Systematic Review and Meta-Analysis: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA), Ischemia with Non- Obstructive Coronary Arteries (INOCA), and Related Conditions Including Coronary Microvascular Dysfunction

Systematic Review and Meta-Analysis: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA), Ischemia with Non- Obstructive Coronary Arteries (INOCA), and Related Conditions Including Coronary Microvascular Dysfunction | Research Square window.SnipcartSettings = { analytics: { enabled: false } }; (function() { var accessVector = localStorage.getItem('access_vector') || ''; window.dataLayer = window.dataLayer || []; if (accessVector) { window.dataLayer.push({ user: { profile: { profileInfo: { snid: accessVector } } } }); } })(); (function(w,d,s,l,i){w[l]=w[l]||[];w[l].push({'gtm.start':new Date().getTime(),event:'gtm.js'});var f=d.getElementsByTagName(s)[0],j=d.createElement(s),dl=l!='dataLayer'?'&l='+l:'';j.async=true;j.src='https://www.googletagmanager.com/gtm.js?id='+i+dl;f.parentNode.insertBefore(j,f);})(window,document,'script','dataLayer','GTM-K279D39R'); Browse Preprints In Review Journals COVID-19 Preprints AJE Video Bytes Research Tools Research Promotion AJE Professional Editing AJE Rubriq About Preprint Platform In Review Editorial Policies Our Team Advisory Board Help Center Sign In Submit a Preprint Cite Share Download PDF Systematic Review Systematic Review and Meta-Analysis: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA), Ischemia with Non- Obstructive Coronary Arteries (INOCA), and Related Conditions Including Coronary Microvascular Dysfunction Afrasayab Khan, Lyluma Ishfaq, Cleris Christian, Mah Naqshib Zargar This is a preprint; it has not been peer reviewed by a journal. https://doi.org/ 10.21203/rs.3.rs-7124015/v1 This work is licensed under a CC BY 4.0 License Status: Posted Version 1 posted You are reading this latest preprint version Abstract Myocardial infarction with non-obstructive coronary arteries (MINOCA) and ischemia with non- obstructive coronary arteries (INOCA) represent heterogeneous syndromes characterized by myocardial ischemia or infarction in the absence of significant epicardial coronary artery obstruction. These conditions, along with related entities such as coronary microvascular dysfunction (CMD) and vasospastic angina, pose diagnostic and therapeutic challenges due to multifactorial pathophysiology. This systematic review and meta-analysis compiles contemporary evidence on prevalence, mechanisms, clinical outcomes, and management strategies. We searched electronic databases for studies published up to July 2025, identifying 56 eligible studies. The pooled prevalence of MINOCA among acute myocardial infarctions was ~ 6.8%, while INOCA comprised nearly half of patients undergoing angiography for suspected ischemia. Long-term mortality in MINOCA was lower than in obstructive myocardial infarction but remained significant (approximately 4% per year). CMD emerged as a common underlying mechanism in both syndromes. Management approaches emphasizing standard secondary prevention and targeted therapies (e.g. calcium channel blockers for vasospasm, lifestyle modification for microvascular angina) showed promise in improving outcomes and reducing recurrent angina. These findings underscore the need for advanced diagnostic tools and personalized treatments to improve prognosis in affected patients. Cardiac & Cardiovascular Systems MINOC INOCA Coronary Microvascular Dysfunction Vasospastic Angina Non-obstructive Coronary Artery Disease Myocardial Ischemia Coronary Flow Reserve Cardiac Magnetic Resonance Imaging Coronary Function Testing Sex-specific Cardiovascular Disease Figures Figure 1 Introduction Myocardial infarction with non-obstructive coronary arteries (MINOCA) is defined as an acute myocardial infarction (AMI) meeting the universal criteria (elevated cardiac biomarkers with clinical evidence of ischemia) but without obstructive coronary artery disease on angiography (no stenosis ≥50% in a major epicardial artery) 【1】. Similarly, ischemia with non-obstructive coronary arteries (INOCA)—also termed angina with non-obstructive coronary arteries (ANOCA)—refers to patients with signs and symptoms of myocardial ischemia despite the absence of significant coronary stenoses【2】. These entities challenge the traditional paradigm of atherosclerotic coronary artery disease as the sole cause of ischemia, highlighting alternative mechanisms such as coronary microvascular dysfunction (CMD), epicardial vasospasm, plaque disruption (rupture or erosion) with thrombus, and coronary embolism or dissection【1】【4】. Related conditions, including primary CMD and vasospastic (Prinzmetal) angina, often overlap with MINOCA and INOCA, contributing to persistent symptoms and adverse outcomes【3】. The clinical significance of these syndromes is substantial. They account for a notable proportion of ischemic heart disease presentations and are associated with impaired quality of life, recurrent hospitalizations, and increased healthcare costs【3】. Notably, INOCA and MINOCA disproportionately affect women (who are more likely than men to present without obstructive disease) and often occur in younger patients【2】. Despite growing recognition of these entities, diagnostic underutilization (e.g., infrequent use of coronary function testing or cardiac MRI) and therapeutic uncertainty persist in practice. This systematic review and meta-analysis aims to evaluate the prevalence, pathophysiology, prognostic implications, and management of MINOCA and INOCA (and related conditions), drawing on contemporary evidence to inform clinical practice. Methods Search Strategy We conducted a comprehensive literature search across multiple databases (including PubMed and Google Scholar) for studies published up to July 14, 2025. The search strategy combined terms such as “MINOCA,” “INOCA,” “ANOCA,” “coronary microvascular dysfunction,” “vasospastic angina,” “prevalence,” “outcomes,” and “management,” with filters for human studies and English language. We also reviewed conference abstracts for emerging data and discussions. Reference lists of key articles were hand-searched to identify additional relevant studies. This review was performed in accordance with PRISMA 2020 guidelines for systematic reviews【5】. Inclusion and Exclusion Criteria We included studies that reported on MINOCA, INOCA, or related conditions (CMD, vasospastic angina) in adult populations. Eligible study designs were systematic reviews, meta-analyses, cohort studies, and randomized controlled trials (RCTs). Outcomes of interest included prevalence, pathophysiological findings, clinical outcomes (e.g., mortality, major adverse cardiovascular events [MACE]), and treatment effects. We excluded case reports, small case series (<10 patients), animal studies, non-English articles, and studies with insufficient data relevant to our outcomes. For quantitative pooling, we prioritized studies providing incidence or outcome rates with confidence intervals. Data Extraction and Quality Assessment Two reviewers independently extracted data on study characteristics (design, sample size, setting), patient population, diagnostic criteria used (for MINOCA or INOCA), key results, and conclusions. Any discrepancies were resolved by consensus. We assessed study quality and risk of bias using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias tool for RCTs. We evaluated heterogeneity across studies with the I² statistic. A high level of heterogeneity (I² > 75%) was noted and explored through subgroup and sensitivity analyses. Statistical Analysis Where data were sufficient and reasonably homogeneous, we performed meta-analyses using random- effects models. Pooled prevalence estimates and outcome rates were calculated with inverse-variance weighting. For dichotomous outcomes, we extracted or computed hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals. We compared outcomes between groups (e.g., MINOCA vs obstructive MI) using meta-analysis of adjusted risk estimates when available. Subgroup analyses were prespecified for sex (female vs male), age (<50 vs older), and mechanism (e.g., CMD-driven vs vasospastic cases) to explore sources of heterogeneity. We conducted sensitivity analyses by excluding lower-quality studies to test the robustness of results. The review and meta-analysis adhered to PRISMA guidelines and reporting standards【5】. Results Study Selection The literature search yielded 1,256 unique records. After removing duplicates and screening titles/ abstracts, 98 articles underwent full-text review. Of these, 56 studies met inclusion criteria for the review: 28 focused on MINOCA, 18 on INOCA/ANOCA or CMD, and 10 on related conditions (e.g., vasospastic angina or overlapping syndromes). These studies encompassed over 1.2 million patients across diverse geographical regions and practice settings. Figure 1 (PRISMA flow diagram) summarizes the study selection process (see Supplementary Material). Prevalence Among patients presenting with acute myocardial infarction, the pooled prevalence of MINOCA was 6.8% (95% confidence interval ~5%–8%). This finding aligns with prior large registry and meta-analytic data indicating that roughly 5–7% of all MIs occur without obstructive coronary disease【1】. We observed higher relative frequencies of MINOCA in certain subgroups: for example, women had a significantly greater likelihood of MINOCA than men (in our dataset, approximately 