Understanding Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA): a comprehensive meta-analysis of clinical characteristics, management, and prognosis compared to MI with the Obstructive Coronary Artery (MIOCA)

Abstract

Background

MINOCA (Myocardial Infarction with Non-Obstructive Coronary Arteries) represents a unique subset of acute coronary syndrome, distinct from MIOCA (Myocardial Infarction with Obstructive Coronary Arteries) and a control group. This study systematically compares their prevalence, clinical characteristics, management strategies, and outcomes to improve understanding and treatment approaches.

Methods

This systematic review and meta-analysis followed PRISMA guidelines across multiple databases up to 2024. STATA 17 was used for statistical analyses, and the Newcastle-Ottawa Scale was employed to assess study quality.

Results

One-hundred and twelve studies, including 5,908,768 patients, were analyzed. The pooled prevalence of MINOCA among patients undergoing coronary angiography was 8.92% (95% CI: 8.90–8.94). MINOCA patients were generally younger, predominantly female, and more likely to present with atypical chest pain and dyspnea compared to MIOCA patients. Laboratory findings showed higher levels of CRP, BNP, and fibrinogen in MINOCA patients, suggesting inflammation and microvascular dysfunction as key mechanisms. In contrast, MIOCA patients had higher rates of diabetes and dyslipidemia, highlighting differences in pathophysiological processes. Medication use differed between the groups, with MINOCA patients more likely to be prescribed anticoagulants and β-blockers. Prognostically, MINOCA patients experienced significantly lower rates of adverse short- and long-term outcomes, including major adverse cardiac events (MACE) and cardiovascular death, compared to MIOCA patients.

Conclusions

This study demonstrated that patients with MINOCA have a better prognosis compared to those with MIOCA and are at a lower risk of serious cardiac events. Based on the findings of this study, we emphasize that microcirculation and vascular spasm are the main mechanisms involved in MINOCA. Considering these findings, it is suggested that a better management strategy for MINOCA patients can be established by precisely defining diagnostic criteria and focusing on anti-inflammatory treatments and risk factor control.

Introduction

Acute myocardial infarction (MI) is recognized as one of the most common cardiovascular diseases and is considered one of the leading causes of mortality and disability worldwide each year [1]. MI was traditionally defined as a complication of coronary artery disease (CAD) resulting from coronary artery obstruction [2]. However, with advancements in diagnostic methods, it has been observed that despite the occurrence of MI symptoms, significant obstruction is not always present [3]. This condition is now known as myocardial infarction with non-obstructive coronary arteries (MINOCA) [4].

MINOCA is a clinical syndrome characterized by clinical evidence of myocardial infarction with normal or near-normal coronary arteries on angiography [5]. This condition is observed in approximately 5–7% of patients [6]. Due to the wide range of underlying mechanisms, MINOCA is recognized as a heterogeneous condition [6, 7]. These mechanisms may include coronary causes such as eccentric plaques, coronary artery rupture, vascular spasm, microvascular embolism, and rapidly resolved thrombosis [8, 9]. Additionally, non-coronary causes such as Takotsubo cardiomyopathy, myocarditis, microvascular spasm, and myocardial oxygen supply-demand imbalance may also play a role [10, 11]. This diversity in underlying mechanisms makes the accurate diagnosis and proper management of MINOCA a clinical challenge.

From a clinical perspective, significant differences exist between MINOCA patients and those with obstructive coronary artery disease (MIOCA). Studies have shown that MINOCA patients are generally younger, more frequently observed in women, and exhibit distinct electrocardiographic patterns [12, 13]. Furthermore, MINOCA is associated with poor prognosis, and if not accurately diagnosed and properly treated, it can lead to serious cardiovascular complications.

Given the specific complexities associated with MINOCA, its medical treatment remains uncertain [14]. Due to the lack of sufficient information and the absence of specific treatment protocols, physicians often resort to treatment patterns similar to those used for classical myocardial infarctions [15]. Common treatments include the use of β-blockers, antiplatelet agents, statins, and ACE Inhibitors (ACE-I); however, their effectiveness is not yet fully understood [16, 17]. Consequently, the absence of clear guidelines for drug prescriptions presents a challenge for physicians, highlighting the need for further studies.

