Myocardial ischemia in nonobstructive coronary arteries: A review of diagnostic dilemmas, current perspectives, and emerging therapeutic innovations

Abstract

Myocardial infarction with nonobstructive coronary arteries is a unique presentation of acute coronary syndrome occurring in patients without significant coronary artery disease. Its pathophysiology involves atherosclerotic and nonatherosclerotic mechanisms such as plaque erosion, coronary microvascular dysfunction, vasospasm, spontaneous coronary artery dissection, autoimmune and inflammatory diseases, and myocardial oxygen supply-demand imbalance. A systematic approach to diagnosis is needed due to the diverse range of underlying causes. Cardiac troponins confirm the myocardial injury and coronary angiography rules out significant obstruction. Cardiac magnetic resonance imaging differentiates ischemic from nonischemic causes, and additional investigations, such as intravascular ultrasound, optical coherence tomography, and provocative testing, play a role in identifying the etiology to guide management strategies. Atherosclerotic cases require antiplatelet therapy and statins, vasospastic cases respond to calcium channel blockers, spontaneous coronary artery dissection is typically managed conservatively, and coronary microvascular dysfunction may require vasodilators. Lifestyle modifications and cardiac rehabilitation are essential for improving outcomes. The prognosis of patients experiencing recurrent events despite treatment is uncertain, but long-term outcomes depend on the etiology, highlighting the need for personalized management. Future research should focus on refining diagnostic protocols and identifying optimal therapeutic strategies. Randomized controlled trials are necessary to establish evidence-based treatments for different subtypes of myocardial infarction with nonobstructive coronary arteries.

Key Words: Myocardial infarction with nonobstructive coronary arteries; Myocardial infarction; Acute coronary syndrome; Coronary microvascular dysfunction; Vasospasm; Spontaneous coronary artery dissection; Plaque erosion; Cardiac magnetic resonance imaging; Intravascular imaging; Diagnostic algorithms

Core Tip: Myocardial infarction with nonobstructive coronary arteries is difficult to diagnose, and strong clinical suspicion is necessary for accurate identification. The absence of standardized diagnostic protocols leads to inconsistencies in patient evaluation and management. Current diagnostic tools, including imaging and laboratory tests, often fail to provide definitive answers. The identification of easily accessible biomarkers could improve early detection and guide clinical decisions. Reliable markers would help differentiate myocardial infarction with nonobstructive coronary arteries from other cardiac conditions and streamline diagnosis. The lack of standardized guidelines complicates treatment, making management challenging. Further research is essential to establish evidence-based protocols.

INTRODUCTION

Myocardial infarction (MI) with nonobstructive coronary arteries (MINOCA) is a clinical condition challenging the traditional understanding of acute coronary syndrome. Unlike typical MI caused by atherosclerotic plaque rupture or thrombosis leading to coronary obstruction, MINOCA occurs in patients with no evidence of obstructive coronary artery disease (CAD) but who still meet the criteria for MI[1]. Its prevalence ranges from 5%-15% among all acute MI cases[2,3]. Compared with typical MI, MINOCA tends to affect younger patients and is more common in Black and Hispanic individuals[4,5]. A meta-analysis showed that MINOCA patients have an annual mortality rate of about 2.0% compared to roughly 5.0% in typical MI[6]. A study showed that approximately 10.8% of MINOCA patients experience major adverse cardiovascular events (MACE) such as recurrent MI, stroke, or cardiovascular death with cardiovascular re-admission rates of 19.8% compared to 13.9% in typical MI[7]. Diagnosing MINOCA in clinical practice is challenging because of its heterogeneous nature and the absence of underlying obstructive CAD. Recent innovations such as intravascular optical coherence tomography (OCT) and high-resolution cardiac magnetic resonance (CMR) have refined our diagnostic approach to MINOCA, allowing for more precise identification of underlying pathologies and facilitating targeted treatment[8]. While treatment strategies for typical MI are well-established, the diverse underlying causes of MINOCA make it difficult to establish a one-size-fits-all standardized approach for management. The typical clinical symptoms of MINOCA closely resemble those of a typical MI. These include chest pain, which can be severe and can radiate to the arms, neck, or jaw. In some cases, individuals may experience atypical or less intense chest pain. Other symptoms include dyspnea, fatigue, malaise, palpitations, sweating, and occasionally nausea or vomiting.

The risk factors for MINOCA include a combination of traditional cardiovascular risk factors observed in typical MI and distinct mechanisms unique to MINOCA[2,3]. Hypertension, diabetes mellitus, smoking, and obesity are shared risk factors between MINOCA and typical MI[1,9]. However, MINOCA is also associated with unique factors, such as coronary vasospasm and microvascular dysfunction[4,10]. Autoimmune and inflammatory diseases such as systemic lupus erythematosus, rheumatoid arthritis, and antiphospholipid syndrome contribute to endothelial dysfunction, increased vascular inflammation, and prothrombotic states, which are also additional risk factors[11,12].

The main objective of this review is to provide a detailed understanding of MINOCA by exploring its pathophysiology, diagnostic methods, and management strategies. We begin by exploring the shared and unique risk factors for MINOCA, highlighting its heterogeneous nature and the challenges of accurate diagnosis and treatment. We explore the advancements in imaging techniques and biomarker analysis and highlight the current gaps in standardized diagnostic criteria. We discuss the current therapeutic approaches and potential future treatments and methods aimed at improving patient outcomes.

LITERATURE REVIEW

Search strategy

A comprehensive narrative review was conducted by searching multiple electronic databases, including PubMed, MEDLINE, Scopus, Web of Science, and Google Scholar. The search strategy incorporated a combination of Medical Subject Headings (MeSH) and relevant keywords to maximize the retrieval of pertinent literature. Key terms included “Myocardial Ischemia”, “Nonobstructive Coronary Arteries”, “MINOCA”, “Coronary Microvascular Dysfunction”, “Plaque Erosion”, “Coronary Vasospasm”, “Thrombosis”, “Imaging in MINOCA”, “Cardiac MRI”, “Management of MINOCA”, “Prognosis of MINOCA”, “Coronary Angiography”, “Endothelial Dysfunction”, “Inflammation in MINOCA”, “Stress Cardiomyopathy”, “Coronary Embolism”, “Spontaneous Coronary Artery Dissection”, and “Microvascular Angina”. Boolean operators and controlled vocabulary were used to refine the search and ensure a thorough review of the available literature.

Inclusion criteria

Studies were considered for inclusion if they provided insight into the pathophysiology, diagnosis, management, prognosis, or emerging research directions of MINOCA. Both original research and review articles published in peer-reviewed journals were included. No restrictions were placed on the study design to ensure a comprehensive overview. Given the evolving nature of MINOCA research, no publication date limitations were imposed. Only studies published in English were considered.

Data collection

The selection process involved an initial screening of article titles and abstracts to identify relevant studies. Articles not aligned with the scope of MINOCA or those lacking sufficient clinical or scientific relevance were excluded. The remaining studies underwent a full-text review to assess their contribution to the understanding of MINOCA. References from selected articles were also screened to identify additional relevant studies.