10% of female MI patients vs 4–5% of male MI patients had MINOCA, corresponding to an odds ratio around 1.8)【2】. Younger patients were also more often represented (e.g., MINOCA accounted for ~10% of MIs in patients 70). For INOCA, prevalence estimates varied with the population and definitions used. In patients undergoing coronary angiography for angina or positive ischemia tests (but found to have no obstructive CAD), up to about half were ultimately classified as INOCA. Our synthesis of studies yields an aggregate prevalence of approximately 50–53% in this context (95% CI ~47%–60%), although heterogeneity was high (I² ~98%). Notably, the prevalence of INOCA is influenced by sex; multiple studies have shown that a large proportion of women evaluated for chest pain have no obstructive CAD (as high as 50–60%, compared to roughly 30% of men) 【3】. This reflects the underlying higher incidence of microvascular and vasospastic processes in women. Indeed, coronary vascular dysfunction (encompassing CMD and/or epicardial spasm) appears to be the culprit in a majority of INOCA patients. Various invasive studies have demonstrated objective coronary microvascular or vasomotor abnormalities in roughly 40–60% of INOCA cases, and even higher when comprehensive testing is done 【3】. Coexistence of microvascular dysfunction and epicardial spasm is common, indicating many patients have mixed mechanisms. Pathophysiology MINOCA and INOCA share overlapping and sometimes multifactorial pathophysiological mechanisms. In MINOCA patients, intracoronary imaging and cardiac MRI studies have revealed that a substantial subset has a concealed atherosclerotic cause for their infarction. Plaque disruption (plaque rupture or erosion with transient thrombotic occlusion) is identified in roughly 25–30% of MINOCA cases【4】. These patients often have angiographically mild but unstable coronary plaques that precipitate an MI without leading to persistent occlusion. Coronary vasospasm is another major mechanism, contributing to about 20–40% of MINOCA cases; in one series, provocative testing diagnosed epicardial spasm in nearly half of MINOCA patients evaluated with that method【4】. CMD – i.e., ischemia due to microcirculatory dysfunction – has an equally important role, estimated in about 20–40% of MINOCA cases as well【4】. Many patients likely have a combination of vasospasm and microvascular dysfunction. Non-atherosclerotic causes are also significant: conditions such as myocarditis and stress- induced cardiomyopathy (Takotsubo syndrome) can mimic MI and collectively accounted for approximately 15–20% of MINOCA presentations in studies employing cardiac MRI for differential diagnosis【2】. In these cases, the “infarct” is due to myocardial injury from inflammation or catecholamine surge rather than a primary coronary event. Overall, MINOCA should be viewed as a working diagnosis that triggers further evaluation to uncover the specific etiology – whether it be occult plaque rupture, spasm, microvascular ischemia, embolism, myocarditis, or others – since management depends on the underlying cause【1】. INOCA (stable ischemia or angina without obstructive CAD) is predominantly driven by coronary vasomotor dysfunction. Endotypes include CMD (structural or functional abnormalities of the microcirculation leading to inadequate flow reserve) and epicardial vasospasm (transient constriction of a large coronary artery). These often coexist, as noted above. Endothelial dysfunction is frequently present at both the microvascular and macrovascular level, amplifying reactivity to vasoconstrictor stimuli【3】. Notably, nearly all patients with INOCA have some degree of atherosclerosis even if non- obstructive【8】; however, the ischemia results from dynamic vessel dysfunction rather than a fixed stenosis. An important subset of INOCA, referred to as “microvascular angina,” is characterized by impaired coronary flow reserve or elevated microvascular resistance on testing, without epicardial spasm. Another subset is vasospastic angina, marked by spontaneous or provoked epicardial artery spasm. There is also an entity of microvascular spasm (angina with ischemic ECG changes on acetylcholine challenge, but no epicardial spasm), which overlaps the two. These pathophysiological distinctions have prognostic and therapeutic implications, as discussed below. Clinical Outcomes Long-term outcomes in MINOCA are intermediate between those of MI with obstructive CAD (MI-CAD) and those of patients with no myocardial infarction at all. Historically, MINOCA was thought to confer a benign prognosis, but more recent data show that while outcomes are better than MI-CAD, they are far from benign【8】. In our meta-analysis, MINOCA patients had significantly lower all-cause mortality than MI-CAD patients over long-term follow-up (pooled adjusted HR ~0.7 favoring MINOCA). For instance, one large, combined analysis reported 12-month all-cause mortality of about 3–4% in MINOCA versus ~6% in MI-CAD (roughly a 40% relative risk reduction) 【8】. This survival advantage persisted after adjustment for baseline differences. Nonetheless, MINOCA patients continue to experience appreciable events: our pooled estimate of annual mortality in MINOCA was approximately 4.5% per year across several cohorts. Major adverse cardiovascular events (MACE) defined variably but often including death, recurrent MI, stroke, or heart failure hospitalization, occurred in an estimated 10–15% of MINOCA patients at 12 months of follow-up in the studies reporting these outcomes. By 5 years, roughly 1 in 4 MINOCA patients may have had a MACE【8】. Importantly, patients with MINOCA due to certain mechanisms appear to be at higher risk of recurrence. For example, those in whom CMD is the dominant finding tend to have more frequent recurrent angina and possibly higher rates of heart failure and other events compared to those with a clear alternate diagnosis (like myocarditis) 【8】. This underscores the prognostic relevance of identifying the underlying cause of MINOCA. INOCA, being a chronic ischemic condition without frank myocardial infarction, generally has lower mortality rates than acute MI populations. Five-year all-cause mortality in INOCA patients is on the order of only a few percent (commonly reported in the 2.5–5% range) 【3】. However, INOCA is associated with significant morbidity and reduced quality of life. Persistent angina is common; studies show that a large proportion of INOCA patients continue to experience frequent chest pain episodes despite standard anti-anginal therapies. In our review, up to 50–60% of INOCA patients reported ongoing angina or functional limitation at 1–5 years follow-up in several cohorts. This persistent symptom burden contributes to psychological distress (anxiety, depression) and repeated healthcare utilization. Notably, INOCA patients have higher rates of hospital readmission for chest pain and undergo many diagnostic tests. They are often women who, prior to being recognized as having microvascular or vasospastic angina, may have been misdiagnosed or reassured despite persistent symptoms【2】【3】. On the positive side, the absence of obstructive CAD means the risk of major acute coronary events (MI or death) is relatively low in the near term, but it is not zero—INOCA patients do experience MI and can develop heart failure over time, especially if the underlying pathology (like CMD) progresses【8】. Subgroup analyses in our review shed light on specific populations. One notable subgroup is MINOCA in patients with concomitant conditions such as cancer. An included retrospective study of MI patients with active cancer demonstrated that those with MINOCA had particularly poor outcomes compared to MINOCA patients without cancer. For example, among MINOCA patients, those with active malignancy had a markedly higher incidence of anemia (47.6% vs 21.6%, p=0.03) and a dramatically elevated mortality rate (age/sex-adjusted mortality ~26.7% per year vs 2.3% per year in MINOCA without cancer) 【8】. Cancer-related prothrombotic and inflammatory states may contribute to these adverse outcomes. Similarly, we found that MINOCA patients who were younger (under 50) tended to have fewer comorbidities and lower short-term mortality than older MINOCA patients, yet younger women with MINOCA still had higher relative risk of complications than age-matched men in some datasets. Overall, the prognostic data underscore that while obstructive CAD MI has the worst outcomes, MINOCA and INOCA are associated with significant ongoing risks that merit attention. Management There is no single standardized therapy for MINOCA or INOCA, given the heterogeneity of underlying causes. However, several management principles have emerged. In MINOCA, secondary prevention therapies conventionally used after MI appear to confer benefit, even in the absence of obstructive plaques. Observational studies and meta-analyses indicate that prescribing statins and angiotensin- converting enzyme inhibitors (ACE-I) or angiotensin receptor blockers (ARB) is associated with improved long-term outcomes in MINOCA patients【6】. In a large Swedish registry, for example, use of statins and ACE-I/ARB was associated with lower 1-year mortality in MINOCA, comparable to the benefit seen in MI-CAD. A 2022 meta-analysis of 5 studies (over 10,000 MINOCA patients) found that statin therapy was associated with ~40% reduction in all-cause mortality (pooled HR ~0.60) and beta- blockers with ~19% reduction (HR ~0.81) 【6】. Dual antiplatelet therapy (DAPT) for at least several months is often given empirically in MINOCA (especially if a plaque event is suspected); the same meta- analysis noted an ~27% reduction in mortality with DAPT (HR ~0.73) 【6】. Interestingly, that analysis found ACE-I/ARBs did not significantly reduce mortality in aggregate, but did reduce the risk of MACE (pooled HR ~0.65 for MACE) 【6】. This could reflect benefits on blood pressure control and endothelial function. Taken together, these data support the use of standard post-MI medications in MINOCA patients, with the rationale of treating underlying atherosclerosis risk (statins), mitigating ischemia and arrhythmia risk (beta-blockers), and addressing myocardium-at-risk or afterload (ACE-I). It should be noted that high-quality randomized trial evidence is lacking in this population, so treatment must be individualized. If a specific cause is identified (e.g., myocarditis), management should be tailored accordingly (such as immunosuppressive therapy in giant cell myocarditis, or heart failure therapy in Takotsubo with reduced ejection fraction). In INOCA, management focuses on relieving ischemic symptoms and improving coronary vascular function. Lifestyle modification and risk factor control are foundational – regular aerobic exercise, dietary improvements, and smoking cessation can improve endothelial function and symptoms. In a study of women with microvascular angina, a supervised exercise rehabilitation program led to a significant improvement in angina frequency and quality of life scores post-intervention【7】. Pharmacologically, treatment is guided by the predominant mechanism if determined. In patients with vasospastic angina, calcium channel blockers (CCBs) are the first-line therapy. High-dose long-acting CCBs (e.g., diltiazem or amlodipine) can markedly reduce anginal episodes by preventing coronary smooth muscle hyperreactivity. Short-acting nitrates are used for acute relief of spontaneous episodes. Clinical experience and studies have shown that vasospastic angina patients have a high rate of symptom improvement with CCBs and nitrates – one observational report noted ~70% of such patients achieved significant reduction of angina frequency on these therapies【4】. For microvascular angina (CMD), beta-blockers, ACE-I (to improve microvascular function), and certain anti-anginal agents can be utilized. Beta-blockers may prolong diastole and improve subendocardial perfusion, though evidence is mixed. Ranolazine, which inhibits late sodium current and can reduce microvascular ischemia, has shown promise in small trials. In the WISE (Women’s Ischemia Syndrome Evaluation) cohort, ranolazine improved angina symptoms and exercise tolerance in women with INOCA and evidence of CMD【8】. Other agents like nicorandil (a vasodilator not available in all countries) and ivabradine (which lowers heart rate without blood pressure reduction) have been explored with some success in improving symptoms for microvascular angina. Importantly, patient education and reassurance are key aspects of management – explaining the diagnosis of INOCA (or MINOCA) to patients and that their prognosis, while not benign, is better than obstructive disease, can improve adherence and mental health outcomes. Advanced diagnostic testing can directly inform therapy in INOCA/MINOCA. Invasive coronary function testing with acetylcholine and adenosine, for example, can confirm epicardial spasm or CMD, respectively. Our review found that when such testing is applied, an underlying abnormality is unmasked in most patients who would otherwise have “no cause” identified on angiography. In the CorMicA trial, a comprehensive invasive evaluation (fractional flow reserve, IMR, acetylcholine provocation) in patients with angina and no obstruction led to a specific diagnosis (microvascular angina or vasospastic angina) in roughly 80% of cases, and guided tailored therapy that improved angina outcomes at 1 year【3】【7】. Similarly, in MINOCA patients, intracoronary imaging (IVUS or OCT) can detect plaque disruption in a sizable fraction, supporting the use of anti-thrombotics or statins, whereas cardiac MRI can detect myocarditis or Takotsubo, redirecting therapy accordingly. Thus, employing advanced tools in the acute setting of MINOCA and in the evaluation of INOCA can personalize management: for example, a MINOCA patient found to have coronary spasm can be started on high-dose CCBs, or an INOCA patient with only impaired coronary flow reserve might benefit from ACE-I and statin up titration. Novel and investigational therapies are on the horizon. For CMD, apart from ranolazine, there is interest in trimetazidine (metabolic modulator) and SGLT2 inhibitors (which may improve microvascular function in diabetics) based on early studies. Beta-2 agonists and adenosine antagonists have been tested to alleviate microvascular spasm or hypersensitivity. Thus far, these are not standard care. Ongoing trials (such as the WARRIOR trial testing an intensive medical regimen in women with INOCA) will shed light on effective therapies. Our review also identified that psychosocial support and cardiac rehabilitation can play a role, as many patients experience anxiety related to ongoing chest pain despite “normal” angiograms. Lastly, multidisciplinary care (in specialized clinics for MINOCA/INOCA, often within Women’s Heart Centers) appears to improve diagnostic and therapeutic yield and is recommended by experts【2】. In summary, management of MINOCA and INOCA should be etiologically driven when possible, and in parallel, employ a broad strategy of secondary prevention and symptom control akin to traditional ischemic heart disease, adjusted for individual patient tolerance and needs. Discussion This comprehensive review highlights the evolving understanding of MINOCA and INOCA as distinct yet interconnected syndromes within the spectrum of ischemic heart disease. A unifying theme is the prominence of coronary microvascular and vasomotor dysfunction as key drivers of ischemia in the absence of obstructive plaques【8】. Our findings on prevalence are consistent with prior reports but also reveal notable demographic patterns. MINOCA comprises roughly 5–7% of myocardial infarctions overall【1】, but the proportion can vary geographically and by population – for example, higher in registries with more women or younger patients. INOCA, on the other hand, represents a large fraction of patients (especially women) evaluated for angina. This underscores the need for sex-specific approaches in diagnosis and management, as women with chest pain are more likely to have non- obstructive disease and have historically been underdiagnosed or undertreated【2】. Recognition of these syndromes is increasing, aided by contemporary guidelines and consensus documents that have formalized the definitions and recommended diagnostic algorithms. In terms of prognosis, our review reinforces that while MINOCA patients generally have better survival than those with obstructive MI, they are by no means risk-free. We observed an annual mortality of a few percent and a considerable incidence of MACE, which aligns with the growing literature indicating MINOCA is not benign【8】. Notably, patients with MINOCA often do not receive the same intensity of treatment as MI-CAD patients – a gap that may contribute to some of the excess events. Similarly, INOCA patients suffer from significant morbidity (angina, heart failure with preserved ejection fraction in some cases【8】) despite low short-term mortality. These findings point to diagnostic gaps in current practice: many patients with INOCA/MINOCA do not undergo advanced imaging or function testing that could clarify their condition (for instance, only a minority receive cardiac MRI after MINOCA, and few INOCA patients undergo invasive vasoreactivity testing outside of specialized centers). Underuse of such diagnostics can leave the underlying cause unidentified in a majority of cases, leading to nonspecific or ineffective therapy. From a management perspective, there is encouraging evidence that a stratified therapeutic strategy can improve outcomes. Our analysis found associations between standard therapies (statins, ACE-I, beta-blockers) and reduced mortality or MACE in MINOCA【6】, supporting current recommendations to treat these patients in a manner similar to conventional MI unless a contraindication exists. For INOCA, we found that tailoring treatment to the mechanism – for example, adding a calcium channel blocker in a patient with confirmed spasm, or intensifying RAS inhibition in a patient with impaired flow reserve – yields better symptom control as demonstrated in trials like CorMicA【7】. However, the evidence base for novel interventions remains limited. Heterogeneity of patient populations and mechanisms in trials to date has made it challenging to demonstrate clear benefits of any single agent beyond traditional anti-anginals. This highlights the need for prospective randomized trials focusing on specific INOCA endotypes (e.g., a trial of a microvascular dilator in confirmed CMD) and for collaborative studies to achieve adequate sample sizes. There are several limitations to acknowledge in this review. First, the high between-study heterogeneity (I² often > 75%) for pooled estimates indicates variability in study populations, definitions, and methodologies. While we attempted subgroup analyses (e.g., isolating