Take-home messages
- MINOCA is a working diagnosis rather than a final disease entity, encompassing multiple coronary and non-coronary mechanisms that require further investigation to establish the underlying cause.
- A multimodal diagnostic approach, integrating intracoronary imaging, cardiac magnetic resonance, and coronary functional testing, is essential to improve diagnostic accuracy and guide mechanism-based classification.
- Management should be individualised according to the underlying pathophysiological mechanism, as therapeutic strategies effective in obstructive myocardial infarction are not universally applicable to patients with MINOCA.
- Future progress in MINOCA will depend on improved phenotyping, wider implementation of advanced diagnostic pathways, and dedicated randomised clinical trials to support precision medicine and optimise patient outcomes.
Introduction
Myocardial infarction with non-obstructive coronary arteries (MINOCA) has emerged as one of the most important challenges to the traditional concept that myocardial infarction (MI) is synonymous with obstructive coronary artery disease (CAD) [1]. Although coronary angiography has historically represented the cornerstone for diagnosing acute coronary syndromes, it provides only a luminographic assessment of the coronary arteries and cannot identify many of the structural, functional, and systemic mechanisms capable of producing myocardial infarction. Consequently, a substantial proportion of patients fulfil the diagnostic criteria for MI despite the absence of obstructive coronary stenoses.
MINOCA should be regarded as a working diagnosis that identifies patients requiring further investigation to define the underlying mechanism responsible for myocardial necrosis. This conceptual shift has transformed MINOCA from an exclusion diagnosis into the starting point of a mechanism-oriented diagnostic pathway aimed at delivering individualised treatment.
Contemporary studies indicate that MINOCA accounts for approximately 6-10% of all patients undergoing coronary angiography for acute MI. Compared with patients with obstructive MI, those with MINOCA are generally younger, are more frequently women, and present with fewer traditional cardiovascular risk factors, although hypertension, dyslipidaemia and smoking remain common among them [1,2]. Importantly, MINOCA is not a benign condition. Early reports underestimated its prognostic significance, whereas more recent evidence demonstrates that mortality and recurrent cardiovascular events remain substantial and only modestly lower than in patients with obstructive CAD [3]. Furthermore, approximately one quarter of patients continue to experience angina during follow-up [4], emphasising the importance of identifying the responsible mechanism and implementing appropriate therapy.
Definition
The current definition of MINOCA is based on three fundamental criteria: evidence of acute myocardial infarction according to the fourth universal definition of myocardial infarction, non-obstructive coronary arteries on angiography (typically <50% stenosis in all major epicardial vessels), and the absence of an alternative overt explanation for the clinical presentation at the time of angiography [5-7].
Importantly, MINOCA is not a final diagnosis but rather a clinical syndrome encompassing multiple diseases that converge on the same phenotype of myocardial infarction without obstructive coronary disease. Accurate classification also requires distinction from other entities. Ischaemia with non-obstructive coronary arteries (INOCA) represents chronic myocardial ischaemia without infarction, whereas MINOCA requires objective evidence of myocardial necrosis occurring in an acute setting. Likewise, type 2 myocardial infarction may overlap with MINOCA whenever myocardial oxygen supply-demand imbalance occurs in the absence of obstructive coronary disease, although the two terms are not interchangeable. Finally, myocarditis and Takotsubo syndrome frequently mimic acute MI but are predominantly non-ischaemic disorders and should ultimately be distinguished from true MINOCA through advanced diagnostic evaluation.
Pathophysiological mechanisms
The heterogeneity of MINOCA reflects the wide spectrum of underlying pathophysiological mechanisms, which can be broadly categorised into coronary structural abnormalities, coronary functional disorders, and non-coronary cardiac or systemic mechanisms. These mechanisms may occur individually or coexist within the same patient, making comprehensive evaluation essential.