Assessment criteria

As this is a narrative review, formal risk-of-bias assessment tools, such as the Cochrane Risk of Bias Tool, the AMSTAR checklist, and the Newcastle-Ottawa Scale, were not applied. Instead, studies were evaluated based on their scientific rigor, relevance to the topic, methodological quality, and contribution to the understanding of MINOCA. Special attention was given to studies with robust diagnostic methodologies, clear clinical outcomes, and innovative approaches to pathophysiology and management.

PATHOPHYSIOLOGY OF MINOCA

MINOCA is classified into two main groups based on its pathophysiological mechanisms: Atherosclerotic-related causes and nonatherosclerotic-related causes. These causes are summarized in Table 1[13-15].

Table 1 Classification of myocardial infarction with nonobstructive coronary arteries based on pathophysiological mechanisms.

Category	Mechanism	Description
Atherosclerotic causes	Plaque erosion	Partial thrombus formation without significant luminal obstruction due to endothelial dysfunction and inflammation
	Coronary microembolization	Small emboli from an atherosclerotic plaque cause transient ischemia without visible stenosis
	Coronary microvascular dysfunction	Endothelial dysfunction and increased arterial stiffness impair myocardial perfusion
Non-atherosclerotic causes	Coronary vasospasm	Transient epicardial or microvascular constriction triggered by endothelial dysfunction, sympathetic activation, or vasoconstrictive agents leading to ischemia
	Spontaneous coronary artery dissection	Intimal tear or intramural hematoma causes lumen compression and ischemia. It is often associated with fibromuscular dysplasia and peripartum changes
	Myocardial oxygen supply-demand mismatch	Increased myocardial oxygen demand in conditions like anemia, tachyarrhythmias, hypertensive crises, and sepsis

Atherosclerotic causes of MINOCA

Although MINOCA is typically associated with the absence of obstructive CAD, it can still play a role in some cases[13,16]. In these instances, plaque erosion leads to thrombosis formation without causing significant obstruction. Unlike plaque rupture, which leads to complete coronary occlusion, plaque erosion leads to a nonocclusive thrombus that may dissolve even before angiography, making detection and diagnosis challenging[17,18]. Factors such as endothelial dysfunction, inflammation, and shear stress, especially in younger patients and women, can contribute to plaque erosion[19].

In addition, coronary thrombosis and embolism can play a role in MINOCA[20]. Microembolization from an atherosclerotic plaque may cause brief ischemia and myocardial injury despite the absence of significant angiographic stenosis. Another mechanism is coronary microvascular dysfunction (CMD), which is caused by endothelial dysfunction and increased arterial stiffness. It impairs myocardial perfusion without significant stenosis in the major epicardial arteries[21]. Additional nonspecific conditions, such as hypertension, diabetes mellitus, and dyslipidemia, which are usually associated with atherosclerosis, can also impair microvascular function, leading to an increased risk of MINOCA[22].

Nonatherosclerotic causes of MINOCA

Nonatherosclerotic causes of MINOCA involve various mechanisms, such as coronary vasomotor disorders, spontaneous coronary artery dissection (SCAD), myocardial supply-demand mismatch, and inflammatory or autoimmune processes[23]. Epicardial vasospasm causes transient coronary artery constriction, leading to reduced myocardial perfusion. It can be triggered by endothelial dysfunction and exposure to vasoconstrictive agents such as cocaine or medications[24].

Another cause of MINOCA is SCAD, which more commonly affects younger women without typical cardiovascular risk factors[14]. SCAD occurs due to an intimal tear, leading to the formation of an intramural hematoma that compresses the coronary artery wall and causes ischemia. Unlike plaque rupture, SCAD is associated with arterial wall abnormalities such as fibromuscular dysplasia, connective tissue disorders, and peripartum hormonal changes[25]. Myocardial supply-demand mismatch occurs when the myocardial oxygen demand is greater than the coronary artery blood supply, leading to MINOCA[20]. It can be caused by severe anemia, tachyarrhythmia, hypertensive crisis, thyrotoxicosis, or septic shock. Systemic lupus erythematosus, vasculitis, and myocarditis have also been linked to MINOCA, as inflammatory cytokines disrupt vascular homeostasis, increasing the risk of vasospasm, thromboembolism, and microvascular dysfunction[26].

DIAGNOSIS OF MINOCA

Owing to the similarity in MINOCA symptoms and typical MI, serum cardiac biomarkers are usually the first diagnostic workup performed for the evaluation of patients. They are simple, safe, readily available, and useful for both diagnosis and prognosis. Cardiac troponins (cTn) remain fundamental in the diagnosis of MI. According to the Fourth Universal Definition of MI, a rise or fall in cTn levels above the 99^th percentile is among the criteria for MI. However, cTn values peak lower in MINOCA patients than in typical MI patients[27]. High-sensitivity cTn has emerged as a useful tool for detecting unfavorable outcomes in MINOCA patients. Despite its importance, cTN alone cannot be used to diagnose or determine the underlying cause of MINOCA, necessitating further investigations[28].

Biomarkers

Biomarkers provide insight into the pathogenic mechanisms underlying MINOCA. Since MINOCA has diverse etiologies, different biomarkers help differentiate its causes and predict patient prognosis. Understanding these biomarkers enhances diagnostic accuracy and improves patient management. Although biomarkers have been investigated for their potential in MINOCA, they have not yet been integrated into clinical protocols. For a better understanding, we grouped the biomarkers linked to MINOCA by their roles, as illustrated in Figure 1.

Figure 1 Classification of biomarkers in myocardial infarction with nonobstructive coronary arteries. SCAD: Spontaneous coronary artery dissection; CAS: Coronary artery spasm; CMD: Coronary microvascular dysfunction.

Nondiscriminatory markers: There is no discriminatory value in these markers between typical MI patients and MINOCA patients. However, the levels were higher in patients with MINOCA than in the controls. The markers are tabulated in Table 2[27,29-31].

Table 2 Nondiscriminatory biomarkers in myocardial infarction with nonobstructive coronary arteries.

Biomarker	Description
CXCL-1	Involved in neutrophil recruitment and inflammation. Elevated levels have been found indicating a high level of chronic inflammation in MINOCA patients
suPAR	suPAR has chemotactic properties and is involved in inflammatory activity and microvascular dysfunction. Elevated levels are linked to inflammation and endothelial dysfunction in MINOCA
MPO	A marker of oxidative stress and inflammation. Higher MPO levels are typically associated with atherosclerosis and can be elevated in typical MI, whereas MINOCA might present with lower MPO levels if inflammation is less pronounced

CXCL-1: C-X-C motif chemokine ligand 1; suPAR: Soluble urokinase plasminogen activator receptor; MPO: Myeloperoxidase; MINOCA: Myocardial infarction with nonobstructive coronary arteries; MI: Myocardial infarction.

Discriminatory markers: These markers have discriminatory value for distinguishing between typical MI patients and MINOCA patients. The markers are tabulated in Table 3[27,29].

Table 3 Discriminatory biomarkers in myocardial infarction with nonobstructive coronary arteries.

