lindbäck J, Budaj A, Cornel JH, et al. Biomarker Concentrations and Their Temporal Changes in Patients With Myocardial Infarction and Nonobstructive Compared With Obstructive Coronary Arteries: Results From the PLATO Trial. J Am Heart Assoc. 2023;12(1):e027466.

68. Mitsis A, Kadoglou NPE, Lambadiari V, Alexiou S, Theodoropoulos KC, Avraamides P, Kassimis G. Prognostic role of inflammatory cytokines and novel adipokines in acute myocardial infarction: An updated and comprehensive review. Cytokine. 2022;153:155848.

69. Hjort M, Eggers KM, Lindhagen L, Agewall S, Brolin EB, Collste O, et al. Increased Inflammatory Activity in Patients 3 Months after Myocardial Infarction with Nonobstructive Coronary Arteries. Clin Chem. 2019;65(8):1023-30.

70. Stangret A, Dykacz W, Jabłoński K, Wesołowska A, Klimczak-Tomaniak D, Kochman J, Tomaniak M. The cytokine trio - visfatin, placental growth factor and fractalkine - and their role in myocardial infarction with non-obstructive coronary arteries (MINOCA). Cytokine Growth Factor Rev. 2023;74:76-85.

71. Ryabov VV, Vorobeva DA, Kologrivova IV, Suslova TE. Pro-Inflammatory Biomarkers and Progression of Atherosclerosis in Patients with Myocardial Infarction with Non-Obstructive Coronary Artery Disease: 1-Year Follow-Up. J Pers Med. 2023;13(12).

72. Kadoglou NP, Sailer N, Moumtzouoglou A, Kapelouzou A, Gerasimidis T, Kostakis A, Liapis CD. Adipokines: a novel link between adiposity and carotid plaque vulnerability. Eur J Clin Invest. 2012;42(12):1278-86.

73. Kadoglou NP, Gkontopoulos A, Kapelouzou A, Fotiadis G, Theofilogiannakos EK, Kottas G, Lampropoulos S. Serum levels of vaspin and visfatin in patients with coronary artery disease-Kozani study. Clin Chim Acta. 2011;412(1-2):48-52.

74. Ma W, Gao S, Huang S, Yuan J, Yu M. Hyperuricemia as a prognostic marker for long-term outcomes in patients with myocardial infarction with nonobstructive coronary arteries. Nutr Metab (Lond). 2021;18(1):107.

75. Gao S, Xu H, Ma W, Yuan J, Yu M. Remnant Cholesterol Predicts Risk of Cardiovascular Events in Patients With Myocardial Infarction With Nonobstructive Coronary Arteries. J Am Heart Assoc. 2022;11(10):e024366.

76. Paolisso P, Foà A, Bergamaschi L, Donati F, Fabrizio M, Chiti C, et al. Hyperglycemia, inflammatory response and infarct size in obstructive acute myocardial infarction and MINOCA. Cardiovasc Diabetol. 2021;20(1):33.

77. Gao S, Ma W, Huang S, Lin X, Yu M. Effect of Lipoprotein (a) Levels on Long-term Cardiovascular Outcomes in Patients with Myocardial Infarction with Nonobstructive Coronary Arteries. Am J Cardiol. 2021;152:34-42.

78. Lin YK, Yeh CT, Kuo KT, Fong IH, Yadav VK, Kounis NG, et al. Apolipoprotein (a)/Lipoprotein(a)-Induced Oxidative-Inflammatory α7-nAChR/p38 MAPK/IL-6/RhoA-GTP Signaling Axis and M1 Macrophage Polarization Modulate Inflammation-Associated Development of Coronary Artery Spasm. Oxid Med Cell Longev. 2022;2022:9964689.

79. 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(2):476-83.

80. Rosano GMC, Tousoulis D, McFadden E, Clarke J, Davies GJ, Kaski JC. Effects of neuropeptide Y on coronary artery vasomotion in patients with microvascular angina. Int J Cardiol. 2017;238:123-7.