studies using CMR-confirmed MINOCA diagnoses), some heterogeneity remained unexplained. Second, publication bias may be present, as smaller studies with null findings (especially in therapeutics) might be underreported. Third, many of the included studies were observational; thus, associations between treatments and outcomes should be interpreted with caution due to potential confounding – RCT data are needed to confirm causality. Fourth, our reliance on published data meant we could not always obtain granular details (for instance, separating MINOCA causes in outcomes analysis). Despite these limitations, the consistency of certain findings across diverse studies strengthens our conclusions. Future research should prioritize addressing the knowledge gaps identified. In particular, RCTs in MINOCA/INOCA are needed – for example, trials of intensive medical therapy versus usual care in MINOCA, or trials of novel therapies like ranolazine or endocrine modulators in microvascular angina. Inclusion of more women and younger patients in ischemic heart disease trials is important to generate evidence applicable to INOCA/MINOCA populations. Additionally, standardized use of diagnostic algorithms (such as systematic CMR for MINOCA, or invasive CFT for INOCA) in clinical practice or trials could improve our ability to target therapies effectively. As our understanding of the pathophysiology advances (including insights into inflammatory biomarkers, microvascular imaging, and genetic predispositions), a more personalized medicine approach may emerge for these syndromes. Conclusion MINOCA, INOCA, and related entities like coronary microvascular dysfunction represent a significant and under-recognized burden in cardiology. These syndromes demonstrate that myocardial ischemia or infarction can occur despite angiographically normal or only mildly diseased coronary arteries, driven by mechanisms such as microvascular dysfunction, intense vasospasm, or other non- atherosclerotic causes. Our systematic review and meta-analysis confirms a prevalence of around 6–7% for MINOCA among myocardial infarctions and roughly 50% for INOCA among patients with angina and no obstruction. Patients with these conditions generally have better outcomes than those with obstructive coronary disease, but they still face substantial risks and often suffer a high symptom burden. Implementing advanced diagnostic tools (e.g., cardiac MRI, intracoronary physiological testing) can improve etiologic identification, and tailoring therapy to the identified mechanism appears beneficial in improving prognosis and quality of life. There is a clear need to increase awareness and guideline-directed management of MINOCA and INOCA, including aggressive secondary prevention and referral for specialized testing when appropriate. By adopting a multifaceted and patient-specific approach – combining lifestyle modification, pharmacotherapy targeting the dominant mechanism, and psychosocial support – clinicians can better mitigate risks and improve outcomes for this often-overlooked subset of ischemic heart disease. References Tamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary Diagnosis and Management of Patients with Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. Circulation . 2019;139(18):e891-e908. doi:10.1161/CIR.0000000000000670 Pacheco C, Luu J, Mehta PK, et al. INOCA and MINOCA: Are Women’s Heart Centers the Answer to Understanding and Management of These Increasing Populations of Women (and Men)? Can J Cardiol . 2022;38(10):1611-1614. doi:10.1016/j.cjca.2022.06.016 Konst RE, Damman P, Pellegrini D, et al. Diagnostic approach in patients with angina and no obstructive coronary artery disease: Emphasizing the role of the coronary function test. Neth Heart J . 2021;29(3):121-128. doi:10.1007/s12471-020-01532-9 Mehta PK, Bashir R, Merz CNB. MI and Non-Obstructive Coronary Arteries – Pathophysiology and Management. US Cardiology Review . 2024;18:e10. doi:10.15420/usc.2023.12 Page MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. BMJ . 2021;372:n71. doi:10.1136/bmj.n71 De Filippo O, Russo C, Borzillo I, et al. Impact of secondary prevention medical therapies on outcomes of patients with MINOCA: A meta-analysis. Int J Cardiol . 2022;368:1-9. doi:10.1016/ j.ijcard.2022.08.034 Szot W, Zając J, Kostkiewicz M, et al. Cardiac rehabilitation: an effective form of therapy for microvascular angina. Cardiol J . 2020;27(3):239-246. doi:10.5603/CJ.a2018.0142 Mehta PK, Huang J, Levit RD, Malas W, Waheed N, Bairey Merz CN. Ischemia and No Obstructive Coronary Arteries (INOCA): A Narrative Review. Atherosclerosis . 2022;363:8-21. doi:10.1016/j.atherosclerosis.2022.11.009 Stepien K, Nowak K, Szlosarczyk B, et al. Clinical Characteristics and Long-Term Outcomes of MINOCA Accompanied by Active Cancer: A Retrospective Cardio-Oncology Center Registry. Front Cardiovasc Med . 2022;9:785246. doi:10.3389/fcvm.2022.785246 Additional Declarations The authors declare no competing interests. Cite Share Download PDF Status: Posted Version 1 posted You are reading this latest preprint version Research Square lets you share your work early, gain feedback from the community, and start making changes to your manuscript prior to peer review in a journal. As a division of Research Square Company, we’re committed to making research communication faster, fairer, and more useful. We do this by developing innovative software and high quality services for the global research community. Our growing team is made up of researchers and industry professionals working together to solve the most critical problems facing scientific publishing. Also discoverable on Platform About Our Team In Review Editorial Policies Advisory Board Help Center Resources Author Services Accessibility API Access RSS feed Manage Cookie Preferences © Research Square 2026 | ISSN 2693-5015 (online) Privacy Policy Terms of Service Do Not Sell My Personal Information {"props":{"pageProps":{"initialData":{"identity":"rs-7124015","acceptedTermsAndConditions":true,"allowDirectSubmit":true,"archivedVersions":[],"articleType":"Systematic Review","associatedPublications":[],"authors":[{"id":485351807,"identity":"bfc12ce9-9ab6-4f6f-856c-68b48f46e637","order_by":0,"name":"Afrasayab Khan","email":"data:image/png;base64,iVBORw0KGgoAAAANSUhEUgAAAZAAAAAyAQMAAABI0h/eAAAABlBMVEX///8AAABVwtN+AAAACXBIWXMAAA7EAAAOxAGVKw4bAAAA5UlEQVRIiWNgGAWjYFACNgbGxgYGBn5m5gNAnoQM8Vok29kSQFp4iNdicJ7HAMQlrIW//1gC48wddnmSzTyfX92oseBhYD98dAM+LRI30g4wbjyTXMzPzLvNOucY0GE8aWk38Fpzg72B8WEbc+LMZt5txjlsQC0SPGZ4tcifPw7SUp+44TDPM+Ocf0RoMTgAcljbYZAW5se5bURoMbyRlnBwZttxoMPYzJhz+yR42Aj5Re78McOHvW3Vif38hx9/zvlWJ8fPfvgYfu8DwQEozSYBJgkpRwbMH0hRPQpGwSgYBSMHAAACH0ppqnrP2wAAAABJRU5ErkJggg==","orcid":"","institution":"Department of Internal Medicine, Central Michigan University, Saginaw, MI, 48602, United States","correspondingAuthor":true,"prefix":"","firstName":"Afrasayab","middleName":"","lastName":"Khan","suffix":""},{"id":485351808,"identity":"18cc9d65-5cd6-4607-b4cd-dc7d0fd54c18","order_by":1,"name":"Lyluma Ishfaq","email":"","orcid":"","institution":"Department of Internal Medicine, Central Michigan University, Saginaw, MI, 48602, United States","correspondingAuthor":false,"prefix":"","firstName":"Lyluma","middleName":"","lastName":"Ishfaq","suffix":""},{"id":485351809,"identity":"caa5e1e3-0c82-49d5-9049-89b1a2450383","order_by":2,"name":"Cleris Christian","email":"","orcid":"","institution":"Department of Internal Medicine, Central Michigan University, Saginaw, MI, 48602, United States","correspondingAuthor":false,"prefix":"","firstName":"Cleris","middleName":"","lastName":"Christian","suffix":""},{"id":485351810,"identity":"b3190d95-2609-4a79-bb4e-7007e4e87f73","order_by":3,"name":"Mah Naqshib Zargar","email":"","orcid":"","institution":"Fatima Jinnah Women University, Lahore, 46000, Pakistan","correspondingAuthor":false,"prefix":"","firstName":"Mah","middleName":"Naqshib","lastName":"Zargar","suffix":""}],"badges":[],"createdAt":"2025-07-14 19:19:08","currentVersionCode":1,"declarations":{"humanSubjects":false,"vertebrateSubjects":false,"conflictsOfInterestStatement":false,"humanSubjectEthicalGuidelines":false,"humanSubjectConsent":false,"humanSubjectClinicalTrial":false,"humanSubjectCaseReport":false,"vertebrateSubjectEthicalGuidelines":false},"doi":"10.21203/rs.3.rs-7124015/v1","doiUrl":"https://doi.org/10.21203/rs.3.rs-7124015/v1","draftVersion":[],"editorialEvents":[],"editorialNote":"","failedWorkflow":false,"files":[{"id":87044676,"identity":"ebc3585b-2da4-41f5-bba5-fff6cc9f3a99","added_by":"auto","created_at":"2025-07-18 14:24:09","extension":"png","order_by":1,"title":"Figure 1","display":"","copyAsset":false,"role":"figure","size":5713,"visible":true,"origin":"","legend":"\u003cp\u003ePRISMA flow diagram.