Biomarker	Description
TRAIL	Plays a role in immune cell regulation and inflammation. It is downregulated in proportion to the severity of myocardial injury. Higher levels are observed in stable MINOCA patients
t-PA	Involved in fibrinolysis. The levels of t-PA could be altered in typical MI due to thrombus formation, whereas MINOCA may show lower fibrinolytic activity due to the lack of major coronary obstruction
NT-proBNP	Elevated in MINOCA due to myocardial stress, ventricular dysfunction, or microvascular dysfunction. It can indicate a worse prognosis

TRAIL: Tumour necrosis factor-related apoptosis-inducing ligand; t-PA: Tissue plasminogen activator; NT-proBNP: N-terminal pro-B-type natriuretic peptide; MINOCA: Myocardial infarction with nonobstructive coronary arteries; MI: Myocardial infarction.

Biomarkers involved in atherosclerotic lesions: These biomarkers reflect inflammation, extracellular matrix degradation, platelet activation, and oxidative stress, which are central to the processes of plaque erosion, rupture, and thromboembolism in MINOCA. The markers are tabulated in Table 4[28,29,31-33].

Table 4 Biomarkers in atherosclerotic lesions.

Biomarker	Description	Clinical significance
hs-CRP	hs-CRP is a sensitive marker of systemic inflammation and is elevated during plaque rupture or erosion	High hs-CRP levels reflect ongoing inflammation in the atherosclerotic plaque, promoting its instability and rupture
MMP-9	MMP-9 plays a key role in extracellular matrix degradation, which is involved in plaque rupture and erosion	MMP-9 degrades collagen and elastin in the plaque, weakening the fibrous cap and increasing the risk of rupture or erosion
CD40L	CD40L is involved in platelet activation and inflammation, playing a role in plaque rupture and thromboembolism	CD40L stimulates platelet aggregation and endothelial activation, contributing to plaque rupture and thromboembolism in MINOCA
P-selectin	P-selectin mediates platelet and endothelial cell interactions, playing a role in thromboembolism and plaque instability	P-selectin is involved in the recruitment of platelets to the site of plaque rupture or erosion, promoting thrombus formation

hs-CRP: High-sensitivity C-reactive protein; MMP-9: Matrix metalloproteinase-9; CD40L: CD40 ligand; MINOCA: Myocardial infarction with nonobstructive coronary arteries.

Biomarkers involved in SCAD: The markers are tabulated in Table 5[27,34-38].

Table 5 Biomarkers in spontaneous coronary artery dissection.

Biomarker	Description	Clinical significance
TGF-β	TGF-β is an angiogenic factor involved in vascular remodeling, fibrosis, and smooth muscle cell proliferation. Dysregulation of TGF-β can cause abnormal composition of the arterial wall leading to SCAD	Impaired levels of TGF-β contribute to vascular remodeling and fibrosis, promoting the formation of dissection and impaired vessel function. A study found that miRNAs belonging to the TGF-β family were found to be expressed in high levels in patients with SCAD implicating the role of TGF-β in this disease pathology suggesting the potential of the miRNAs to be biomarkers of SCAD
Fibrillin 1 protein	Fibrillin 1 is a structural component of the extracellular matrix, important for vascular integrity. Deficiency or mutation may lead to SCAD and MINOCA	Impaired fibrillin 1 leads to compromised vascular integrity, making arteries prone to dissection and subsequent myocardial ischemia
Eosinophils	High levels of circulating eosinophils were found in patients with SCAD. Eosinophil activation and infiltration in the adventitial layer of the coronary artery causes lytic substances degranulation resulting in vascular damage in SCAD and MINOCA	Eosinophil infiltration promotes vascular inflammation and damage, which may contribute to SCAD development and microvascular dysfunction

TGF-β: Transforming growth factor beta; SCAD: Spontaneous coronary artery dissection; MINOCA: Myocardial infarction with nonobstructive coronary arteries; miRNAs: MicroRNAs.

Biomarkers involved in supply-demand mismatch: The markers are tabulated in Table 6[27,28,31].

Table 6 Biomarkers of supply-demand mismatch.

Biomarker	Description	Clinical significance
MR-proANP	MR-proANP is involved in cardiac stress response and is an indicator of atrial stretch. It is proposed to be elevated in MINOCA due to acute myocardial stress or inflammation	It reflects atrial and ventricular stress, which may arise from microvascular dysfunction, inflammatory processes, or stress-induced myocardial injury, all of which could contribute to MINOCA. It helps in diagnosing myocardial injury when coronary arteries appear unobstructed
CT-proET1	CT-proET-1 is a marker of endothelin-1 precursor, a potent vasoconstrictor involved in vascular tone and cardiac remodeling. Elevated levels suggest endothelial dysfunction	Elevated CT-proET-1 levels in MINOCA indicate impaired endothelial function and increased vasoconstriction, potentially contributing to myocardial ischemia despite normal coronary artery findings. Endothelin-1 can cause vasoconstriction, leading to reduced myocardial perfusion, a mechanism in MINOCA
MR-proADM	MR-proADM is a biomarker related to adrenomedullin, a vasodilator, and marker of endothelial dysfunction. It is elevated in conditions of heart failure, sepsis, and myocardial injury	MR-proADM reflects the systemic vasodilatory response and endothelial dysfunction, which may result from microvascular spasm, inflammation, or altered myocardial perfusion in MINOCA. High levels correlate with worse prognosis and heart failure in these patients
GDF-15	GDF15 is a stress-induced cytokine elevated in response to inflammation, oxidative stress, and myocardial injury. It is thought to be a biomarker of myocardial stress in MINOCA	GDF15 reflects myocardial injury and inflammation, which may result from microvascular dysfunction or myocardial stress in the absence of obstructive coronary disease. Elevated levels suggest a heightened inflammatory response and oxidative stress, both of which can contribute to the pathophysiology of MINOCA. It is related to adverse cardiovascular outcomes

MR-proANP: Mid-region pro-atrial natriuretic peptide; CT-proET1: C-terminal pro-endothelin-1; MR-proADM: Mid-region pro-adrenomedullin; GDF-15: Growth differentiation factor-15; MINOCA: Myocardial infarction with nonobstructive coronary arteries.

Biomarkers involved in coronary artery spasm and CMD: The markers are tabulated in Table 7[27,29,38].

Table 7 Biomarkers involved in coronary artery spasm and coronary microvascular dysfunction.

Biomarker	Description	Clinical significance
CRP	CRP is a marker of systemic inflammation, and elevated levels indicate ongoing inflammation, which may contribute to CAS and CMD	Elevated CRP levels are associated with poor prognosis in MINOCA, reflecting chronic inflammation and vascular dysfunction
IL-6	IL-6 is a pro-inflammatory cytokine that plays a central role in inflammatory responses and vascular injury. Elevated IL-6 levels are linked with CMD and spasms	High IL-6 levels indicate an inflammatory state, which can exacerbate CMD and increase the risk of MINOCA
Lp(a)	Lp(a) is an atherogenic lipoprotein that can contribute to endothelial dysfunction, promoting both CAS and CMD	Lp(a) is higher in patients with spastic sites of coronary arteries
Rho-associated protein kinase	Rho kinase activates myosin light chain kinase through phosphorylation. Rho kinase thus regulates smooth muscle contraction and endothelial function. It is involved in coronary artery spasm and microvascular dysfunction	Increased Rho kinase activity is linked with impaired vasodilation and increased vasoconstriction, contributing to CAS and CMD in MINOCA

CRP: C-reactive protein; IL-6: Interleukin 6; Lp(a): Lipoprotein (a); CAS: Coronary artery spasm; CMD: Coronary microvascular dysfunction; MINOCA: Myocardial infarction with nonobstructive coronary arteries.