81. Fong SW, Few LL, See Too WC, Khoo BY, Nik Ibrahim NN, Yahaya SA, et al. Systemic and coronary levels of CRP, MPO, sCD40L and PlGF in patients with coronary artery disease. BMC Res Notes. 2015;8:679.

82. 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. J Clin Med. 2020;9(5).

83. Li S, Lee C, Song J, Lu C, Liu J, Cui Y, et al. Circulating microRNAs as potential biomarkers for coronary plaque rupture. Oncotarget. 2017;8(29):48145-56.

84. Singh T, Khan H, Gamble DT, Scally C, Newby DE, Dawson D. Takotsubo Syndrome: Pathophysiology, Emerging Concepts, and Clinical Implications. Circulation. 2022;145(13):1002-19.

85. Del Buono MG, Damonte JI, Moroni F, Ravindra K, Westman P, Chiabrando JG, et al. QT Prolongation and In-Hospital Ventricular Arrhythmic Complications in Patients With Apical Ballooning Takotsubo Syndrome. JACC Clin Electrophysiol. 2022;8(12):1500-10.

86. Smiseth OA, Rider O, Cvijic M, Valkovič L, Remme EW, Voigt JU. Myocardial Strain Imaging: Theory, Current Practice, and the Future. JACC Cardiovasc Imaging. 2025;18(3):340-81.

87. Haugaa KH, Grenne BL, Eek CH, Ersbøll M, Valeur N, Svendsen JH, et al. Strain echocardiography improves risk prediction of ventricular arrhythmias after myocardial infarction. JACC Cardiovasc Imaging. 2013;6(8):841-50.

88. Chen L, Qiu B, Abdu FA, Liu L, Zhang W, Wang C, et al. Prognostic Value of Strain by Tissue Tracking Cardiac Magnetic Resonance in Myocardial Infarction With Nonobstructive Coronary Arteries. J Am Heart Assoc. 2025;14(8):e039395.

89. Leo I, Bisaccia G, Miaris N, Procopio MC, Licordari R, Bucciarelli-Ducci C. Imaging patients with myocardial infarction with non-obstructive coronary arteries (MINOCA). Heart. 2024;110(3):209-17.

90. Collet JP, Thiele H, Barbato E, Barthélémy O, Bauersachs J, Bhatt DL, et al. 2020 ESC Guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J. 2021;42(14):1289-367.

91. Rampidis GP, Kampaktsis P, Kouskouras K, Samaras A, Benetos G, Giannopoulos A, et al. Role of cardiac CT in the diagnostic evaluation and risk stratification of patients with myocardial infarction and non-obstructive coronary arteries (MINOCA): rationale and design of the MINOCA-GR study. BMJ Open. 2022;12(2):e054698.

92. Raman SV, Simonetti OP, Winner MW, 3rd, Dickerson JA, He X, Mazzaferri EL, Jr., Ambrosio G. Cardiac magnetic resonance with edema imaging identifies myocardium at risk and predicts worse outcome in patients with non-ST-segment elevation acute coronary syndrome. J Am Coll Cardiol. 2010;55(22):2480-8.

93. Hausvater A, Smilowitz NR, Li B, Redel-Traub G, Quien M, Qian Y, et al. Myocarditis in Relation to Angiographic Findings in Patients With Provisional Diagnoses of MINOCA. JACC Cardiovasc Imaging. 2020;13(9):1906-13.

94. Ferreira VM, Schulz-Menger J, Holmvang G, Kramer CM, Carbone I, Sechtem U, et al. Cardiovascular Magnetic Resonance in Nonischemic Myocardial Inflammation: Expert Recommendations. J Am Coll Cardiol. 2018;72(24):3158-76.

95. Friedrich MG, Sechtem U, Schulz-Menger J, Holmvang G, Alakija P, Cooper LT, et al. Cardiovascular magnetic resonance in myocarditis: A JACC White Paper. J Am Coll Cardiol. 2009;53(17):1475-87.