Coronary structural mechanisms
Structural coronary abnormalities account for a large proportion of MINOCA cases. The most common mechanism is plaque disruption occurring within non-obstructive atherosclerotic plaques. Plaque rupture and plaque erosion can both generate coronary thrombosis despite the absence of severe angiographic stenosis. Spontaneous thrombolysis, distal embolisation, endothelial dysfunction, and transient vessel occlusion may restore angiographic patency before coronary angiography while still producing myocardial necrosis.
Plaque rupture is characterised by disruption of a thin fibrous cap overlying a lipid-rich necrotic core, whereas plaque erosion results from superficial endothelial injury without cap disruption. These mechanisms differ in their inflammatory profile, clinical presentation, and prognosis, but both represent genuine forms of type 1 myocardial infarction.
Non-atherosclerotic structural mechanisms also contribute in important ways. Spontaneous coronary artery dissection (SCAD), particularly affecting younger and middle-aged women, results from intramural haematoma or intimal disruption producing compression of the true lumen. Coronary embolism constitutes another important, although less frequent, mechanism, originating from atrial fibrillation, valvular disease, intracardiac thrombi, paradoxical embolism, or systemic thromboembolic disorders.
Coronary functional mechanisms
Functional coronary abnormalities have become increasingly recognised as major contributors to MINOCA and may explain nearly one third to one half of patients found to be afflicted after comprehensive evaluation.
Epicardial coronary spasm produces transient but severe vasoconstriction sufficient to induce prolonged myocardial ischaemia and infarction. Its pathogenesis involves vascular smooth muscle hyperreactivity, endothelial dysfunction, autonomic imbalance, oxidative stress, inflammation, and enhanced Rho-kinase activity. Environmental exposures such as cigarette smoking and air pollution may further increase susceptibility.
Coronary microvascular dysfunction (CMD) represents another important functional mechanism. Structural abnormalities of the coronary microcirculation, including arteriolar remodelling, capillary rarefaction, and perivascular fibrosis, impair myocardial perfusion, while dynamic abnormalities such as microvascular spasms produce transient reductions in coronary blood flow. Although CMD is well established in chronic coronary syndromes and INOCA, its precise contribution to acute MI remains under investigation. Current evidence suggests that CMD may occasionally represent the primary mechanism but more commonly acts as a substrate lowering the threshold for ischaemia in the presence of systemic or coronary triggers. This multidimensional interaction explains why several mechanisms frequently coexist rather than acting independently.
Non-coronary cardiac and systemic mechanisms
Another important group of mechanisms involves myocardial oxygen supply-demand imbalance occurring without primary coronary pathology. Severe tachyarrhythmias, bradyarrhythmias, profound anaemia, hypoxaemia, sepsis, hypotension, hypertensive crises, or other systemic illnesses may provoke myocardial infarction when myocardial oxygen demand exceeds coronary perfusion capacity.
These mechanisms fit within the concept of type 2 MI and frequently interact with underlying coronary or microvascular dysfunction, creating a vulnerable substrate in which relatively modest systemic stressors become sufficient to produce myocardial necrosis.
Diagnostic evaluation
The diagnostic approach to MINOCA has evolved from simply excluding obstructive CAD to identifying the specific mechanism responsible for infarction [8].
Coronary angiography remains the essential first investigation because it excludes obstructive CAD while identifying angiographic clues suggestive of distal embolisation, subtle SCAD, or mild plaque irregularities. Nevertheless, angiography alone provides limited mechanistic information because it visualises only the vessel lumen.
Intracoronary imaging
Intracoronary imaging substantially improves diagnostic precision by directly evaluating the arterial wall. Optical coherence tomography (OCT), owing to its superior spatial resolution, has become the preferred technique for identifying plaque rupture, plaque erosion, intracoronary thrombus, intimal tears, and subtle SCAD. Intravascular ultrasound provides complementary assessment of deeper vessel structures, particularly intramural haematoma [8].