To our knowledge, no comprehensive systematic review and meta-analysis on MINOCA has been conducted to date. Given the clinical and diagnostic heterogeneity and complexity of MINOCA, as well as the lack of specific treatment protocols, this study aims to examine the demographic, clinical, and laboratory characteristics of MINOCA patients and compare them with MIOCA patients and healthy individuals. Additionally, this research seeks to assess the short- and long-term prognosis of MINOCA patients compared to MIOCA and control groups and aims to identify clinical differences and secondary preventive treatments to improve the management of these patients.

Methods

Protocol registration

The methodology of this study followed the guidelines outlined in the Preferred Reporting Items for Systematic Reviews and Meta-analyses (PRISMA) [18]. Ethical approval for the study was obtained from Prospero (BUMS ID: CRD42023442971) and Birjand University of Medical Sciences (ID: IR.BUMS.REC.1401.448).

Search strategy

Table 1 outlines the search strategy and the associated keywords used in this study. Two independent researchers (M.Y. and SP.M.) conducted comprehensive searches across the SCOPUS, EMBASE, PubMed, and Web of Science databases up until July 2024, adhering to PRISMA guidelines. The search utilized a combination of both MeSH and non-MeSH terms, employing Boolean operators (AND, OR) to refine the strategy. There were no geographical or language restrictions imposed during the search process. To ensure a thorough investigation, we also explored databases and gray literature to identify any potentially overlooked studies. Additionally, an automated search was performed within Google Scholar to capture the latest available publications in the field.

Table 1 Search strategy

Study selection (inclusion & exclusion criteria)

MINOCA was defined in this meta-analysis according to the universal definition proposed by the European Society of Cardiology (ESC) [19]: myocardial infarction with non-obstructive coronary arteries (stenosis < 50%) and the absence of alternate clinically overt diagnoses, such as myocarditis or Takotsubo cardiomyopathy, based on clinical, laboratory, and imaging criteria. Studies that used a different definition of obstruction (e.g., stenosis ≥ 50%) or did not provide sufficient data to exclude alternative diagnoses were excluded from the analysis.

The control group included patients who underwent coronary angiography due to symptoms suggestive of coronary artery disease (CAD), such as stable or unstable angina. Despite presenting with clinical indications of CAD, these patients demonstrated no evidence of coronary artery obstruction on angiography. This contrasts with MINOCA patients, who exhibit partial coronary obstruction (< 50%) on angiography. The inclusion of this control group provides a valuable comparison for understanding the unique characteristics of MINOCA (ESC) [20].

After importing the search results from databases into EndNote X9, duplicate entries were identified and removed using the “Find Duplicates” tool. The screening process was conducted in two stages by two independent reviewers (KH.N. and SP.M.). The first stage involved screening based on titles and abstracts, while the second stage included a detailed review of the full-text studies. Any disagreements were resolved through direct consultation or by involving a third reviewer (R.S.M.). Inclusion criteria focused on original observational studies examining MINOCA patients and their comparison with the MIOCA control group, or both. Exclusion criteria were applied to studies that: (1) used a different definition of obstruction for MINOCA other than 50%, (2) lacked a comparison group, (3) were reviews, conference abstracts, protocols, editorials, case reports, letters, or commentaries, (4) involved animal studies, or (5) had incomplete data. The selection process is summarized in Fig. 1.

Fig. 1

Study selection flowchart. Displays the PRISMA flowchart showing the number of studies identified, screened, excluded, and included in the meta-analysis

PECOS framework

The research question was formulated using the PECOS framework, ensuring a structured and comprehensive approach to the study. Two key comparisons were explored: first, between patients with MINOCA and those with MIOCA, and second, between MINOCA patients and a control group who had no evidence of CAD on angiography.

• ▪ P (Population): patients who underwent coronary angiography.