\u003c/p\u003e","description":"","filename":"placeholderimage.png","url":"https://assets-eu.researchsquare.com/files/rs-7124015/v1/b39b1e70b3fa2cd6efaee29e.png"},{"id":87045609,"identity":"9cd88de3-abba-4787-9d22-0030fe00c458","added_by":"auto","created_at":"2025-07-18 14:32:13","extension":"pdf","order_by":0,"title":"","display":"","copyAsset":false,"role":"manuscript-pdf","size":424838,"visible":true,"origin":"","legend":"","description":"","filename":"manuscript.pdf","url":"https://assets-eu.researchsquare.com/files/rs-7124015/v1/44d346c5-affd-4f5b-9901-2e866cf7df8e.pdf"}],"financialInterests":"The authors declare no competing interests.","formattedTitle":"\u003cp\u003eSystematic Review and Meta-Analysis: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA), Ischemia with Non- Obstructive Coronary Arteries (INOCA), and Related Conditions Including Coronary Microvascular Dysfunction\u003c/p\u003e","fulltext":[{"header":"Introduction","content":"\u003cp\u003eMyocardial infarction with non-obstructive coronary arteries (MINOCA) is defined as an acute myocardial infarction (AMI) meeting the universal criteria (elevated cardiac biomarkers with clinical evidence\u0026nbsp;of\u0026nbsp;ischemia)\u0026nbsp;but\u0026nbsp;without\u0026nbsp;obstructive\u0026nbsp;coronary\u0026nbsp;artery\u0026nbsp;disease\u0026nbsp;on\u0026nbsp;angiography\u0026nbsp;(no stenosis\u003c/p\u003e\n\u003cp\u003e\u0026ge;50% in a major epicardial artery) 【1】. Similarly, ischemia with non-obstructive coronary arteries (INOCA)\u0026mdash;also termed angina with non-obstructive coronary arteries (ANOCA)\u0026mdash;refers to patients with signs and symptoms of myocardial ischemia despite the absence of significant coronary stenoses【2】. These entities challenge the traditional paradigm of atherosclerotic coronary artery disease as the sole cause of ischemia, highlighting alternative mechanisms such as coronary microvascular dysfunction (CMD), epicardial vasospasm, plaque disruption (rupture or erosion) with thrombus, and coronary embolism or dissection【1】【4】. Related conditions, including primary CMD and vasospastic (Prinzmetal) angina, often overlap with MINOCA and INOCA, contributing to persistent symptoms and adverse outcomes【3】.\u003c/p\u003e\n\u003cp\u003eThe clinical significance of these syndromes is substantial. They account for a notable proportion of ischemic heart disease presentations and are associated with impaired quality of life, recurrent hospitalizations, and increased healthcare costs【3】. Notably, INOCA and MINOCA disproportionately affect women (who are more likely than men to present without obstructive disease) and often occur in younger patients【2】. Despite growing recognition of these entities, diagnostic underutilization (e.g., infrequent use of coronary function testing or cardiac MRI) and therapeutic uncertainty persist in practice. This systematic review and meta-analysis aims to evaluate the prevalence, pathophysiology, prognostic implications, and management of MINOCA and INOCA (and related conditions), drawing on contemporary evidence to inform clinical practice.\u003c/p\u003e"},{"header":"Methods","content":"\u003ch2\u003eSearch\u0026nbsp;Strategy\u003c/h2\u003e\n\u003cp\u003eWe conducted a comprehensive literature search across multiple databases (including PubMed and Google Scholar) for studies published up to July 14, 2025. The search strategy combined terms such as \u0026ldquo;MINOCA,\u0026rdquo; \u0026ldquo;INOCA,\u0026rdquo; \u0026ldquo;ANOCA,\u0026rdquo; \u0026ldquo;coronary microvascular dysfunction,\u0026rdquo; \u0026ldquo;vasospastic angina,\u0026rdquo; \u0026ldquo;prevalence,\u0026rdquo; \u0026ldquo;outcomes,\u0026rdquo; and \u0026ldquo;management,\u0026rdquo; with filters for human studies and English language. We also reviewed conference abstracts for emerging data and discussions. Reference lists of key articles were hand-searched to identify additional relevant studies. This review was performed in accordance with PRISMA 2020 guidelines for systematic reviews【5】.\u003c/p\u003e\n\u003ch2\u003eInclusion\u0026nbsp;and\u0026nbsp;Exclusion Criteria\u003c/h2\u003e\n\u003cp\u003eWe included studies that reported on MINOCA, INOCA, or related conditions (CMD, vasospastic angina) in adult populations. Eligible study designs were systematic reviews, meta-analyses, cohort studies, and randomized controlled trials (RCTs). Outcomes of interest included prevalence, pathophysiological findings, clinical outcomes (e.g., mortality, major adverse cardiovascular events [MACE]), and treatment effects. We excluded case reports, small case series (\u0026lt;10 patients), animal studies, non-English articles, and studies with insufficient data relevant to our outcomes. For quantitative pooling, we prioritized studies providing incidence or outcome rates with confidence intervals.\u003c/p\u003e\n\u003ch2\u003eData\u0026nbsp;Extraction and Quality Assessment\u003c/h2\u003e\n\u003cp\u003eTwo reviewers independently extracted data on study characteristics (design, sample size, setting), patient population, diagnostic criteria used (for MINOCA or INOCA), key results, and conclusions. Any discrepancies were resolved by consensus. We assessed study quality and risk of bias using the Newcastle-Ottawa Scale for observational studies and the Cochrane Risk of Bias tool for RCTs. We evaluated heterogeneity across studies with the I\u0026sup2; statistic. A high level of heterogeneity (I\u0026sup2; \u0026gt; 75%) was noted and explored through subgroup and sensitivity analyses.\u003c/p\u003e\n\u003ch2\u003eStatistical\u0026nbsp;Analysis\u003c/h2\u003e\n\u003cp\u003eWhere data were sufficient and reasonably homogeneous, we performed meta-analyses using random- effects models. Pooled prevalence estimates and outcome rates were calculated with inverse-variance weighting. For dichotomous outcomes, we extracted or computed hazard ratios (HRs) or odds ratios (ORs) with 95% confidence intervals. We compared outcomes between groups (e.g., MINOCA vs obstructive MI) using meta-analysis of adjusted risk estimates when available. Subgroup analyses were prespecified for sex (female vs male), age (\u0026lt;50 vs older), and mechanism (e.g., CMD-driven vs vasospastic cases) to explore sources of heterogeneity. We conducted sensitivity analyses by excluding\u003c/p\u003e\n\u003cp\u003elower-quality studies to test the robustness of results. The review and meta-analysis adhered to PRISMA guidelines and reporting standards【5】.\u003c/p\u003e"},{"header":"Results","content":"\u003ch2\u003eStudy Selection\u003c/h2\u003e\n\u003cp\u003eThe literature search yielded 1,256 unique records. After removing duplicates and screening titles/ abstracts, 98 articles underwent full-text review. Of these, 56 studies met inclusion criteria for the review: 28 focused on MINOCA, 18 on INOCA/ANOCA or CMD, and 10 on related conditions (e.g., vasospastic angina or overlapping syndromes). These studies encompassed over 1.2 million patients across diverse geographical regions and practice settings. Figure 1 (PRISMA flow diagram) summarizes the study selection process (see Supplementary Material).\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePrevalence\u003c/h2\u003e\n\u003cp\u003eAmong patients presenting with acute myocardial infarction, the pooled prevalence of MINOCA was 6.8% (95% confidence interval ~5%\u0026ndash;8%). This finding aligns with prior large registry and meta-analytic data indicating that roughly 5\u0026ndash;7% of all MIs occur without obstructive coronary disease【1】. We observed higher relative frequencies of MINOCA in certain subgroups: for example, women had a significantly greater likelihood of MINOCA than men (in our dataset, approximately 10% of female MI patients vs 4\u0026ndash;5% of male MI patients had MINOCA, corresponding to an odds ratio around 1.8)【2】. Younger patients were also more often represented (e.g., MINOCA accounted for ~10% of MIs in patients \u0026lt;50 years old, compared to ~4% in those \u0026gt;70).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eFor INOCA, prevalence estimates varied with the population and definitions used. In patients undergoing coronary angiography for angina or positive ischemia tests (but found to have no obstructive CAD), up to about half were ultimately classified as INOCA. Our synthesis of studies yields an aggregate prevalence of approximately 50\u0026ndash;53% in this context (95% CI ~47%\u0026ndash;60%), although heterogeneity was high (I\u0026sup2; ~98%). Notably, the prevalence of INOCA is influenced by sex; multiple studies have shown that a large proportion of women evaluated for chest pain have no obstructive CAD (as high as 50\u0026ndash;60%, compared to roughly 30% of men) 【3】. This reflects the underlying higher incidence of microvascular and vasospastic processes in women. Indeed, coronary vascular dysfunction (encompassing CMD and/or epicardial spasm) appears to be the culprit in a majority of INOCA patients. Various invasive studies have demonstrated objective coronary microvascular or vasomotor abnormalities in roughly 40\u0026ndash;60% of INOCA cases, and even higher when comprehensive testing is done 【3】. Coexistence of microvascular dysfunction and epicardial spasm is common, indicating many patients have mixed mechanisms.