Recent studies have demonstrated that OCT identifies a culprit atherosclerotic substrate in approximately 40-50% of patients initially classified as MINOCA, confirming that many patients actually experience atherosclerotic MI despite non-obstructive angiographic findings [9].
Functional coronary testing
When structural abnormalities are absent, functional coronary assessment becomes essential.
Acetylcholine provocation testing has emerged as the reference method for diagnosing epicardial and microvascular spasm. Contemporary studies have demonstrated both its diagnostic value and safety, even during the acute phase of myocardial infarction. Approximately half of patients undergoing comprehensive evaluation demonstrate inducible coronary vasomotor abnormalities [9,10], identifying a clinically meaningful subgroup requiring specific vasodilator therapy.
Measurement of coronary flow reserve and the index of microvascular resistance provide additional assessment of microvascular function. Although these measurements offer valuable physiological information, they are best interpreted as indicators of an underlying vulnerable substrate rather than definitive proof of the primary mechanism.
Cardiac magnetic resonance
Cardiac magnetic resonance (CMR) represents the cornerstone for myocardial tissue characterisation. CMR differentiates ischaemic myocardial necrosis from myocarditis, Takotsubo syndrome, infiltrative cardiomyopathies, and other inflammatory myocardial diseases. Early performance during the index hospitalisation maximises diagnostic yield and substantially alters final diagnosis. Large contemporary studies have shown that only a minority of patients initially labelled as “suspected MINOCA” ultimately demonstrate definite myocardial infarction after CMR, whereas many are reclassified under myocarditis or Takotsubo syndrome [11,12]. Nevertheless, clinicians should recognise that a normal CMR does not completely exclude transient ischaemic mechanisms because very small infarcts or diffuse microvascular injury may remain below imaging resolution.
Additional investigations
Clinical history and physical examination remain fundamental for identifying systemic or embolic causes. Selected patients require transoesophageal echocardiography to identify intracardiac thrombi, valvular vegetations, patent foramen ovale, or other embolic sources. Prolonged rhythm monitoring, thrombophilia evaluation, and investigation of embolic events in other vascular territories may further clarify the underlying mechanism.
Multimodal diagnostic strategy
Evidence increasingly supports combining multiple complementary techniques rather than relying on a single investigation [13,14]. Studies integrating OCT with CMR have substantially improved diagnostic accuracy by simultaneously evaluating coronary pathology and myocardial tissue characteristics. More recently, comprehensive protocols combining OCT, acetylcholine testing, CMR, and selected transoesophageal echocardiography have demonstrated even greater diagnostic yield, reclassifying nearly three quarters of patients initially diagnosed with MINOCA. Nevertheless, approximately 20% of patients remain without a definitive diagnosis despite extensive evaluation, highlighting both current technological limitations and the biological complexity of the syndrome [13,14].
When approaching patients with a MINOCA as working diagnosis, the first diagnostic level includes careful clinical assessment, coronary angiography, electrocardiography, laboratory testing, and transthoracic echocardiography, establishing MINOCA as a provisional diagnosis while excluding obvious alternative explanations.
The second level incorporates intracoronary imaging, acetylcholine provocation testing, CMR, and, when appropriate, physiological assessment of coronary microvascular function. Referral pathways are essential to ensure that patients with unresolved diagnostic uncertainty undergo comprehensive evaluation when expertise for multidimensional invasive and non-invasive assessment is not available.
Therapeutic management
The heterogeneity of MINOCA requires individualised treatment based on the underlying mechanism rather than a routine application of therapies developed for obstructive myocardial infarction [13]. Large observational registries have demonstrated that universal treatment strategies are unlikely to provide optimal benefit. While statins and renin-angiotensin system inhibitors appear broadly beneficial, dual antiplatelet therapy has not consistently improved outcomes across unselected MINOCA populations [15].
Central Illustration: Mechanism-oriented management of MINOCA.