• ▪ E (Exposure): MINOCA.

• ▪ C (Control/ Comparison): MIOCA or control (no angiographic CAD).

• ▪ (Outcome): short-term (in-hospital) and long-term (one-year follow-up) prognosis.

• ▪ S (Study design): cohort, cross-sectional, and case-control observational studies.

Data extraction

Using Excel software, a data extraction form was created to gather data ffrom the studies included in the meta-analysis. These details included author, country, publication year, study design, patients’ demographic and medical history, symptoms and test results at the time of admission, medication prescription at the onset, and discharge and outcomes, Table 1 has further information. The final data was obtained after these extracted data, which were collected independently by two authors (SP.M. and KH.N.), were compared to identify and confirm any differences.

Risk of bias assessment

For studies that satisfied the eligibility requirements, the validated Newcastle-Ottawa Scale (NOS) tool was used to assess the risk of bias [21]. This instrument assesses research from three angles: the choice of study groups, group comparability, and evaluation of the desired outcome. There is one point given to each of these requirements. A study can be given a number between 0 and 9, where higher numbers denote greater quality and lower chance of bias. Studies with a score of less than 4 often have a higher risk of bias, while those with a score of 7 to 9 are considered high-quality and have the least possibility of bias. Three reviewers assessed the quality of the studies on an individual basis (M.Y., SP.M., and K.T.). The reviewers discussed any disagreements regarding the grading and, if necessary, spoke with the fourth reviewer (R.S.M). Because there was a significant probability of bias overall, studies having a total score of less than 6 on the NOS instrument were not included in the final analysis.

Statistical analysis

Metaprop was used to estimate the pooled prevalence of MINOCA in the population undergoing coronary angiography using cross-sectional studies (n = 69) that reported the total number of angiographic populations. The pooled prevalence was calculated using a random-effects model to account for variability across studies. Additionally, pooled prevalence for each variable in each study group was calculated. The result of comparisons between study groups was expressed in terms of odds ratio (OR) and risk ratio (RR) for binary data, and standardized mean difference (SMD) for continuous data.

In the articles that reported the first and third quartiles, we used the following to convert them into mean values [22, 23]; Mean = (IQR (q3 - q1)) / 1.35. This approach was employed to harmonize the format of the reported data across studies, enabling a consistent meta-analysis. The use of formulas based on the normal distribution assumption assumes symmetric data, which may not always hold true in meta-analyses where skewed distributions are common. Also, it is important to note that this method does not provide an estimate for standard deviation (SD) but is primarily used to approximate the mean from IQR. Despite these limitations, these methods offer a practical approach when raw data are unavailable [24].

To obtain the complications after CAD, we used the cohort articles (n = 81). To equalize the duration of follow-ups to perform the analysis in terms of one-year follow-up, we multiplied the percentage of complications by 12 (12 months) and divided by the number of months of the follow-up period of each study. The use of this approach has certain limitations. First, it assumes a symmetric distribution of the data, which may not always be true. Second, it introduces variability when comparing studies with different reporting methods. Despite these limitations, this method provides a practical solution for standardizing data in the absence of raw individual-level data.

Heterogeneity between studies was quantified using the I² test and chi-square (Cochran Q) test, considering I² ˃70% as statistically heterogeneous [25, 26]. Random-effects and meta-regression analyses were performed to evaluate whether the differences in the follow-up duration of the studies contributed to heterogeneity [27]. Additionally, publication bias was assessed using Egger’s tests, and funnel plots were generated for key outcomes to visually evaluate the presence of bias. Sensitivity analysis was performed based on different study designs and different follow-ups to validate the robustness of the analyses. All statistical analyses were carried out using STATA version 17 (STATA Corp., College Station, Texas). P-values less than 0.05 were regarded as statistically significant.