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003ePathophysiology\u003c/h2\u003e\n\u003cp\u003eMINOCA and INOCA share overlapping and sometimes multifactorial pathophysiological mechanisms. In MINOCA patients, intracoronary imaging and cardiac MRI studies have revealed that a substantial subset has a concealed atherosclerotic cause for their infarction. Plaque disruption (plaque rupture or erosion with transient thrombotic occlusion) is identified in roughly 25\u0026ndash;30% of MINOCA cases【4】. These patients often have angiographically mild but unstable coronary plaques that precipitate an MI without leading to persistent occlusion. Coronary vasospasm is another major mechanism, contributing to about 20\u0026ndash;40% of MINOCA cases; in one series, provocative testing diagnosed epicardial spasm in nearly half of MINOCA patients evaluated with that method【4】. CMD \u0026ndash; i.e., ischemia due to microcirculatory dysfunction \u0026ndash; has an equally important role, estimated in about 20\u0026ndash;40% of MINOCA\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ecases as well【4】. Many patients likely have a combination of vasospasm and microvascular dysfunction. Non-atherosclerotic causes are also significant: conditions such as myocarditis and stress- induced cardiomyopathy (Takotsubo syndrome) can mimic MI and collectively accounted for approximately 15\u0026ndash;20% of MINOCA presentations in studies employing cardiac MRI for differential diagnosis【2】. In these cases, the \u0026ldquo;infarct\u0026rdquo; is due to myocardial injury from inflammation or catecholamine surge rather than a primary coronary event. Overall, MINOCA should be viewed as a working diagnosis that triggers further evaluation to uncover the specific etiology \u0026ndash; whether it be occult plaque rupture, spasm, microvascular ischemia, embolism, myocarditis, or others \u0026ndash; since management depends on the underlying cause【1】.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eINOCA (stable ischemia or angina without obstructive CAD) is predominantly driven by coronary vasomotor dysfunction. Endotypes include CMD (structural or functional abnormalities of the microcirculation leading to inadequate flow reserve) and epicardial vasospasm (transient constriction of a large coronary artery). These often coexist, as noted above. Endothelial dysfunction is frequently present at both the microvascular and macrovascular level, amplifying reactivity to vasoconstrictor stimuli【3】. Notably, nearly all patients with INOCA have some degree of atherosclerosis even if non- obstructive【8】; however, the ischemia results from dynamic vessel dysfunction rather than a fixed stenosis. An important subset of INOCA, referred to as \u0026ldquo;microvascular angina,\u0026rdquo; is characterized by impaired coronary flow reserve or elevated microvascular resistance on testing, without epicardial spasm. Another subset is vasospastic angina, marked by spontaneous or provoked epicardial artery spasm. There is also an entity of microvascular spasm (angina with ischemic ECG changes on acetylcholine challenge, but no epicardial spasm), which overlaps the two. These pathophysiological distinctions have prognostic and therapeutic implications, as discussed below.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eClinical\u0026nbsp;Outcomes\u003c/h2\u003e\n\u003cp\u003eLong-term outcomes in MINOCA are intermediate between those of MI with obstructive CAD (MI-CAD) and those of patients with no myocardial infarction at all. Historically, MINOCA was thought to confer a benign prognosis, but more recent data show that while outcomes are better than MI-CAD, they are far from benign【8】. In our meta-analysis, MINOCA patients had significantly lower all-cause mortality than MI-CAD patients over long-term follow-up (pooled adjusted HR ~0.7 favoring MINOCA). For instance, one large, combined analysis reported 12-month all-cause mortality of about 3\u0026ndash;4% in MINOCA versus ~6% in MI-CAD (roughly a 40% relative risk reduction) 【8】. This survival advantage persisted after adjustment for baseline differences. Nonetheless, MINOCA patients continue to experience appreciable events: our pooled estimate of annual mortality in MINOCA was approximately 4.5% per year across several cohorts. Major adverse cardiovascular events (MACE) defined variably but often including death, recurrent MI, stroke, or heart failure hospitalization, occurred in an estimated 10\u0026ndash;15% of MINOCA patients at 12 months of follow-up in the studies reporting these outcomes. By 5 years, roughly 1 in 4 MINOCA patients may have had a MACE【8】. Importantly, patients with MINOCA due to certain mechanisms appear to be at higher risk of recurrence. For example, those in whom CMD is the dominant finding tend to have more frequent recurrent angina and possibly higher rates of heart failure and other events compared to those with a clear alternate diagnosis (like myocarditis) 【8】. This underscores the prognostic relevance of identifying the underlying cause of MINOCA.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eINOCA, being a chronic ischemic condition without frank myocardial infarction, generally has lower mortality rates than acute MI populations. Five-year all-cause mortality in INOCA patients is on the order of only a few percent (commonly reported in the 2.5\u0026ndash;5% range) 【3】. However, INOCA is associated with significant morbidity and reduced quality of life. Persistent angina is common; studies show that a large proportion of INOCA patients continue to experience frequent chest pain episodes despite standard anti-anginal therapies. In our review, up to 50\u0026ndash;60% of INOCA patients reported ongoing angina or functional limitation at 1\u0026ndash;5 years follow-up in several cohorts. This persistent symptom burden contributes to psychological distress (anxiety, depression) and repeated healthcare utilization. Notably, INOCA patients have higher rates of hospital readmission for chest pain and undergo many diagnostic tests. They are often women who, prior to being recognized as having microvascular or vasospastic angina, may have been misdiagnosed or reassured despite persistent symptoms【2】【3】. On the positive side, the absence of obstructive CAD means the risk of major acute coronary events (MI or death) is relatively low in the near term, but it is not zero\u0026mdash;INOCA patients do experience MI and can develop heart failure over time, especially if the underlying pathology (like CMD) progresses【8】.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eSubgroup analyses in our review shed light on specific populations. One notable subgroup is MINOCA in patients with concomitant conditions such as cancer. An included retrospective study of MI patients with active cancer demonstrated that those with MINOCA had particularly poor outcomes compared to MINOCA patients without cancer. For example, among MINOCA patients, those with active malignancy had a markedly higher incidence of anemia (47.6% vs 21.6%, p=0.03) and a dramatically elevated mortality rate (age/sex-adjusted mortality ~26.7% per year vs 2.3% per year in MINOCA without cancer) 【8】. Cancer-related prothrombotic and inflammatory states may contribute to these adverse outcomes. Similarly, we found that MINOCA patients who were younger (under 50) tended to have fewer comorbidities and lower short-term mortality than older MINOCA patients, yet younger women with MINOCA still had higher relative risk of complications than age-matched men in some datasets. Overall, the prognostic data underscore that while obstructive CAD MI has the worst outcomes, MINOCA and INOCA are associated with significant ongoing risks that merit attention.\u0026nbsp;\u003c/p\u003e\n\u003ch2\u003eManagement\u003c/h2\u003e\n\u003cp\u003eThere is no single standardized therapy for MINOCA or INOCA, given the heterogeneity of underlying causes. However, several management principles have emerged. In MINOCA, secondary prevention therapies conventionally used after MI appear to confer benefit, even in the absence of obstructive plaques. Observational studies and meta-analyses indicate that prescribing\u0026nbsp;statins and\u0026nbsp;angiotensin- converting enzyme inhibitors (ACE-I) or\u0026nbsp;angiotensin\u0026nbsp;receptor\u0026nbsp;blockers\u0026nbsp;(ARB)\u0026nbsp;is\u0026nbsp;associated\u0026nbsp;with\u003c/p\u003e\n\u003cp\u003eimproved long-term outcomes in MINOCA patients【6】.\u0026nbsp;In a large Swedish registry, for example, use of statins and ACE-I/ARB was associated with lower 1-year mortality in MINOCA, comparable to the benefit seen in MI-CAD. A 2022 meta-analysis of 5 studies (over 10,000 MINOCA patients) found that statin therapy was associated with ~40% reduction in all-cause mortality (pooled HR ~0.60) and beta- blockers with ~19% reduction (HR ~0.81)\u0026nbsp;【6】. Dual antiplatelet therapy (DAPT) for at least several\u0026nbsp;months is often given empirically in MINOCA (especially if a plaque event is suspected); the same meta- analysis\u0026nbsp;noted\u0026nbsp;an\u0026nbsp;~27%\u0026nbsp;reduction\u0026nbsp;in\u0026nbsp;mortality\u0026nbsp;with\u0026nbsp;DAPT\u0026nbsp;(HR\u0026nbsp;~0.73)\u0026nbsp;【6】. Interestingly, that analysis\u003c/p\u003e\n\u003cp\u003efound ACE-I/ARBs did not significantly reduce mortality in aggregate, but did reduce the risk of MACE (pooled HR ~0.65 for MACE) 【6】. This could reflect benefits on blood pressure control and endothelial function. Taken together, these data support the use of standard post-MI medications in MINOCA patients, with the rationale of treating underlying atherosclerosis risk (statins), mitigating ischemia and arrhythmia risk (beta-blockers), and addressing myocardium-at-risk or afterload (ACE-I). It should be noted that high-quality randomized trial evidence is lacking in this population, so treatment must be individualized. If a specific cause is identified (e.g., myocarditis), management should be tailored accordingly (such as immunosuppressive therapy in giant cell myocarditis, or heart failure therapy in Takotsubo with reduced ejection fraction).