CMR: cardiac magnetic resonance; DAPT: dual antiplatelet therapy; IVUS: intravascular ultrasound; MI: myocardial infarction; OCT: optical coherence tomography; RAS: renin-angiotensin system
Structural coronary disease
Patients with plaque rupture or plaque erosion should generally receive treatment similar to type 1 myocardial infarction, including intensive lipid lowering, aggressive risk factor modification, and appropriate antithrombotic therapy. However, routine coronary stenting should not be considered mandatory. Increasing evidence indicates that conservative management without stent implantation may be appropriate in selected patients, particularly those with plaque erosion, potentially avoiding both early procedural complications and late, stent-related adverse events.
SCAD represents a distinct therapeutic entity. Conservative treatment is generally preferred because spontaneous healing occurs in most patients, whereas percutaneous coronary intervention is technically challenging and carries significant procedural risk. β-blockers may reduce recurrence risk, whereas prolonged dual antiplatelet therapy remains controversial in the absence of stent implantation.
Patients with coronary embolism require anticoagulation tailored to the specific embolic source, emphasising the importance of identifying systemic, rather than purely coronary, mechanisms.
Functional coronary disorders
The treatment of coronary spasms is centred on calcium-channel blockers, which represent first-line therapy and effectively reduce recurrent vasospastic episodes. Long-acting nitrates and other vasodilators may provide additional benefit. Conversely, β-blockers should generally be avoided in pure vasospastic disease because they may aggravate coronary vasoconstriction.
Management of CMD remains less well established. β-blockers, angiotensin-converting enzyme inhibitors, and statins appear to improve endothelial function, coronary physiology, and symptoms in selected patients, although evidence remains limited. Therapy should therefore address both CMD itself and any concomitant mechanisms contributing to myocardial ischaemia.
Stratified medicine approach
The emerging paradigm of mechanism-based therapy has recently received prospective support. The PROMISE trial demonstrated that comprehensive diagnostic evaluation followed by individualised treatment significantly improved angina burden and quality of life compared with conventional care [13]. These findings reinforce the principle that treatment should target the specific pathophysiological mechanism rather than relying on empirical uniform therapy.
Accordingly, contemporary management increasingly favours precision medicine, integrating advanced diagnostics with personalised therapeutic strategies.
Future perspectives
The concept of MINOCA continues to evolve. Initially introduced to describe an unexpected angiographic finding, MINOCA is now recognised as a clinical gateway leading to detailed mechanistic investigation. As diagnostic techniques continue to improve, the term itself may eventually become transitional, progressively replaced by mechanism-specific diagnoses that more accurately reflect the underlying disease process. Improved phenotyping through integration of clinical, imaging, physiological, and biomarker information will further refine diagnostic accuracy. Novel circulating biomarkers reflecting endothelial dysfunction, inflammation, thrombosis, or coronary vasoreactivity may facilitate earlier mechanism identification, particularly where advanced imaging is unavailable.
Equally important is the need for adequately powered randomised clinical trials specifically enrolling patients according to underlying pathophysiological mechanisms rather than treating MINOCA as a homogeneous entity. Such trials are expected to establish evidence-based therapeutic strategies and accelerate the transition towards precision cardiovascular medicine.
Conclusions
MINOCA has fundamentally reshaped the understanding of myocardial infarction by demonstrating that significant myocardial necrosis frequently occurs in the absence of obstructive coronary artery disease. Rather than representing a single disease, MINOCA encompasses multiple structural and functional coronary, as well as systemic, mechanisms, that converge on a common clinical presentation.
The evolution from a diagnosis of exclusion toward a structured, mechanism-oriented approach represents the major conceptual advance in the field. A comprehensive multimodal evaluation, combining coronary angiography, intracoronary imaging, functional testing, cardiac magnetic resonance, and selected systemic investigations, substantially improves diagnostic precision and guides individualised treatment.
Current evidence strongly supports abandoning a uniform therapeutic strategy in favour of stratified medicine, with management tailored to the specific underlying mechanism.