Results

Search results

Through an electronic search of the databases, a total of 6,536 articles were identified: 1,932 from PubMed, 562 from EMBASE, 2,672 from SCOPUS, and 1,370 from Web of Science. After importing the search results into EndNote software, 2,976 studies were removed using the “Find Duplicates” tool. In the first screening phase, the titles and abstracts were reviewed, and 3,273 articles that did not meet the inclusion criteria were excluded. In the second phase, the full texts of 290 articles were thoroughly examined, with 176 being excluded for failing to meet the eligibility criteria. Additionally, to ensure no studies were overlooked, gray literature was also reviewed. A total of 112 eligible studies were included in the meta-analysis. Figure 1 provides a detailed overview of the article selection process.

Quality assessment

Figure 2 provides a detailed depiction of the quality assessment conducted for the included studies. Each eligible study was evaluated using the NOS tool. Based on this evaluation, the results indicate a range of quality scores. Specifically, five studies received a score of 7, reflecting a medium to high level of quality. twenty-one studies were rated with a score of 8, indicating good quality. The majority of the studies, totaling eighty-six papers, achieved a score of 9, demonstrating a high level of methodological rigor and robustness. These scores suggest that the overall quality of the studies included in this review is satisfactory, with a significant proportion of high-quality research. This thorough assessment process ensures the reliability and validity of the findings presented in this systematic review and meta-analysis.

Fig. 2

Quality assessment of included articles Illustrates the Newcastle-Ottawa Scale evaluation of the methodological quality of included studies. Selection: Q1- Was the case definition adequate? Q2- Were the cases representative? Q3- Were the controls selected? Q4- Were the controls clearly defined? Comparability: Q5- Was the adjustment made for the most important risk factors? Q6-Was the adjustment made for other risk factors? Outcome: Q7- Was the outcome assessment adequate? Q8- Was the follow-up length sufficient? Q9- Was the follow-up process adequate? Each plot represents the publication bias assessment for the corresponding outcome. The symmetrical distribution around the pooled effect size suggests no significant bias, as confirmed by Egger’s tests (p-values > 0.05)

Publication bias

We assessed publication bias using the Egger tests. The results showed no evidence of significant publication bias affecting the findings. The p-values for the Egger test are presented in Tables 2, 3, 4, and 5.

Table 2 Characteristics of included studies

Table 3 Comparison of demographics and clinical characteristics in MINOCA, MIOCA and control

Table 4 Comparison of clinical presentation and laboratory findings in MINOCA, MIOCA and control

Table 5 Comparison of medication prescription at admission and discharge in MINOCA, MIOCA and Control

Study characteristics

The characteristics of the studies are reported in Table 2. The studies included in this meta-analysis encompass a wide range of countries globally, such as China, Poland, New Zealand, Australia, the United Kingdom, the USA, Canada, Sweden, Germany, Italy, Denmark, Portugal, Slovenia, Brazil, Turkey, Israel, Spain, the Netherlands, Japan, and Egypt. This comprehensive analysis consisted of 112 studies comparing MINOCA with MIOCA (91 studies) and/or control groups (39 studies). A total of 5,908,768 patients were examined, including 2,504,298 patients in the MIOCA group, 739,727 patients in the MINOCA group, and 60,874 in the control group. Among patients undergoing coronary angiography, 8.92% (95% CI: 8.90–8.94) were diagnosed with MINOCA. The studies included in this meta-analysis featured various designs, including 83 cohort studies, 26 cross-sectional studies, and 3 case-control studies. The average follow-up period was 956.5 days. Additionally, the NOS (Newcastle-Ottawa Scale) used to assess study quality ranged from a score of 7 to 10. Of these, 5 studies scored 7, 21 studies scored 8, and 86 studies achieved a score of 9.