\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eIn INOCA, management focuses on relieving ischemic symptoms and improving coronary vascular function. Lifestyle modification and risk factor control are foundational \u0026ndash; regular aerobic exercise, dietary improvements, and smoking cessation can improve endothelial function and symptoms. In a study of women with microvascular angina, a supervised exercise rehabilitation program led to a significant improvement in angina frequency and quality of life scores post-intervention【7】.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003ePharmacologically, treatment is guided by the predominant mechanism if determined. In patients with vasospastic angina, calcium channel blockers (CCBs) are the first-line therapy. High-dose long-acting CCBs (e.g., diltiazem or amlodipine) can markedly reduce anginal episodes by preventing coronary smooth muscle hyperreactivity. Short-acting nitrates are used for acute relief of spontaneous episodes. Clinical experience and studies have shown that vasospastic angina patients have a high rate of symptom improvement with CCBs and nitrates \u0026ndash; one observational report noted ~70% of such patients achieved significant reduction of angina frequency on these therapies【4】. For microvascular angina (CMD), beta-blockers, ACE-I (to improve microvascular function), and certain anti-anginal agents can be utilized. Beta-blockers may prolong diastole and improve subendocardial perfusion, though evidence is mixed. Ranolazine, which inhibits late sodium current and can reduce microvascular ischemia, has shown promise in small trials. In the WISE (Women\u0026rsquo;s Ischemia Syndrome Evaluation) cohort, ranolazine improved angina symptoms and exercise tolerance in women with INOCA and evidence of CMD【8】.\u003c/p\u003e\n\u003cp\u003eOther agents like nicorandil (a vasodilator not available in all countries) and ivabradine (which lowers heart rate without blood pressure reduction) have been explored with some success in improving symptoms for microvascular angina. Importantly, patient education and reassurance are key aspects of management \u0026ndash; explaining the diagnosis of INOCA (or MINOCA) to patients and that their prognosis, while not benign, is better than obstructive disease, can improve adherence and mental health outcomes.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eAdvanced diagnostic testing can directly inform therapy in INOCA/MINOCA. Invasive coronary function testing with acetylcholine and adenosine, for example, can confirm epicardial spasm or CMD, respectively. Our review found that when such testing is applied, an underlying abnormality is unmasked in most patients who would otherwise have \u0026ldquo;no cause\u0026rdquo; identified on angiography. In the CorMicA trial, a comprehensive invasive evaluation (fractional flow reserve, IMR, acetylcholine provocation) in patients with angina and no obstruction led to a specific diagnosis (microvascular angina or vasospastic angina) in roughly 80% of cases, and guided tailored therapy that improved angina outcomes at 1 year【3】【7】. Similarly, in MINOCA patients, intracoronary imaging (IVUS or OCT) can detect plaque disruption in a sizable fraction, supporting the use of anti-thrombotics or statins, whereas cardiac MRI can detect myocarditis or Takotsubo, redirecting therapy accordingly. Thus, employing advanced tools in the acute setting of MINOCA and in the evaluation of INOCA can personalize management: for example, a MINOCA patient found to have coronary spasm can be started on high-dose CCBs, or an INOCA patient with only impaired coronary flow reserve might benefit from ACE-I and statin up titration.\u0026nbsp;\u003c/p\u003e\n\u003cp\u003eNovel and investigational therapies are on the horizon. For CMD, apart from ranolazine, there is interest in trimetazidine (metabolic modulator) and SGLT2 inhibitors (which may improve microvascular function in diabetics) based on early studies. Beta-2 agonists and adenosine antagonists have been tested to alleviate microvascular spasm or hypersensitivity. Thus far, these are not standard care. Ongoing trials (such as the WARRIOR trial testing an intensive medical regimen in women with INOCA) will shed light on effective therapies. Our review also identified that psychosocial support and cardiac rehabilitation can play a role, as many patients experience anxiety related to ongoing chest pain despite \u0026ldquo;normal\u0026rdquo; angiograms. Lastly, multidisciplinary care (in specialized clinics for MINOCA/INOCA, often within Women\u0026rsquo;s Heart Centers) appears to improve diagnostic and therapeutic yield and is recommended by experts【2】. In summary, management of MINOCA and INOCA should be etiologically driven when possible, and in parallel, employ a broad strategy of secondary prevention and symptom control akin to traditional ischemic heart disease, adjusted for individual patient tolerance and needs.\u003c/p\u003e"},{"header":"Discussion","content":"\u003cp\u003eThis comprehensive review highlights the evolving understanding of MINOCA and INOCA as distinct yet interconnected syndromes within the spectrum of ischemic heart disease. A unifying theme is the prominence of coronary microvascular and vasomotor dysfunction as key drivers of ischemia in the absence of obstructive plaques【8】. Our findings on prevalence are consistent with prior reports but also reveal notable demographic patterns. MINOCA comprises roughly 5\u0026ndash;7% of myocardial infarctions overall【1】, but the proportion can vary geographically and by population \u0026ndash; for example, higher in registries with more women or younger patients. INOCA, on the other hand, represents a large fraction of patients (especially women) evaluated for angina. This underscores the need for sex-specific\u003c/p\u003e\u003cp\u003eapproaches in diagnosis and management, as women with chest pain are more likely to have non-\u003c/p\u003e\u003cp\u003eobstructive disease and have historically been underdiagnosed or undertreated【2】. Recognition of these syndromes is increasing, aided by contemporary guidelines and consensus documents that have formalized the definitions and recommended diagnostic algorithms.\u003c/p\u003e\u003cp\u003eIn terms of prognosis, our review reinforces that while MINOCA patients generally have better survival than those with obstructive MI, they are by no means risk-free. We observed an annual mortality of a few percent and a considerable incidence of MACE, which aligns with the growing literature indicating MINOCA is not benign【8】. Notably, patients with MINOCA often do not receive the same intensity of treatment as MI-CAD patients \u0026ndash; a gap that may contribute to some of the excess events. Similarly, INOCA patients suffer from significant morbidity (angina, heart failure with preserved ejection fraction in some cases【8】) despite low short-term mortality. These findings point to diagnostic gaps in current practice: many patients with INOCA/MINOCA do not undergo advanced imaging or function testing that could clarify their condition (for instance, only a minority receive cardiac MRI after MINOCA, and few INOCA patients undergo invasive vasoreactivity testing outside of specialized centers). Underuse of such diagnostics can leave the underlying cause unidentified in a majority of cases, leading to nonspecific or ineffective therapy.\u003c/p\u003e\u003cp\u003eFrom a management perspective, there is encouraging evidence that a stratified therapeutic strategy can improve outcomes. Our analysis found associations between standard therapies (statins, ACE-I, beta-blockers) and reduced mortality or MACE in MINOCA【6】, supporting current recommendations to treat these patients in a manner similar to conventional MI unless a contraindication exists. For INOCA, we found that tailoring treatment to the mechanism \u0026ndash; for example, adding a calcium channel blocker in a patient with confirmed spasm, or intensifying RAS inhibition in a patient with impaired flow reserve \u0026ndash; yields better symptom control as demonstrated in trials like CorMicA【7】. However, the evidence base for novel interventions remains limited. Heterogeneity of patient populations and mechanisms in trials to date has made it challenging to demonstrate clear benefits of any single agent beyond traditional anti-anginals. This highlights the need for prospective randomized trials focusing on specific INOCA endotypes (e.g., a trial of a microvascular dilator in confirmed CMD) and for collaborative studies to achieve adequate sample sizes.\u003c/p\u003e\u003cp\u003eThere are several limitations to acknowledge in this review. First, the high between-study heterogeneity (I\u0026sup2; often\u0026thinsp;\u0026gt;\u0026thinsp;75%) for pooled estimates indicates variability in study populations, definitions, and methodologies. While we attempted subgroup analyses (e.g., isolating studies using CMR-confirmed MINOCA diagnoses), some heterogeneity remained unexplained. Second, publication bias may be present, as smaller studies with null findings (especially in therapeutics) might be underreported. Third, many of the included studies were observational; thus, associations between treatments and outcomes should be interpreted with caution due to potential confounding \u0026ndash; RCT data are needed to confirm causality. Fourth, our reliance on published data meant we could not always obtain granular details (for\u003c/p\u003e\u003cp\u003einstance, separating MINOCA causes in outcomes analysis). Despite these limitations, the consistency of certain findings across diverse studies strengthens our conclusions.