96. Eitel I, von Knobelsdorff-Brenkenhoff F, Bernhardt P, Carbone I, Muellerleile K, Aldrovandi A, et al. Clinical characteristics and cardiovascular magnetic resonance findings in stress (takotsubo) cardiomyopathy. Jama. 2011;306(3):277-86.

97. Dastidar AG, Baritussio A, De Garate E, Drobni Z, Biglino G, Singhal P, et al. Prognostic Role of CMR and Conventional Risk Factors in Myocardial Infarction With Nonobstructed Coronary Arteries. JACC Cardiovasc Imaging. 2019;12(10):1973-82.

98. Heitner JF, Senthilkumar A, Harrison JK, Klem I, Sketch MH, Jr., Ivanov A, et al. Identifying the Infarct-Related Artery in Patients With Non-ST-Segment-Elevation Myocardial Infarction. Circ Cardiovasc Interv. 2019;12(5):e007305.

99. Dastidar AG, Rodrigues JCL, Johnson TW, De Garate E, Singhal P, Baritussio A, et al. Myocardial Infarction With Nonobstructed Coronary Arteries: Impact of CMR Early After Presentation. JACC Cardiovasc Imaging. 2017;10(10 Pt A):1204-6.

100. Rajwani A, Giudicatti L, Telyuk P, Maredia N, Ihdayhid A, Chieng D, et al. Clinical impact of cardiac magnetic resonance imaging in myocardial infarction with non-obstructive coronary arteries: a prospective multicentre cohort study. Heart. 2025;112(2):95-102.

101. Williams MGL, Liang K, De Garate E, Spagnoli L, Fiori E, Dastidar A, et al. Peak Troponin and CMR to Guide Management in Suspected ACS and Nonobstructive Coronary Arteries. JACC Cardiovasc Imaging. 2022;15(9):1578-87.

102. Bergamaschi L, Foà A, Paolisso P, Renzulli M, Angeli F, Fabrizio M, et al. Prognostic Role of Early Cardiac Magnetic Resonance in Myocardial Infarction With Nonobstructive Coronary Arteries. JACC Cardiovasc Imaging. 2024;17(2):149-61.

103. Ciliberti G, Fortuni F, Santucci A, Timi A, Barnoffi E, Coiro S, et al. Temporal trends of characteristics and management of patients with suspected MINOCA. Int J Cardiol. 2025;424:133039.

104. Alasnag M, Jelani Q-u-a, Johnson T, Parapid B, Balghaith M, Al-Shaibi K. The Role of Imaging for MINOCA (Myocardial Infarction with No Obstructive Coronary Artery Disease): a Review of Literature and Current Perspectives. Current Cardiovascular Imaging Reports. 2020;13.

105. Shin ES, Ann SH, Singh GB, Lim KH, Yoon HJ, Hur SH, et al. OCT-Defined Morphological Characteristics of Coronary Artery Spasm Sites in Vasospastic Angina. JACC Cardiovasc Imaging. 2015;8(9):1059-67.

106. Emond M, Mock MB, Davis KB, Fisher LD, Holmes DR, Jr., Chaitman BR, et al. Long-term survival of medically treated patients in the Coronary Artery Surgery Study (CASS) Registry. Circulation. 1994;90(6):2645-57.

107. Curzen N, Rana O, Nicholas Z, Golledge P, Zaman A, Oldroyd K, et al. Does routine pressure wire assessment influence management strategy at coronary angiography for diagnosis of chest pain?: the RIPCORD study. Circ Cardiovasc Interv. 2014;7(2):248-55.

108. Driessen RS, Danad I, Stuijfzand WJ, Raijmakers PG, Schumacher SP, van Diemen PA, et al. Comparison of Coronary Computed Tomography Angiography, Fractional Flow Reserve, and Perfusion Imaging for Ischemia Diagnosis. J Am Coll Cardiol. 2019;73(2):161-73.