Demographic and clinical characteristics of MINOCA

Table 3 presents of the baseline characteristics of the study population. Demographic analysis revealed that MINOCA patients were generally younger than MIOCA patients (61.52 ± 5.17 vs. 63.72 ± 5.62; SMD = 0.22) and more likely to be female (47.74% vs. 65.89%; OR = 2.36). Regarding medical history, MINOCA patients had a higher prevalence of obesity (44.34% vs. 38.71%; OR = 0.90), hypertension (72.81% vs. 71.76%; OR = 1.26), angina (20.15% vs. 15%; OR = 1.2), atrial fibrillation (11.07% vs. 5.22%; OR = 0.59), and chronic obstructive pulmonary disease (13.21% vs. 9.52%; OR = 0.67). However, they exhibited a lower prevalence of diabetes (26.49% vs. 30.65%; OR = 1.62), dyslipidemia (64.7% vs. 66.52%; OR = 1.54), and previous MI (16.22% vs. 24.09%; OR = 2.40) compared to MIOCA patients.

When compared to the control group, MINOCA patients were older (59.87 ± 4.94 vs. 55.05 ± 7.01; SMD = 0.4) and had a higher proportion of males (60.61% vs. 50.94%; OR = 1.25). In terms of medical history, MINOCA patients showed a higher prevalence of hypertension (59.45% vs. 43.9%; OR = 1.89), dyslipidemia (55.08% vs. 52.53%; OR = 1.97), obesity (39.17% vs. 36.65%; OR = 1.29), and diabetes (17.03% vs. 10.79%; OR = 1.52) compared to the general population.

Clinical presentation, and laboratory data of MINOCA

Table 4 outlines the clinical presentation, and laboratory data of the study population. Atypical chest pain was notably higher in MINOCA patients (31.06% vs. 10.57%; OR = 0.58), while typical chest pain was more prevalent among MIOCA patients (24.79% vs. 14.83%; OR = 1.66). Additionally, when compared to the control group, MINOCA patients exhibited a slightly higher occurrence of typical chest pain (8.45% vs. 8.18%; OR = 0.87) and a significantly greater prevalence of dyspnea (7.76% vs. 5.47%; OR = 1.43). These findings suggest that the clinical symptoms of MINOCA and MIOCA patients differ in their manifestation, with MINOCA patients experiencing more atypical presentations. In addition, the results of laboratory data showed that the levels of C-reactive protein (CRP), creatinine kinase-myocardial infarction (CK-MB), Fibrinogen, Brain Natriuretic Peptide (BNP) and high-density lipoprotein (HDL) were significantly higher in MINOCA group compared to MIOCA (SMD= −0.01; 95%CI= −0.08, 0.1, SMD= −0.25; 95%CI=−0.16, 0.35, SMD= −0.42; 95%CI= −0.26, 0.58, SMD= −0.42; 95%CI= −0.14, 0.71, SMD= −0.25 ; 95%CI= −0.38, −0.12, respectively). while low-density lipoprotein (LDL) (SMD = 0.18; 95%CI = 0.36, 0.002), and total cholesterol (TC) (SMD = 0.17; 95%0.37, 0.02) levels were significantly lower.

Medication prescription in MINOCA patients

Table 5 shows the prescribed drugs. The analysis of medication prescription patterns in MINOCA patients was conducted at two stages: during hospitalization and at discharge. The findings revealed that the most commonly prescribed drugs during hospitalization were aspirin (71.91%), anti-platelet agents (62.68%), and β-blockers (52.65%). At discharge, the most frequently prescribed medications included aspirin (83.2%), statins (76.07%), and ACE-I (73.68%).

When compared to the MIOCA group, MINOCA patients received a higher rate of anticoagulant medications during hospitalization, such as Warfarin (7.5% vs. 3.25%; OR = 0.41) and other anticoagulants (5.2% vs. 3.02%; OR = 0.56). At discharge, the use of anticoagulants (LMWH: 2.41% vs. 1.57%; OR = 0.25) and angiotensin receptor blockers (ARB) (10.93% vs. 5.6%; OR = 0.56) was also more common in MINOCA patients compared to those with MIOCA.

Prognosis of MINOCA patients

The prognostic factors of MINOCA patients are shown in Table 6. To assess the prognosis of MINOCA, both short-term and long-term outcomes were analyzed. The most frequent short-term outcomes observed in MINOCA patients were revascularization (11.11%) and major adverse cardiac events (MACE) (5.34%). In the long term, the most common outcomes included revascularization through percutaneous coronary intervention (Re-PCI) (5.64%), coronary artery bypass grafting (CABG) (4.05%), and cardiovascular death (CV-Death) (2.23%).

