Copyright
©The Author(s) 2025.
World J Cardiol. May 26, 2025; 17(5): 106541
Published online May 26, 2025. doi: 10.4330/wjc.v17.i5.106541
Published online May 26, 2025. doi: 10.4330/wjc.v17.i5.106541
Table 1 Classification of myocardial infarction with nonobstructive coronary arteries based on pathophysiological mechanisms
| Category | Mechanism | Description |
| Atherosclerotic causes | Plaque erosion | Partial thrombus formation without significant luminal obstruction due to endothelial dysfunction and inflammation |
| Coronary microembolization | Small emboli from an atherosclerotic plaque cause transient ischemia without visible stenosis | |
| Coronary microvascular dysfunction | Endothelial dysfunction and increased arterial stiffness impair myocardial perfusion | |
| Non-atherosclerotic causes | Coronary vasospasm | Transient epicardial or microvascular constriction triggered by endothelial dysfunction, sympathetic activation, or vasoconstrictive agents leading to ischemia |
| Spontaneous coronary artery dissection | Intimal tear or intramural hematoma causes lumen compression and ischemia. It is often associated with fibromuscular dysplasia and peripartum changes | |
| Myocardial oxygen supply-demand mismatch | Increased myocardial oxygen demand in conditions like anemia, tachyarrhythmias, hypertensive crises, and sepsis |
Table 2 Nondiscriminatory biomarkers in myocardial infarction with nonobstructive coronary arteries
| Biomarker | Description |
| CXCL-1 | Involved in neutrophil recruitment and inflammation. Elevated levels have been found indicating a high level of chronic inflammation in MINOCA patients |
| suPAR | suPAR has chemotactic properties and is involved in inflammatory activity and microvascular dysfunction. Elevated levels are linked to inflammation and endothelial dysfunction in MINOCA |
| MPO | A marker of oxidative stress and inflammation. Higher MPO levels are typically associated with atherosclerosis and can be elevated in typical MI, whereas MINOCA might present with lower MPO levels if inflammation is less pronounced |
Table 3 Discriminatory biomarkers in myocardial infarction with nonobstructive coronary arteries
| Biomarker | Description |
| TRAIL | Plays a role in immune cell regulation and inflammation. It is downregulated in proportion to the severity of myocardial injury. Higher levels are observed in stable MINOCA patients |
| t-PA | Involved in fibrinolysis. The levels of t-PA could be altered in typical MI due to thrombus formation, whereas MINOCA may show lower fibrinolytic activity due to the lack of major coronary obstruction |
| NT-proBNP | Elevated in MINOCA due to myocardial stress, ventricular dysfunction, or microvascular dysfunction. It can indicate a worse prognosis |
Table 4 Biomarkers in atherosclerotic lesions
| Biomarker | Description | Clinical significance |
| hs-CRP | hs-CRP is a sensitive marker of systemic inflammation and is elevated during plaque rupture or erosion | High hs-CRP levels reflect ongoing inflammation in the atherosclerotic plaque, promoting its instability and rupture |
| MMP-9 | MMP-9 plays a key role in extracellular matrix degradation, which is involved in plaque rupture and erosion | MMP-9 degrades collagen and elastin in the plaque, weakening the fibrous cap and increasing the risk of rupture or erosion |
| CD40L | CD40L is involved in platelet activation and inflammation, playing a role in plaque rupture and thromboembolism | CD40L stimulates platelet aggregation and endothelial activation, contributing to plaque rupture and thromboembolism in MINOCA |
| P-selectin | P-selectin mediates platelet and endothelial cell interactions, playing a role in thromboembolism and plaque instability | P-selectin is involved in the recruitment of platelets to the site of plaque rupture or erosion, promoting thrombus formation |
Table 5 Biomarkers in spontaneous coronary artery dissection
| Biomarker | Description | Clinical significance |
| TGF-β | TGF-β is an angiogenic factor involved in vascular remodeling, fibrosis, and smooth muscle cell proliferation. Dysregulation of TGF-β can cause abnormal composition of the arterial wall leading to SCAD | Impaired levels of TGF-β contribute to vascular remodeling and fibrosis, promoting the formation of dissection and impaired vessel function. A study found that miRNAs belonging to the TGF-β family were found to be expressed in high levels in patients with SCAD implicating the role of TGF-β in this disease pathology suggesting the potential of the miRNAs to be biomarkers of SCAD |
| Fibrillin 1 protein | Fibrillin 1 is a structural component of the extracellular matrix, important for vascular integrity. Deficiency or mutation may lead to SCAD and MINOCA | Impaired fibrillin 1 leads to compromised vascular integrity, making arteries prone to dissection and subsequent myocardial ischemia |
| Eosinophils | High levels of circulating eosinophils were found in patients with SCAD. Eosinophil activation and infiltration in the adventitial layer of the coronary artery causes lytic substances degranulation resulting in vascular damage in SCAD and MINOCA | Eosinophil infiltration promotes vascular inflammation and damage, which may contribute to SCAD development and microvascular dysfunction |
Table 6 Biomarkers of supply-demand mismatch
| Biomarker | Description | Clinical significance |