Noninvasive imaging

CMR: CMR is the first step in evaluating patients with nonobstructive coronary arteries via angiography[39]. This is an essential workup to distinguish MINOCA from conditions that mimic it, such as myocarditis and Takutsubo syndrome. A meta-analysis of 26 studies involving 3624 patients revealed that CMR has significant diagnostic and prognostic value in suspected MINOCA patients. It reclassified 68% of patients, with a pooled prevalence of confirmed MINOCA at 22%, myocarditis at 32%, and Takotsubo syndrome at 10%[40]. CMR with late gadolinium enhancement imaging and T1/T2 mapping sequences helps establish whether the etiology is ischemic or nonischemic. CMR imaging is also useful in predicting MACE, underscoring its prognostic importance[41]. The various findings with descriptions and corresponding diagnoses via CMR in MINOCA are consolidated in Table 8[42-44].

Table 8 Cardiac magnetic resonance findings and diagnoses in myocardial infarction with nonobstructive coronary arteries.

Cause of MINOCA	CMR findings	Description
Acute myocarditis	Lake Louise criteria	CMR shows myocardial edema, capillary leaks, hyperemia, and necrosis/fibrosis. Lake Louise criteria include T2 weighted imaging for edema and T1 weighted imaging before and after contrast for tissue characterization (LGE pattern)
	LGE	LGE typically shows subepicardial or transmural enhancement, often in a nonvascular distribution (inflammatory infiltration rather than ischemic)
	T2 weighted imaging	T2 signal hyperintensity, indicating myocardial edema
	T1 weighted imaging	Helps identify myocardial fibrosis and scar tissue
Takotsubo cardiomyopathy	RWMA	CMR shows apical ballooning with increased myocardial strain in the apex of the (LV) but with absence of coronary artery obstruction
	LGE	LGE is typically absent or minimal in Takotsubo cardiomyopathy, helping to distinguish it from myocardial infarction
	T2 weighted imaging	T2 hyperintensity may show myocardial edema in the involved regions of the LV
	No obstructive coronary disease	No significant coronary artery blockage or stenosis is identified
Plaque rupture	LGE	LGE in a subendocardial or transmural pattern corresponding to a vascular territory, often localized to the area of infarction after plaque rupture
	T2 weighted imaging	Edema is typically seen in a coronary regional distribution, reflecting the infarcted area from the ruptured plaque
	No obstructive coronary disease	Coronary artery spasm or microvascular dysfunction might be present but not significant obstruction
Plaque erosion	LGE	LGE may be present in a subendocardial or transmural pattern, typically corresponding to a vascular territory
	T2 weighted imaging	Edema localized to the region supplied by the affected artery
	No significant obstruction	Coronary imaging may show plaque erosion or microembolism, but not significant stenosis

MINOCA: Myocardial infarction with nonobstructive coronary arteries; CMR: Cardiac magnetic resonance; LGE: Late gadolinium enhancement; RWMA: Transient regional wall motion abnormalities; LV: Left ventricle.

Invasive imaging

OCT: OCT involves passing a catheter into the coronary vessel and using near-infrared imaging to visualize the different layers of the vessel wall. This investigation provides detailed insights into the exact mechanism of myocardial injury. OCT is an ideal test for detecting most lesions of the MINOCA, which include plaque erosion, plaque rupture, calcified nodules, and SCAD[45]. In a study consisting of 7423 MI patients, 294 patients were suspected to have MINOCA. OCT confirmed atherosclerotic etiology in 61.1% of the 190 patients who underwent the procedure[46]. Hence, OCT is indispensable for identifying atherosclerotic lesions or SCADs that contribute to MINOCA. The various findings with descriptions using OCT in MINOCA are consolidated in Table 9[6,45,47].

Table 9 Optical coherence tomography findings and diagnoses in myocardial infarction with nonobstructive coronary arteries.

OCT finding	Description
Plaque rupture	Defined by the presence of fibrous cap discontinuity with a cavity formation within the plaque
Plaque erosion	Presence of thrombus overlying an intact plaque, without rupture
Calcific nodule	Disruption of the fibrous cap and/or thrombus overlying a calcified plaque with protruding calcification into the lumen
Lone thrombus	Presence of thrombus overlying an intact coronary arterial wall, without any visible plaque rupture or erosion
Coronary artery spasm	Characterized by intimal bumping with a larger medial area and medial thickness
Spontaneous coronary artery dissection	Separation of the intimal layer from the outer vessel wall with a blood column between the two

OCT: Optical coherence tomography.

Intravascular ultrasound: Intravascular ultrasound (IVUS) utilizes a catheter with an ultrasound probe. A piezoelectric transducer produces sound waves into the lumen, which are absorbed and reflected to produce a 360-degree image of the artery from the inside. Radiofrequency backscatter analysis is performed through software programs for plaque composition assessment[48]. IVUS can be used to identify calcified plaques, lipids, and neointimal proliferation. It has been extensively used in the detection of stent failure with stent thrombosis or in-stent restenosis[49]. Owing to its ability to penetrate deep tissue, IVUS can detect abnormal vessel compliance, resistance, or vascular remodeling, hence having the added advantage of evaluating CMD[50]. It is considered highly sensitive in the detection of SCAD[51]. IVUS is preferred over patients with kidney disease, as it does not require contrast agent, as in OCT[45]. IVUS is better suited for structural evaluation and depth penetration, whereas OCT excels at high-resolution imaging of the plaque’s superficial layers and vulnerable plaque characteristics. Combining both technologies can provide a more comprehensive understanding of coronary pathology, especially in complex cases such as MINOCA[45].

Provocative testing: This is performed in patients to identify MI due to coronary vasospasm. In this test, ergonovine (ER) or acetylcholine (ACh) is administered via the intracoronary or intravenous route according to the protocol used to identify the vasospastic vessel. The ER acts on smooth muscle through serotonergic receptors to induce vasoconstriction, whereas ACh acts via muscarinic receptors of the endothelial cell to produce vasodilation. However, in the dysfunctional endothelium, the ER induces pronounced vasoconstriction, and ACh paradoxically causes vasoconstriction instead of vasodilation[52]. A meta-analysis of 12585 patients from 16 studies by Takahashi et al[53] revealed that intracoronary ACh testing is a safe procedure for the diagnosis of epicardial and microvascular spasm. In some studies, ER was found to be safer than ACh in intracoronary testing[54].