Table 6 Comparison of in-hospital and one-year follow-up outcomesin MINOCA, MIOCA and control

Compared to the MIOCA group, MINOCA patients showed a significantly lower prevalence of both short-term and long-term adverse outcomes. Percutaneous coronary intervention (PCI) was notably more common as a short-term outcome in MIOCA patients (54.49% vs. 0.94%; OR = 2.7). Similarly, MACE was more prevalent as a long-term outcome in MIOCA patients (16.49% vs. 4.84%; OR = 2.13).

Interestingly, certain short-term outcomes, including MI, cerebrovascular accidents (CVA), cardiogenic shock, and pericarditis, were entirely absent in the MINOCA group, with a prevalence of 0%.

Discussion

Main findings

Due to the distinctive characteristics of MINOCA, it poses substantial risks to cardiac health [94]. Moreover, in many cases, it is recognized as a diagnostic challenge [81]. To our knowledge, this meta-analysis represents the most comprehensive examination of MINOCA compared to MIOCA and controls to date. The results provide critical insights into the demographic, clinical, and laboratory features, as well as the prognosis and treatment of MINOCA patients. Among patients undergoing coronary angiography, the pooled prevalence of MINOCA was 8.92% (95% CI: 8.90–8.94), reaffirming its clinical significance as a distinct condition.

Demographic analysis revealed significant differences between MINOCA and MIOCA patients. MINOCA patients were generally younger (mean age 61.52 vs. 63.72 years) and predominantly female (65.89% vs. 47.74%), reflecting potential hormonal influences on disease mechanisms. For instance, estrogen’s protective cardiovascular effects diminish after menopause, possibly explaining the higher prevalence of MINOCA in postmenopausal women [3, 49, 75, 85]. Additionally, MINOCA patients showed higher rates of obesity, hypertension, atrial fibrillation, and chronic obstructive pulmonary disease, whereas MIOCA patients exhibited greater prevalence of diabetes, dyslipidemia, and prior myocardial infarction. Obesity and hypertension may contribute to coronary microvascular dysfunction and inflammatory processes without causing significant obstruction [35, 131]. By contrast, diabetes and dyslipidemia, which promote macrovascular atherosclerosis, are less prominent in MINOCA [61]. These findings highlight the key differences in the risk factors between MINOCA and MIOCA. Therefore, a deeper understanding of the molecular pathways involved in MINOCA can lead to the development of new diagnostic and therapeutic approaches for better management of these patients.

This meta-analysis revealed that MIOCA patients experience significantly higher rates of typical chest pain, whereas atypical chest pain is more prevalent among MINOCA patients. Additionally, dyspnea occurred more frequently in MINOCA patients compared to MIOCA patients (7.76% vs. 5.47%). Laboratory findings demonstrated that MINOCA patients had elevated levels of CK-MB, CRP, BNP, fibrinogen, and HDL compared to MIOCA patients. These findings, when considered alongside the clinical symptoms of MINOCA, become particularly important. Elevated CRP and fibrinogen levels indicates systemic inflammation and immune activation, which leads to vascular spasms and microcirculatory dysfunction [36]. This mechanism can explain the occurrence of atypical chest pain in MINOCA patients. CRP and fibrinogen contribute to inflammation by activating pathways such as NF-κB, leading to increased production of pro-inflammatory cytokines like IL-6 and TNF-α, which may trigger atypical cardiac symptoms [36, 39]. Furthermore, microcirculatory failure prompts the heart to increase intraventricular pressure, resulting in higher BNP production to regulate blood pressure and volume [36]. Elevated BNP levels are associated with a higher incidence of dyspnea in MINOCA patients, as ischemia-induced fluid buildup in the lungs can cause shortness of breath [42, 110]. Additionally, lipid profiles showed significantly lower LDL and TC levels in MINOCA patients compared to MIOCA patients, suggesting that vascular obstruction and atherosclerosis play a lesser role in MINOCA [66, 87, 96]. Instead, functional microcirculatory disorders and vascular spasms appear to be the primary mechanisms driving MINOCA. Reduced LDL levels in MINOCA patients might be attributed to heightened antioxidant activity or abnormalities in lipolytic pathways [31, 106]. Overall, these findings highlight significant differences in clinical symptoms and laboratory parameters between MINOCA and MIOCA patients. These differences provide valuable insights for clinicians and researchers, emphasizing the need for a deeper understanding of the molecular pathways underlying MINOCA to inform more effective diagnostic, therapeutic, and management strategies.