109. Gould KL, Johnson NP. Coronary Physiology Beyond Coronary Flow Reserve in Microvascular Angina: JACC State-of-the-Art Review. J Am Coll Cardiol. 2018;72(21):2642-62.

110. Herzog BA, Husmann L, Valenta I, Gaemperli O, Siegrist PT, Tay FM, et al. Long-term prognostic value of 13N-ammonia myocardial perfusion positron emission tomography added value of coronary flow reserve. J Am Coll Cardiol. 2009;54(2):150-6.

111. Ng MK, Yeung AC, Fearon WF. Invasive assessment of the coronary microcirculation: superior reproducibility and less hemodynamic dependence of index of microcirculatory resistance compared with coronary flow reserve. Circulation. 2006;113(17):2054-61.

112. Vrints C, Andreotti F, Koskinas KC, Rossello X, Adamo M, Ainslie J, et al. 2024 ESC Guidelines for the management of chronic coronary syndromes. Eur Heart J. 2024;45(36):3415-537.

113. Reynolds HR, Smilowitz NR. Ischaemia with non-obstructive coronary arteries in the 2024 European Society of Cardiology guidelines for the management of chronic coronary syndromes. Eur Heart J Acute Cardiovasc Care. 2025;14(3):173-7.

114. Ford TJ, Stanley B, Good R, Rocchiccioli P, McEntegart M, Watkins S, et al. Stratified Medical Therapy Using Invasive Coronary Function Testing in Angina: The CorMicA Trial. J Am Coll Cardiol. 2018;72(23 Pt A):2841-55.

115. Byrne RA, Rossello X, Coughlan JJ, Barbato E, Berry C, Chieffo A, et al. 2023 ESC Guidelines for the management of acute coronary syndromes. Eur Heart J. 2023;44(38):3720-826.

116. Montone RA, Meucci MC, De Vita A, Lanza GA, Niccoli G. Coronary provocative tests in the catheterization laboratory: Pathophysiological bases, methodological considerations and clinical implications. Atherosclerosis. 2021;318:14-21.

117. Marrone A, Pavasini R, Scollo E, Gibiino F, Pompei G, Caglioni S, et al. Acetylcholine Use in Modern Cardiac Catheterization Laboratories: A Systematic Review. J Clin Med. 2022;11(4).

118. Buxton A, Goldberg S, Hirshfeld JW, Wilson J, Mann T, Williams DO, et al. Refractory ergonovine-induced coronary vasospasm: importance of intracoronary nitroglycerin. Am J Cardiol. 1980;46(2):329-34.

119. Ciliberti G, Seshasai SRK, Ambrosio G, Kaski JC. Safety of intracoronary provocative testing for the diagnosis of coronary artery spasm. Int J Cardiol. 2017;244:77-83.

120. Takahashi T, Samuels BA, Li W, Parikh MA, Wei J, Moses JW, et al. Safety of Provocative Testing With Intracoronary Acetylcholine and Implications for Standard Protocols. J Am Coll Cardiol. 2022;79(24):2367-78.

121. Montone RA, Rinaldi R, Del Buono MG, Gurgoglione F, La Vecchia G, Russo M, et al. Safety and prognostic relevance of acetylcholine testing in patients with stable myocardial ischaemia or myocardial infarction and non-obstructive coronary arteries. EuroIntervention. 2022;18(8):e666-e76.

122. Ciliberti G, Mancone M, Guerra F, Capucci A. Is invasive coronary provocation testing cost-effective among MINOCA patients? Eur Heart J. 2018;39(35):3334.

123. Belmonte M, Gallinoro E, Bermpeis K, Bertolone DT, Paolisso P, Viscusi MM, et al. Comprehensive invasive evaluation of coronary microcirculation in patients with Takotsubo syndrome. Atherosclerosis. 2023;385:117332.