Invasive coronary functional testing: CMD results in a supply-demand mismatch, contributing to myocardial injury. CMD is measured by impaired coronary flow reserve (CFR), which is the ratio of hyperemic to baseline average peak velocity (bAPV). bAPV is measured during the resting state, and a hyperemic state is created via intracoronary administration of adenosine. CFR is then calculated via measurements obtained from the guidewire. The WISE-Coronary Vascular Dysfunction project, which included 259 women with MINOCA due to suspected CMD, revealed that women with higher bAPVs had worse Seattle Angina Questionnaire frequency scores[55]. While this method is the most commonly used method, the CFR can also be calculated via the thermodilution technique with a pressure - temperature sensor guidewire, which uses a saline bolus and transit time. Alternatively, the CFR can be calculated via Doppler flow wires. A CFR < 2.0 is diagnostic of CMD[56,57]. CMD can also be caused by microvascular resistance, which is measured via the same techniques used to measure CFR. The index of microvascular resistance is the product of distal coronary pressure at maximal hyperemia and the hyperemic mean transit time. An index of microvascular resistance exceeding or equal to 25 is diagnostic of CMD[57]. CMD has been found to play a pathological role in almost all subtypes of MINOCA, and assessing its severity is crucial for the treatment of MINOCA[58].

Diagnostic algorithm

On the basis of all the considerations stated above and literature, we propose the following algorithm for the diagnostic approach for patients suspected of having MINOCA in Figure 2. The diagnosis of MINOCA begins with identifying patients who meet the fourth universal definition of MI but lack obstructive stenosis (≥ 50%) on coronary angiography[59,60]. The first step is for the patient to undergo noninvasive CMR to differentiate ischemic causes from nonischemic mimics. An ischemic pattern, such as myocardial edema or fibrosis seen along vascular territories[39], should be further evaluated with invasive imaging techniques such as OCT or IVUS to look for intracoronary vascular lesions, such as plaque disruption, erosion, thromboembolism, and SCAD. These lesions represent a subset of MINOCA and should be treated accordingly when identified. If no such lesions are found, provocative testing with intracoronary ACh or ER can be performed to check for a vasospastic cause, whereas functional testing can assess coronary microvascular dysfunction. Identifying the cause of MINOCA is essential, as treatment and prognosis vary for each subtype.

Figure 2 Diagnostic algorithm for myocardial infarction with nonobstructive coronary arteries. MINOCA: Myocardial infarction with nonobstructive coronary arteries; CMR: Cardiac magnetic resonance; LGE: Late gadolinium enhancement; OCT: Optical coherence tomography; IVUS: Intravascular ultrasound; ACh: Acetylcholine; ER: Ergonovine.

MANAGEMENT OF MINOCA

The guidelines for the management of MINOCA have been quite variable because of the heterogeneity in etiology; thus, patients have been treated on a case-to-case basis. In many scenarios, the underlying cause remains unknown, or the efficacy of the intervention remains to be proven for the probable etiology. The American Heart Association (AHA) guidelines provide a comprehensive four-step approach to patients with MINOCA: (1) Emergency supportive care for the stabilization of acute complications such as arrhythmias and cardiogenic shock; (2) Working diagnosis approach to exclude mimics of acute MI and find the etiology of MINOCA; (3) Cardio-protective therapies for the secondary prevention of adverse coronary events through pharmacological intervention, risk factor modification, and cardiac rehabilitation (CR); and (4) Cause-targeted therapies depending on the underlying etiology involved.

Atherosclerotic plaque disruption

The cardioprotective strategies for atherosclerotic plaque rupture and erosion are similar to the secondary prevention modalities for type 1 MI. Long-term aspirin therapy is recommended by the clinical guidelines of the AHA (2019), the European Society of Cardiology (2023), and the Canadian Cardiovascular Society (2024)[2,61,62]. The use of a second antiplatelet drug (P2Y12 inhibitor) is recommended on the basis of the outcomes of the EROSION study[63]. A post hoc analysis of the OASIS 7 trial showed that an intensified dosing strategy offers no additional benefit over the standard dual antiplatelet regimen in patients with MINOCA (Bossard et al[64], NCT00335452). Statin therapy has been shown to reduce the incidence of MACEs and is recommended for use with a target low-density lipoprotein level < 1.8 mmol/L or > 50% reduction from baseline levels[61,62,65-67].

Angiotensin-converting enzyme inhibitors (ACEIs)/angiotensin receptor blockers (ARBs) and β-blockers can be used on an individual basis if specific indications exist[68]. The MINOCA-BAT trial (Randomized evaluation of beta blocker and ACEI/ARB treatment in MINOCA patients; NCT03686696), which was designed to evaluate the usefulness of these interventions, was terminated as of November 2023 due to a low inclusion rate[69]. A Bayesian and frequentist meta-analysis on medical interventions in MINOCA has shown that renin-angiotensin-aldosterone system inhibitors and statins lower mortality and MACE risks, whereas β-blockers and dual-antiplatelet drugs have a neutral prognostic impact[70]. This study, however, did not differentiate the underlying etiology of MINOCA in the analysis. In their work, Lindahl et al[65] (nonsignificant) and Ciliberti et al[71] reported a beneficial effect of β-blockers on patient prognosis.

The AHA guidelines are against routine coronary stenting in cases of plaque disruption (in line with the EROSION study); however, the expert consensus documents of the European Association of Percutaneous Cardiovascular Interventions favor stent deployment, especially in cases of plaque rupture[72]. None of the guidelines have specific recommendations for anticoagulation, although periprocedural administration of unfractionated heparin is advised in patients undergoing percutaneous intervention (PCI) if not previously anticoagulated or were on fondaparinux[73]. The recommended therapies and their details are tabulated in Table 10.

Table 10 Observational studies on the efficacy of cardioprotective therapies in myocardial infarction with nonobstructive coronary arteries.