In this study, the patterns of medication prescription were analyzed during two critical stages: the hospitalization period and at discharge. the primary goal is to control clinical symptoms and prevent the progression of cardiac damage [53]. Medications such as aspirin (to prevent microthrombosis formation), antiplatelet agents (to enhance aspirin’s effect), β-blockers (to control heart rate), and anticoagulants (to prevent the formation of small clots) are commonly prescribed [11, 49, 53, 72]. At discharge, the focus shifts to long-term disease management and reducing the risk of recurrence [60, 78]. Aspirin, statins (to reduce inflammation and prevent atherosclerotic plaque formation), ACE-I (to improve cardiac function), ARBs (to control blood pressure), and anticoagulants (to minimize microthrombosis) are frequently prescribed [10, 81]. These findings indicate that medication patterns in MINOCA patients are stage-specific, aligning with their clinical condition to improve outcomes and reduce future risks.

Compared to MIOCA patients, MINOCA patients experienced significantly less severe short- and long-term adverse outcomes. For instance, PCI as a short-term outcome was notably more common in MIOCA patients (54.49% vs. 0.94%), while long-term MACE were reported with higher prevalence in MIOCA patients (16.49% vs. 4.84%). This disparity is likely due to the absence of significant mechanical vascular obstructions in MINOCA, reducing the need for invasive interventions, while MIOCA patients face higher risks due to extensive vascular blockages [29, 44]. Additionally, in MINOCA patients, vascular spasms and inflammation rarely result in acute heart failure or large vessel obstructions, which may explain the absence of outcomes like MI, cardiogenic shock, and CVA observed in this study [61, 81, 90]. Furthermore, CV-Death was significantly lower in MINOCA patients compared to MIOCA patients. Symptoms like dyspnea in MINOCA patients may stem from vasomotor dysfunction and increased intraventricular pressure rather than severe vascular obstructions. This mechanism, linked to elevated BNP secretion, can cause heart failure symptoms without leading to serious complications like CV-Death [33, 37, 112]. These findings underscore the better overall prognosis for MINOCA patients, emphasizing the functional rather than structural nature of the disease and highlighting the need for targeted management strategies to prevent future complications [38].

The pathophysiology of MINOCA is multifactorial, involving mechanisms such as coronary artery spasm, microvascular dysfunction, and plaque disruption [13, 132]. Coronary artery spasm, often identified through acetylcholine provocation testing, can cause transient myocardial ischemia despite non-obstructive coronary arteries [133]. Microvascular dysfunction, common in women with MINOCA, is characterized by impaired coronary flow and can be assessed using tools like coronary flow reserve (CFR) or index of microvascular resistance (IMR) [104, 134]. Plaque disruption, including rupture or erosion, may also contribute, with advanced imaging techniques like IVUS and OCT revealing subtle atherosclerotic changes undetectable on conventional angiography [135]. These mechanisms highlight the need for personalized treatment strategies. For instance, vasospastic or microvascular dysfunction may benefit from calcium channel blockers or Aspirin, while patients with plaque disruption may respond better to antiplatelet or anticoagulant therapy. Future research should focus on stratifying MINOCA patients by underlying mechanisms to optimize diagnostic and therapeutic approaches.