124. Ciliberti G, Verdoia M, Merlo M, Zilio F, Vatrano M, Bianco F, et al. Pharmacological therapy for the prevention of cardiovascular events in patients with myocardial infarction with non-obstructed coronary arteries (MINOCA): Insights from a multicentre national registry. Int J Cardiol. 2021;327:9-14.

125. Nordenskjöld AM, Lagerqvist B, Baron T, Jernberg T, Hadziosmanovic N, Reynolds HR, et al. Reinfarction in Patients with Myocardial Infarction with Nonobstructive Coronary Arteries (MINOCA): Coronary Findings and Prognosis. Am J Med. 2019;132(3):335-46.

126. Nordenskjöld AM, Qvarnström M, Wettermark B, Lindahl B. Adherence to secondary preventive treatment following myocardial infarction with and without obstructive coronary artery disease. PLoS One. 2025;20(5):e0324072.

127. Bossard M, Gao P, Boden W, Steg G, Tanguay JF, Joyner C, et al. Antiplatelet therapy in patients with myocardial infarction without obstructive coronary artery disease. Heart. 2021;107(21):1739-47.

128. Jansen TPJ, Konst RE, de Vos A, Paradies V, Teerenstra S, van den Oord SCH, et al. Efficacy of Diltiazem to Improve Coronary Vasomotor Dysfunction in ANOCA: The EDIT-CMD Randomized Clinical Trial. JACC Cardiovasc Imaging. 2022;15(8):1473-84.

129. Saw J, Humphries K, Aymong E, Sedlak T, Prakash R, Starovoytov A, Mancini GBJ. Spontaneous Coronary Artery Dissection: Clinical Outcomes and Risk of Recurrence. J Am Coll Cardiol. 2017;70(9):1148-58.

130. Slipczuk L, Blankstein R, Bucciarelli-Ducci C, Braun LT, Phillips LM, Piña P, et al. State of the Art: Evaluation and Medical Management of Nonobstructive Coronary Artery Disease in Patients With Chest Pain: A Scientific Statement From the American Heart Association. Circulation. 2025;152(23):e443-e66.

131. Montone RA, Cosentino N, Gorla R, Biscaglia S, La Vecchia G, Rinaldi R, et al. Stratified treatment of myocardial infarction with non-obstructive coronary arteries: the PROMISE trial. Eur Heart J. 2026;47(12):1456-66.

132. Nordenskjöld AM, Agewall S, Atar D, Baron T, Beltrame J, Bergström O, et al. Randomized evaluation of beta blocker and ACE-inhibitor/angiotensin receptor blocker treatment in patients with myocardial infarction with non-obstructive coronary arteries (MINOCA-BAT): Rationale and design. Am Heart J. 2021;231:96-104.

133. Lindahl B, Nordenskjöld A, Pasupathy S, Tavella R, Agewall S, Atar D, et al. Health related quality of life and cardiac symptoms following admission for suspected MINOCA: A post-hoc analysis of the MINOCA-BAT randomized clinical trial. Am Heart J Plus. 2026;70:100856.

134. He CJ, Zhu CY, Zhu YJ, Zou ZX, Wang SJ, Zhai CL, Hu HL. Effect of exercise-based cardiac rehabilitation on clinical outcomes in patients with myocardial infarction in the absence of obstructive coronary artery disease (MINOCA). Int J Cardiol. 2020;315:9-14.

135. Murphy T, Jones DA, Friebel R, Uchegbu I, Mohiddin SA, Petersen SE. A Cost Analysis of Cardiac Magnetic Resonance Imaging in the Diagnostic Pathway of Patients Presenting With Unexplained Acute Myocardial Injury and Culprit-Free Coronary Angiography. Front Cardiovasc Med. 2021;8:749668.

136. Montone RA, Cosentino N, Graziani F, Gorla R, Del Buono MG, La Vecchia G, et al. Precision medicine versus standard of care for patients with myocardial infarction with non-obstructive coronary arteries (MINOCA): rationale and design of the multicentre, randomised PROMISE trial. EuroIntervention. 2022;18(11):e933-e9.