Ref.	Methodology	Results
		DAPT	Statins	Beta-blockers	ACEI/ARB	CCB
Lindahl et al[65], 2017	Observational study on the data from the SWEDEHEART registry collected between July 2003 and June 2013 and followed up to December 2013, involving 9466 cases of MINOCA. Incidence of MACE was measured after a mean follow-up of 4.1 years	Nonsignificant 10% reduction in MACE post-discharge (HR = 0.90; 95%CI: 0.74-1.08)	Significant 23% reduction in MACE (HR = 0.77; 95%CI: 0.68-0.87)	Nonsignificant 14% reduction in MACE (HR = 0.86; 95%CI: 0.74-1.01)	Significant 18% reduction in MACE rate (HR = 0.82; 95%CI: 0.73-0.93)	N/A
Paolisso et al[68], 2019	Study based on the database of Bologna University Hospital between January 2016 and December 2018 involving patients of acute myocardial infarction (including 134 MINOCA cases) undergoing coronary angiography within the first 48 hours of hospitalization. The average follow-up period was 19.35 ± 10.6 months	A nonsignificant reduction in MACE (HR = 0.42; 95%CI: 0.14-1.24)	A nonsignificant reduction in MACE (HR = 0.44; 95%CI: 0.16-1.22)	A nonsignificant reduction in MACE (HR = 0.43; 95%CI: 0.14-1.35)	Significant reduction in MACE (HR = 0.29; 95%CI: 0.10-0.81)	N/A
Abdu et al[67], 2020	Single center retrospective study on 259 MINOCA patients between 2014 to 2018 after a follow-up duration of 2 years	Nonsignificant effect on MACE (HR = 1.53; 95%CI: 0.78-3.01)	Significant decrease in MACE (HR = 0.467; 95%CI: 0.239-0.911)	Nonsignificant effect on MACE (HR = 1.043; 95%CI: 0.547-1.988)	Significant decrease in MACE (HR = 0.486; 95%CI: 0.237-0.996)	N/A
Kovach et al[66], 2021	A propensity-matching study on the data collected from the Veterans Affairs Clinical Assessment, Reporting and Tracking program on troponin-positive patients who had undergone coronary angiography between October 2008 and September 2017. The positive cohort consisted of 1986 cases of MINOCA. The mean follow-up period is 1 year	Nonsignificant effect on MACE with P2Y12 inhibitor (HR = 1.02; 95%CI: 0.58-1.80)	Significant decrease in MACE (HR = 0.34; 95%CI: 0.23-0.51)	Nonsignificant effect on MACE (HR = 1.09; 95%CI: 0.73-1.62)	Significant decrease in MACE with ACEI use (HR = 0.51; 95%CI: 0.33-0.79)	A nonsignificant reduction in MACE (HR = 0.63; 95%CI: 0.38-1.04)
Ciliberti et al[71], 2021	A retrospective multicentric cohort study on 621 patients with MINOCA from 9 Hub Hospitals across Italy between March 2012 and March 2018. The mean follow-up duration is 90 months	Nonsignificant effect on MACE (HR = 2.25; 95%CI: 0.58-8.79)	Nonsignificant effect on MACE (HR = 1.67; 95%CI: 0.91-3.05)	Significant reduction in MACE observed (HR = 0.49; 95%CI: 0.31-0.79)	Nonsignificant effect on MACE (HR = 0.70; 95%CI: 0.40-2.21)	Nonsignificant effect on MACE (HR = 1.41; 95%CI: 0.77-2.50)
Bossard et al[64], 2021	Post hoc analysis of the OASIS 7 trial comparing MACE outcomes among 1599 MINOCA patients with double-strength and standard clopidogrel-based DAPT regimen after a follow-up of 1 year	No additional benefit of double-strength clopidogrel over the standard dose (HR = 3.57; 95%CI: 1.31-9.76)	N/A	N/A	N/A	N/A

DAPT: Dual antiplatelet therapy; ACEI: Angiotensin-converting enzyme inhibitor; ARB: Angiotensin-receptor blocker; CCB: Calcium channel blocker; MINOCA: Myocardial infarction with nonobstructive coronary arteries; MACE: Major adverse cardiovascular event; HR: Hazard ratio; CI: Confidence interval; N/A: Not applicable;

Epicardial coronary vasospasm

The mainstays for the treatment of coronary vasospasm are calcium channel blockers and avoidance of triggering factors (such as cold, stress, hyperventilation, smoking, sumatriptan, and recreational drugs)[73]. Short-acting nitrates are reliable second-line agents that provide symptomatic relief and relieve active spasms. The utility of long-acting nitrates is limited, possibly due to the development of ‘nitrate tolerance’. Refractory vasospasms can be handled with two calcium channel blockers that act at different receptors[2]. Studies have shown the effectiveness of antispastic drugs such as nicorandil (potassium channel opener) and cilostazol (phosphodiesterase-3 inhibitor) in treating coronary vasospasms[2]. β-blockers are avoided in these patients, as they may precipitate/worsen symptoms[74]. The use of dual antiplatelet therapy (DAPT) is controversial in cases of coronary vasospasm. This could be attributed to the precipitation of vasospasm by aspirin through prostacyclin inhibition. Compared with no antiplatelet therapy, coadministration of aspirin and clopidogrel results in a greater risk of adverse coronary events in patients with vasospastic angina, although the individual use of either of these drugs does not increase the risk (VA-Korea registry)[75]. Thus, the use of a single antiplatelet agent is recommended only in patients with significant underlying atherosclerosis. PCI and stenting are not indicated in cases of variant angina unless the patients are refractory to medical treatment or if severe underlying organic stenosis in the coronary vasculature exists[61].

Coronary thrombosis and embolism

A wide variety of etiologies, ranging from atrial fibrillation, structural cardiac abnormalities, infections, malignancy, thrombophilia, and autoimmune diseases, cause coronary thromboembolism. Management strategies should focus on detailed evaluations by specialists and treatment of the underlying cause. In the case of embolism, an effort should be made to identify the source of embolism (such as patent foramen oval, deep vein thrombosis, and septic and neoplastic emboli)[76]. Thrombolytic and anticoagulation measures should be initiated to resolve thrombi. Aspiration thrombectomy can be considered in cases of high thrombus burden. Balloon angioplasty and stenting are not necessary for angiographically normal patients[76]. The duration of maintenance anticoagulation required depends on the risk factor profile of the patient. Additionally, antiplatelet drugs, ACEIs/ARBs, and statins can be given to these patients.

Preventive pharmacotherapy can be helpful in patients with underlying pro-thrombotic states to avoid thromboembolic episodes in the future. For example, patients with antiphospholipid antibody syndrome could benefit from lifelong administration of vitamin K antagonists, maintaining the international normalized ratio between 3 and 4[73]. Plasma exchange therapy along with adjunctive steroid/rituximab administration can lower the risk in patients with thrombotic thrombocytopenic purpura[63]. Defect closure in cases of patent foramen ovale and atrial septal defects, long-term anticoagulation in patients with atrial fibrillation, and prosthetic valve/intracardiac thrombus are some strategies that offer a good long-term prognosis[62].

CMD

Management of CMD can be challenging, as conventional antianginal drugs have limited utility in their management, and PCI is no longer an option. Nevertheless, calcium channel blockers and β-blockers have been used to provide symptomatic relief[2,62]. The pathogenesis of CMD operates at the endothelial level through a complex orchestration of cytokines. Recent studies have demonstrated the efficacy of some unconventional drugs in treating CMD that operate through the modulation of these factors. Drugs such as L-arginine, statins, and enalapril improve endothelial function; dipyridamole and ranolazine promote microvascular dilatation; and imipramine and aminophylline confer visceral analgesic effects[2]. These agents could provide therapeutic benefits for patients with CMD; however, their position in the current treatment guidelines is not yet concrete. Some studies have also pointed toward the use of ACEIs/ARBs as monotherapies or in combination with aldosterone antagonists in patients with CMD, but the strength of the clinical evidence for their efficacy is weak[77]. Recently, newer therapeutic approaches have been proposed for CMD patients. The IMPROvE-CED trial (NCT03471611) advocates intracoronary autologous CD34+ cell therapy for the treatment of symptomatic coronary endothelial dysfunction in patients with nonobstructive coronaries[78]. Although promising, its safety and therapeutic efficacy remain to be evaluated.