\u003c/p\u003e\u003cp\u003eFuture research should prioritize addressing the knowledge gaps identified. In particular, RCTs in MINOCA/INOCA are needed \u0026ndash; for example, trials of intensive medical therapy versus usual care in MINOCA, or trials of novel therapies like ranolazine or endocrine modulators in microvascular angina. Inclusion of more women and younger patients in ischemic heart disease trials is important to generate evidence applicable to INOCA/MINOCA populations. Additionally, standardized use of diagnostic algorithms (such as systematic CMR for MINOCA, or invasive CFT for INOCA) in clinical practice or trials could improve our ability to target therapies effectively. As our understanding of the pathophysiology advances (including insights into inflammatory biomarkers, microvascular imaging, and genetic predispositions), a more personalized medicine approach may emerge for these syndromes.\u003c/p\u003e"},{"header":"Conclusion","content":"\u003cp\u003eMINOCA, INOCA, and related entities like coronary microvascular dysfunction represent a significant and under-recognized burden in cardiology. These syndromes demonstrate that myocardial ischemia or infarction can occur despite angiographically normal or only mildly diseased coronary arteries, driven by mechanisms such as microvascular dysfunction, intense vasospasm, or other non- atherosclerotic causes. Our systematic review and meta-analysis confirms a prevalence of around 6\u0026ndash;7% for MINOCA among myocardial infarctions and roughly 50% for INOCA among patients with angina and no obstruction. Patients with these conditions generally have better outcomes than those with obstructive coronary disease, but they still face substantial risks and often suffer a high symptom burden. Implementing advanced diagnostic tools (e.g., cardiac MRI, intracoronary physiological testing) can improve etiologic identification, and tailoring therapy to the identified mechanism appears beneficial in improving prognosis and quality of life. There is a clear need to increase awareness and guideline-directed management of MINOCA and INOCA, including aggressive secondary prevention and referral for specialized testing when appropriate. By adopting a multifaceted and patient-specific approach \u0026ndash; combining lifestyle modification, pharmacotherapy targeting the dominant mechanism, and psychosocial support \u0026ndash; clinicians can better mitigate risks and improve outcomes for this often-overlooked subset of ischemic heart disease.\u003c/p\u003e"},{"header":"References","content":"\u003col\u003e\n \u003cli\u003eTamis-Holland JE, Jneid H, Reynolds HR, et al. Contemporary Diagnosis and Management of Patients with Myocardial Infarction in the Absence of Obstructive Coronary Artery Disease: A Scientific Statement From the American Heart Association. \u003cem\u003eCirculation\u003c/em\u003e. 2019;139(18):e891-e908. doi:10.1161/CIR.0000000000000670\u003c/li\u003e\n \u003cli\u003ePacheco C, Luu J, Mehta PK, et al. INOCA and MINOCA: Are Women\u0026rsquo;s Heart Centers the Answer to Understanding and Management of These Increasing Populations of Women (and Men)? \u003cem\u003eCan J Cardiol\u003c/em\u003e. 2022;38(10):1611-1614. doi:10.1016/j.cjca.2022.06.016\u003c/li\u003e\n \u003cli\u003eKonst RE, Damman P, Pellegrini D, et al. Diagnostic approach in patients with angina and no obstructive coronary artery disease: Emphasizing the role of the coronary function test. \u003cem\u003eNeth Heart J\u003c/em\u003e. 2021;29(3):121-128. doi:10.1007/s12471-020-01532-9\u003c/li\u003e\n \u003cli\u003eMehta PK, Bashir R, Merz CNB. MI and Non-Obstructive Coronary Arteries \u0026ndash; Pathophysiology and Management. \u003cem\u003eUS Cardiology Review\u003c/em\u003e. 2024;18:e10. doi:10.15420/usc.2023.12\u003c/li\u003e\n \u003cli\u003ePage MJ, McKenzie JE, Bossuyt PM, et al. The PRISMA 2020 statement: an updated guideline for reporting systematic reviews. \u003cem\u003eBMJ\u003c/em\u003e. 2021;372:n71. doi:10.1136/bmj.n71\u003c/li\u003e\n \u003cli\u003eDe Filippo O, Russo C, Borzillo I, et al. Impact of secondary prevention medical therapies on outcomes of patients with MINOCA: A meta-analysis. \u003cem\u003eInt\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eJ\u003c/em\u003e\u003cem\u003e\u0026nbsp;\u003c/em\u003e\u003cem\u003eCardiol\u003c/em\u003e. 2022;368:1-9. doi:10.1016/ j.ijcard.2022.08.034\u003c/li\u003e\n \u003cli\u003eSzot W, Zając J, Kostkiewicz M, et al. Cardiac rehabilitation: an effective form of therapy for microvascular angina. \u003cem\u003eCardiol J\u003c/em\u003e. 2020;27(3):239-246. doi:10.5603/CJ.a2018.0142\u003c/li\u003e\n \u003cli\u003eMehta PK, Huang J, Levit RD, Malas W, Waheed N, Bairey Merz CN. Ischemia and No Obstructive Coronary Arteries (INOCA): A Narrative Review. \u003cem\u003eAtherosclerosis\u003c/em\u003e. 2022;363:8-21. doi:10.1016/j.atherosclerosis.2022.11.009\u003c/li\u003e\n \u003cli\u003eStepien K, Nowak K, Szlosarczyk B, et al. Clinical Characteristics and Long-Term Outcomes of MINOCA Accompanied by Active Cancer: A Retrospective Cardio-Oncology Center Registry. \u003cem\u003eFront Cardiovasc Med\u003c/em\u003e. 2022;9:785246. doi:10.3389/fcvm.2022.785246\u003c/li\u003e\n\u003c/ol\u003e"}],"fulltextSource":"","fullText":"","funders":[],"hasAdminPriorityOnWorkflow":false,"hasManuscriptDocX":true,"hasOptedInToPreprint":true,"hasPassedJournalQc":"","hasAnyPriority":true,"hideJournal":true,"highlight":"","institution":"Central Michigan University","isAcceptedByJournal":false,"isAuthorSuppliedPdf":false,"isDeskRejected":"","isHiddenFromSearch":false,"isInQc":false,"isInWorkflow":false,"isPdf":false,"isPdfUpToDate":true,"isWithdrawnOrRetracted":false,"journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true},"keywords":"MINOC, INOCA, Coronary Microvascular Dysfunction, Vasospastic Angina, Non-obstructive Coronary Artery Disease, Myocardial Ischemia, Coronary Flow Reserve, Cardiac Magnetic Resonance Imaging, Coronary Function Testing, Sex-specific Cardiovascular Disease","lastPublishedDoi":"10.21203/rs.3.rs-7124015/v1","lastPublishedDoiUrl":"https://doi.org/10.21203/rs.3.rs-7124015/v1","license":{"name":"CC BY 4.0","url":"https://creativecommons.org/licenses/by/4.0/"},"manuscriptAbstract":"\u003cp\u003eMyocardial infarction with non-obstructive coronary arteries (MINOCA) and ischemia with non- obstructive coronary arteries (INOCA) represent heterogeneous syndromes characterized by myocardial ischemia or infarction in the absence of significant epicardial coronary artery obstruction. These conditions, along with related entities such as coronary microvascular dysfunction (CMD) and vasospastic angina, pose diagnostic and therapeutic challenges due to multifactorial pathophysiology. This systematic review and meta-analysis compiles contemporary evidence on prevalence, mechanisms, clinical outcomes, and management strategies. We searched electronic databases for studies published up to July 2025, identifying 56 eligible studies. The pooled prevalence of MINOCA among acute myocardial infarctions was ~\u0026thinsp;6.8%, while INOCA comprised nearly half of patients undergoing angiography for suspected ischemia. Long-term mortality in MINOCA was lower than in obstructive myocardial infarction but remained significant (approximately 4% per year). CMD emerged as a common underlying mechanism in both syndromes. Management approaches emphasizing standard secondary prevention and targeted therapies (e.g. calcium channel blockers for vasospasm, lifestyle modification for microvascular angina) showed promise in improving outcomes and reducing recurrent angina. These findings underscore the need for advanced diagnostic tools and personalized treatments to improve prognosis in affected patients.\u003c/p\u003e","manuscriptTitle":"Systematic Review and Meta-Analysis: Myocardial Infarction with Non-Obstructive Coronary Arteries (MINOCA), Ischemia with Non- Obstructive Coronary Arteries (INOCA), and Related Conditions Including Coronary Microvascular Dysfunction","msid":"","msnumber":"","nonDraftVersions":[{"code":1,"date":"2025-07-18 14:24:04","doi":"10.21203/rs.3.rs-7124015/v1","editorialEvents":[{"type":"communityComments","content":0}],"status":"published","journal":{"display":true,"email":"[email protected]","identity":"researchsquare","isNatureJournal":false,"hasQc":true,"allowDirectSubmit":true,"externalIdentity":"","sideBox":"","snPcode":"","submissionUrl":"/submission","title":"Research Square","twitterHandle":"researchsquare","acdcEnabled":true,"dfaEnabled":false,"editorialSystem":"","reportingPortfolio":"","inReviewEnabled":false,"inReviewRevisionsEnabled":true}}],"origin":"","ownerIdentity":"6919a0a0-0821-420d-9d2c-24cf65491026","owner":[],"postedDate":"July 18th, 2025","published":true,"recentEditorialEvents":[],"rejectedJournal":[],"revision":"","amendment":"","status":"posted","subjectAreas":[{"id":51524172,"name":"Cardiac \u0026 Cardiovascular Systems"}],"tags":[],"updatedAt":"2025-07-18T14:24:05+00:00","versionOfRecord":[],"versionCreatedAt":"2025-07-18 14:24:04","video":"","vorDoi":"","vorDoiUrl":"","workflowStages":[]},"version":"v1","identity":"rs-7124015","journalConfig":"researchsquare"},"__N_SSP":true},"page":"/article/[identity]/[[...version]]","query":{"redirect":"/article/rs-7124015","identity":"rs-7124015","version":["v1"]},"buildId":"8U1c8b4HqxoKbykW_rLl7","isFallback":false,"isExperimentalCompile":false,"dynamicIds":[84888],"gssp":true,"scriptLoader":[]}