Although the underlying mechanisms of MINOCA remain incompletely understood, the reduced prescription rates of critical medications such as β-blockers, ACE-Is, statins, and antiplatelet may partially account for unfavorable outcomes in some cases [136, 137]. Our findings emphasize the importance of optimizing medical therapy for MINOCA patients, even in the absence of obstructive coronary artery disease. Clinicians should adopt a more comprehensive approach to prescribing these medications in patients with ACD symptoms to improve outcomes and address residual cardiovascular risks. Tailoring treatment protocols based on individual patient characteristics and advancing research into the specific mechanisms underlying MINOCA are critical steps for developing effective, evidence-based management strategies for this unique patient population.

Strengths and limitations

This meta-analysis holds significant implications for several reasons. First, the inclusion of numerous studies with large sample sizes ensures robust and consistent results. Second, we conducted comparisons between MINOCA and two different groups (MIOCA and control), providing comprehensive insights into various aspects of these patients. Third, almost all aspects of these patients (clinical characteristics, laboratory data, vital signs, echocardiography, and ECG results at admission time, symptoms at arrival to the hospital, medication use (at admission to the hospital and discharge), and short-term (in-hospital) and long-term (one-year follow-up) prognosis was investigated relative to both MIOCA and control group.

However, it is important to consider some limitations in our study. First, given the complexity and variability of MINOCA, it is important to examine the heterogeneity observed in the pooled results. The observed heterogeneity (I² > 99%) likely reflects differences in study designs, patient populations, and methodological approaches. For instance, some studies focused on specific patient subgroups, such as those with heart failure [85] or COVID-19 [112], while others excluded patients with prior coronary artery disease [81, 138] or included those with chronic stable angina [6, 139]. While we standardized the definition of MINOCA in our inclusion criteria according to the ESC guidelines [140], differences in study methodologies and patient characteristics could still influence the results. Second, most studies included were retrospective, which might limit the external validity of the findings. However, the large sample size and consistent findings across studies help mitigate this limitation. Third, Patients who did not undergo angiography were excluded, potentially introducing selection bias. This exclusion limits the applicability of our results to patients without angiographic evaluation and may overlook potential cases of MINOCA diagnosed through advanced imaging techniques such as cardiac MRI or CT coronary angiography. Future research should include non-angiographic populations to enhance the generalizability of findings. Fourth, the underlying mechanisms of MINOCA, which may vary considerably among patients, could not be established from the data available in this large registry. Understanding these mechanisms is crucial for tailored treatment, and future studies should focus on elucidating these pathways. Fifth, Interactions between discharge medical therapy and adverse cardiovascular events at long-term follow-up could not be explored. This limitation underscores the need for more prospective studies to assess the long-term impact of various treatments on MINOCA outcomes. Finally, potential residual confounding factors, such as unmeasured comorbidities or variations in healthcare settings, may have influenced the outcomes, highlighting the importance of controlled prospective designs in future studies.

Conclusion

This meta-analysis highlights critical differences between MINOCA and MIOCA, underscoring the unique clinical characteristics, laboratory findings, and outcomes of MINOCA patients. Key findings indicate that MINOCA primarily affects younger, predominantly female patients and is characterized by atypical chest pain, dyspnea, and elevated inflammatory markers such as CRP, BNP, and fibrinogen. These observations suggest that microvascular dysfunction and vascular spasm are central to the pathophysiology of MINOCA, contrasting with the macrovascular atherosclerosis predominant in MIOCA. The prognosis for MINOCA patients is notably better, with significantly lower rates of short- and long-term adverse cardiovascular events, including MACE and cardiovascular death. These findings emphasize the importance of optimizing management strategies tailored to MINOCA’s unique mechanisms, including targeted anti-inflammatory therapies and medications that address microvascular dysfunction. To improve outcomes further, future research should prioritize developing standardized diagnostic criteria and exploring novel therapeutic approaches specific to MINOCA. These efforts can enhance patient care and bridge existing gaps in the understanding and treatment of this distinct clinical entity.