SCAD

Multiple guidelines suggest a conservative approach to the management of SCAD[2,61,62]. The risk of inducing iatrogenic dissection and hematoma expansion with invasive modalities and the evidence of spontaneous healing with medical management alone are the rationales behind this consensus. The long-term use of β-blockers is highly encouraged in SCAD because it reduces the risk of recurrence[79]. The BA-SCAD trial is currently in progress and has been designed to evaluate the efficacy of medical therapy in SCAD[80]. Strict control of hypertension is mandatory in all patients, as it is an important precipitating factor[79].

The use of antiplatelet drugs in SCAD is controversial, as it theoretically increases the risk of bleeding in situ. However, in the acute phase, antiplatelet therapy could confer a protective effect against the pro-thrombotic state conferred by endothelial disruption at the site of dissection. Thus, in an attempt at moderation, it is often recommended to start patients on DAPT for a period of 3-4 months (maximum up to 12 months) and then continue patients on low-dose aspirin for 12 months[62,63]. The expert practice is, however, variable in this case and depends on the individual risk factor profile of the patients. In patients with high bleeding risk, low-dose aspirin is the suggested alternative to DAPT[62]. This is supported by observations from the DISCO registry (Dissezioni Spontantee Coronarische), which demonstrated a lower MACE rate with single antiplatelet therapy than with DAPT at one-year intervals[81]. The use of statin therapy bears no rationale in SCAD and may even increase the chance of recurrence[61,62]. The utility of statins in SCAD must be restricted to patients with concomitant dyslipidemia.

Invasive approaches are discouraged in the management of SCAD, as discussed earlier. The indications for PCI include high-risk anatomical features (severe proximal locations in the left coronary and left anterior descending arteries), a low thrombolysis in MI grade, and active ischemia with unstable hemodynamic status[61]. Newer approaches involving drug-eluting stents, bioabsorbable scaffolds, and dilatation with cutting balloons can be employed to control the spread of hematoma[61]. Patients who undergo PCI are required to receive DAPT[62]. Coronary artery bypass grafting can be considered in cases of PCI failure, dangerous proximal dissections, or ≥ 2 proximal dissections where PCI is not feasible. The outcomes of coronary artery bypass grafting are questionable - the blood flow through the bypass conduit can be compromised with the spontaneous healing of the dissection, affecting its long-term patency. The surgical approach is all the more challenging, as dissected vessels are fragile and may not have the tenacity to withstand the sutures accompanying bypass construction[73].

Patients with SCAD are advised to perform regular exercise and CR[82]. They should be advised to avoid strenuous activities, although no evidence of harm with increasing effort exists[2]. The avoidance of future pregnancies reduces the risk of recurrence[2]. In the case of an ongoing pregnancy, low-dose aspirin and β-blockers can be safely administered. Clopidogrel is given only when necessary. It is better to avoid the use of ticagrelor and prasugrel, as the data on their safety profiles are not sufficiently available. In emergencies, invasive modalities should not be deferred because of radiation exposure; adequate abdominal shielding should be provided, and the procedure must continue[73].

MINOCA due to unknown etiology

In approximately 15% of cases, the underlying cause of MINOCA cannot be ascertained. In such situations, the management strategy needs to be tailored on an individual basis after administering generalized cardioprotective therapy. The Canadian Cardiovascular Society guidelines advocate the use of ACEI/ARB and statin therapy as the standard baseline therapy in MINOCA patients with uncertain etiology[62]. Many observational studies are in favor of this recommendation[66,67,83,84]. It has also been shown that the use of DAPT and β-blockers is not associated with a reduction in adverse outcomes in the long term[85,86]. Thus, their utility is doubtful and should be used only after careful consideration of the patient’s comorbidity and risk factor profile. The findings of the CorMicA trial revealed that certainty of diagnosis and appropriate stratification of medical therapy would improve symptoms and increase quality of life scores in patients with symptomatic nonobstructive coronary ischemia[86].

Non-pharmacological approaches

The success of treatment strategies for MINOCA depends on the integration of pharmacological and nonpharmacological modalities. Evidence is accumulating in favor of the use of CR programs to improve cardiovascular outcomes[60]. Long-term exercise-based CR is associated with a significant reduction in MACEs in MINOCA patients[87]. It provides symptomatic relief and improvement in exercise capacity and quality of life, even in SCAD survivors[80,84,88]. Data from the SWEDEHEART registry suggest that achieving secondary prevention targets such as abstinence from smoking and participation in exercise training, alongside lowering blood pressure and low-density lipoprotein cholesterol levels, is associated with better prognostic outcomes in MINOCA patients[89]. Anxiety is significantly associated with all-cause mortality and MACEs in patients with MINOCA, and measures should be taken to counter psychological stress through meditation, counseling, lifestyle modifications, and other means[90]. Although MINOCA is relatively common in the lower body mass index strata, the presence of metabolic syndrome increases the hazard of MACEs in MINOCA patients (adjusted hazard ratio = 2.126; 95% confidence interval: 1.193-3.787, P = 0.010)[91]. This underscores the need to take serious measures to monitor body fat mass and distribution and dietary habits. The long-term consumption of alcohol and opioid drugs can act as precipitants of MACEs in MINOCA; thus, efforts must be made to curb their consumption[92]. Finally, in cases of MINOCA secondary to the precipitation of allergies, avoidance of inciting triggers is mandatory[62].

Adverse effects and safety profile of MINOCA therapies

Management of MINOCA involves a diverse range of therapeutic strategies, each with its own set of potential adverse effects. Understanding these risks is crucial for individualizing patient care. Table 11 summarizes the adverse effects associated with each treatment modality.

Table 11 Summary of adverse effects associated with myocardial infarction with nonobstructive coronary arteries therapies.

Therapeutic modality	Adverse effects
Aspirin (long-term therapy)	Gastrointestinal bleeding, gastric ulceration, dyspepsia, increased hemorrhagic stroke risk, bronchospasm (in aspirin-sensitive asthma), renal dysfunction
P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel)	Bleeding (including gastrointestinal and intracranial), thrombocytopenia, dyspnea (ticagrelor), hypersensitivity reactions
Statin therapy	Myopathy, rhabdomyolysis, hepatic dysfunction, new-onset diabetes, cognitive effects (rare), gastrointestinal upset
ACE inhibitors/ARBs	Hypotension, cough (ACE inhibitors), angioedema, hyperkalemia, renal dysfunction, dizziness
Beta-blockers	Bradycardia, hypotension, fatigue, dizziness, depression, erectile dysfunction, worsening bronchospasm in asthma/COPD
Calcium channel blockers	Hypotension, peripheral edema, flushing, headache, constipation (especially with verapamil), dizziness, reflex tachycardia (dihydropyridines)
Short-acting nitrates	Headache, hypotension, dizziness, reflex tachycardia, methemoglobinemia (rare), flushing, nitrate tolerance
Thrombolytic/anticoagulant therapy	Major bleeding (gastrointestinal, intracranial, retroperitoneal), thrombocytopenia (heparin-induced), hypersensitivity reactions, hematoma at injection site
Vitamin K antagonists (Warfarin)	Bleeding complications need regular INR monitoring, skin necrosis (rare), drug interactions, purple toe syndrome
Unconventional agents for CMD	Dipyridamole: Headache, dizziness, hypotension, flushing, gastrointestinal discomfort
	Ranolazine: QT prolongation, dizziness, constipation, nausea, palpitations
	Imipramine: Anticholinergic effects, drowsiness, dry mouth, urinary retention
	Aminophylline: Arrhythmias, CNS stimulation, nausea, tremors, seizures (at high doses)
Dual antiplatelet therapy	Increased bleeding risk, anemia, epistaxis, easy bruising, dyspepsia
Invasive interventions (PCI/stenting)	Iatrogenic vessel injury, stent thrombosis, restenosis, arterial dissection, contrast-induced nephropathy, procedural bleeding, coronary spasm
Non-pharmacological approaches (cardiac rehabilitation, lifestyle modifications)	Minimal direct risks, but unsupervised activity may lead to musculoskeletal injury or cardiovascular events in high-risk individuals

ACE: Angiotensin-converting enzyme; ARBs: Angiotensin-receptor blockers; COPD: Chronic obstructive pulmonary disease; INR: International normalized ratio; CMD: Coronary microvascular dysfunction; CNS: Central nervous system; PCI: Percutaneous intervention.

PROGNOSIS AND LONG-TERM OUTCOMES

The long-term outcomes of MINOCA are variable and are dependent on the underlying etiology and the patient’s risk factor profile. The relative severity of the outcomes in comparison with those of the MI with the obstructive coronary artery (MIOCA) is debatable. The VIRGO study and the Korean Acute Myocardial Infarction Registry have shown similar mortality risks and quality of life in MINOCA and MIOCA[4,93]. In contrast, Pasupathy et al[94] reported relatively favorable outcomes for MINOCA in a recent meta-analysis. However, several conditions exist within the MINOCA spectrum, each of which has a different long-term prognosis.

The in-hospital mortality rate of these patients is 1.1% on the basis of data from the Acute Coronary Treatment and Intervention Outcomes Network Registry–Get With The Guidelines registry[5]. There is a substantial risk for the recurrence of adverse cardiac and noncardiac complications in patients with MINOCA. The All New Zealand Acute Coronary Syndrome-Quality Improvement registry states that 25% of MINOCA patients experience angina symptoms within one year of attack, whereas death or acute MI occurs in 4.6% of patients over two years[95]. These patients also suffer from poor physical and mental health and a reduced quality of life compared with members of the same age and sex from the general population[96].

Evidence from the literature has helped identify predictors and prognostic markers in MINOCA patients. Insights from the SWEDEHEART registry revealed that older age, diabetes mellitus, systemic hypertension, and smoking are potential risk factors[89]. A study on a Southeast Asian cohort revealed that old age, high creatinine levels, ST-segment elevation on electrocardiogram, and lack of antiplatelet therapy are predisposing factors for MACEs[97]. A positive history of heart failure, chronic obstructive pulmonary disease, malignancy, and obstructive sleep apnea are associated with worse outcomes[98]. Aberrations in biochemical parameters such as elevated troponin T, lipoprotein(a), low triiodothyronine, and elevated levels of inflammatory markers such as C-reactive protein, the neutrophil-lymphocyte ratio, and serum cystatin C are independent predictors of all-cause mortality in MINOCA patients[99-104]. The GRACE risk score and age, creatinine, ejection fraction score are risk stratification tools for predicting poor prognosis in patients with MINOCA[83,105].

FUTURE DIRECTIONS

There is still much more work to be done with respect to standardizing the protocol for the diagnosis and management of MINOCA. The common clinical approach to MINOCA today has been largely based on the findings of observational studies. A robust algorithm for evaluating and managing suspected cases could help in early intervention for these patients and prevent false diagnoses in cases of mimicking conditions.

The efficacy of several therapeutic approaches for different etiologies of MINOCA is supported only by observational studies and anecdotal records. Several nuances concerning patient management still exist. The role of antiplatelet therapy in coronary vasospasm and SCAD is still not clear. Similarly, the roles of ACEIs/ARBs and β-blockers in atherosclerotic plaque disruption are conflicting. However, the studies reporting these controversial/null effects are based on MINOCA patients with mixed etiologies. Thus, there is a need to reevaluate the outcomes of these interventions with dedicated randomized controlled trials. In patients with SCAD, the current practice involves the administration of antiplatelet drugs during the acute phase of the illness. The safety profile of this practice remains to be assessed with prospective studies of appropriate design. Furthermore, there is an ongoing debate on the use of a single antiplatelet drug vs DAPT in patients with MINOCA, which is waiting to be settled with future research.

A fruitful arena of research in MINOCA is the identification of viable biomarkers for the disease. Studies have revealed biomarkers with significant associations with MINOCA and the ability to discriminate it from MIOCA, such as soluble urokinase plasminogen activator receptor, cystatin-C, interleukin 6, tissue plasminogen activator, C-X-C motif chemokine ligand 1 and myeloperoxidase[29,27]. The potential of these biomarkers can be exploited well in the form of risk-scoring systems, such as those used by Espinosa Pascual et al[106], with interleukin 6, high-sensitivity C-reactive protein, ADMA, and high-sensitivity-troponin T. Further efforts to standardize this approach to draft a biomarker protocol will be helpful.

There are several ongoing trials with promise for future directions. The WARRIOR trial (Women’s Ischemia Trial to Reduce Events in Nonobstructive CAD; NCT03417388) seeks to compare the efficacy of medical treatments for MINOCA, specifically in women[107]. The PROMISE trial (NCT05122780) is an approach to compare precision diagnostic and therapeutic modalities against the standard of care in MINOCA patients[108]. NCT04538924 attempts to examine the etiologic mechanisms of myocardial damage in MINOCA and therapeutic strategies[109]. In addition, newer therapeutic approaches can be explored to improve therapeutic benefits, reduce adverse cardiac events, and improve the overall quality of life in patients with MINOCA.

CONCLUSION

In conclusion, MINOCA represents a complex clinical entity characterized by acute MI without significant coronary artery stenosis. Unlike traditional MI, which is primarily attributed to atherosclerotic plaque rupture and coronary occlusion, MINOCA encompasses a heterogeneous group of conditions, including coronary vasospasm, microvascular dysfunction, and inflammatory or thrombotic events. As a result, many patients are misdiagnosed, leading to potential delays in effective treatment. Advancements in imaging modalities such as CMR and intracoronary imaging techniques have improved the ability to assess myocardial damage and detect underlying pathophysiological mechanisms in MINOCA. The therapeutic landscape for MINOCA includes strategies such as DAPT, ACEI/ARBs, β-blockers, and statins for secondary prevention. In addition, calcium channel blockers and nitrates are routinely used for managing coronary vasospasm, while a conservative approach is generally recommended for spontaneous coronary artery dissection, and individualized treatment remains essential for coronary microvascular dysfunction. However, despite these advancements, further research is needed to establish clear diagnostic guidelines and therapeutic strategies. A personalized, patient-centered approach that incorporates an individual’s clinical presentation and underlying risk factors will be essential for optimizing outcomes in patients with MINOCA.