| MR-proANP | MR-proANP is involved in cardiac stress response and is an indicator of atrial stretch. It is proposed to be elevated in MINOCA due to acute myocardial stress or inflammation | It reflects atrial and ventricular stress, which may arise from microvascular dysfunction, inflammatory processes, or stress-induced myocardial injury, all of which could contribute to MINOCA. It helps in diagnosing myocardial injury when coronary arteries appear unobstructed |
| CT-proET1 | CT-proET-1 is a marker of endothelin-1 precursor, a potent vasoconstrictor involved in vascular tone and cardiac remodeling. Elevated levels suggest endothelial dysfunction | Elevated CT-proET-1 levels in MINOCA indicate impaired endothelial function and increased vasoconstriction, potentially contributing to myocardial ischemia despite normal coronary artery findings. Endothelin-1 can cause vasoconstriction, leading to reduced myocardial perfusion, a mechanism in MINOCA |
| MR-proADM | MR-proADM is a biomarker related to adrenomedullin, a vasodilator, and marker of endothelial dysfunction. It is elevated in conditions of heart failure, sepsis, and myocardial injury | MR-proADM reflects the systemic vasodilatory response and endothelial dysfunction, which may result from microvascular spasm, inflammation, or altered myocardial perfusion in MINOCA. High levels correlate with worse prognosis and heart failure in these patients |
| GDF-15 | GDF15 is a stress-induced cytokine elevated in response to inflammation, oxidative stress, and myocardial injury. It is thought to be a biomarker of myocardial stress in MINOCA | GDF15 reflects myocardial injury and inflammation, which may result from microvascular dysfunction or myocardial stress in the absence of obstructive coronary disease. Elevated levels suggest a heightened inflammatory response and oxidative stress, both of which can contribute to the pathophysiology of MINOCA. It is related to adverse cardiovascular outcomes |
Table 7 Biomarkers involved in coronary artery spasm and coronary microvascular dysfunction
| Biomarker | Description | Clinical significance |
| CRP | CRP is a marker of systemic inflammation, and elevated levels indicate ongoing inflammation, which may contribute to CAS and CMD | Elevated CRP levels are associated with poor prognosis in MINOCA, reflecting chronic inflammation and vascular dysfunction |
| IL-6 | IL-6 is a pro-inflammatory cytokine that plays a central role in inflammatory responses and vascular injury. Elevated IL-6 levels are linked with CMD and spasms | High IL-6 levels indicate an inflammatory state, which can exacerbate CMD and increase the risk of MINOCA |
| Lp(a) | Lp(a) is an atherogenic lipoprotein that can contribute to endothelial dysfunction, promoting both CAS and CMD | Lp(a) is higher in patients with spastic sites of coronary arteries |
| Rho-associated protein kinase | Rho kinase activates myosin light chain kinase through phosphorylation. Rho kinase thus regulates smooth muscle contraction and endothelial function. It is involved in coronary artery spasm and microvascular dysfunction | Increased Rho kinase activity is linked with impaired vasodilation and increased vasoconstriction, contributing to CAS and CMD in MINOCA |
Table 8 Cardiac magnetic resonance findings and diagnoses in myocardial infarction with nonobstructive coronary arteries
| Cause of MINOCA | CMR findings | Description |
| Acute myocarditis | Lake Louise criteria | CMR shows myocardial edema, capillary leaks, hyperemia, and necrosis/fibrosis. Lake Louise criteria include T2 weighted imaging for edema and T1 weighted imaging before and after contrast for tissue characterization (LGE pattern) |
| LGE | LGE typically shows subepicardial or transmural enhancement, often in a nonvascular distribution (inflammatory infiltration rather than ischemic) | |
| T2 weighted imaging | T2 signal hyperintensity, indicating myocardial edema | |
| T1 weighted imaging | Helps identify myocardial fibrosis and scar tissue | |
| Takotsubo cardiomyopathy | RWMA | CMR shows apical ballooning with increased myocardial strain in the apex of the (LV) but with absence of coronary artery obstruction |
| LGE | LGE is typically absent or minimal in Takotsubo cardiomyopathy, helping to distinguish it from myocardial infarction | |
| T2 weighted imaging | T2 hyperintensity may show myocardial edema in the involved regions of the LV | |
| No obstructive coronary disease | No significant coronary artery blockage or stenosis is identified | |
| Plaque rupture | LGE | LGE in a subendocardial or transmural pattern corresponding to a vascular territory, often localized to the area of infarction after plaque rupture |
| T2 weighted imaging | Edema is typically seen in a coronary regional distribution, reflecting the infarcted area from the ruptured plaque | |
| No obstructive coronary disease | Coronary artery spasm or microvascular dysfunction might be present but not significant obstruction | |
| Plaque erosion | LGE | LGE may be present in a subendocardial or transmural pattern, typically corresponding to a vascular territory |
| T2 weighted imaging | Edema localized to the region supplied by the affected artery | |
| No significant obstruction | Coronary imaging may show plaque erosion or microembolism, but not significant stenosis |
Table 9 Optical coherence tomography findings and diagnoses in myocardial infarction with nonobstructive coronary arteries
| OCT finding | Description |
| Plaque rupture | Defined by the presence of fibrous cap discontinuity with a cavity formation within the plaque |
| Plaque erosion | Presence of thrombus overlying an intact plaque, without rupture |
| Calcific nodule | Disruption of the fibrous cap and/or thrombus overlying a calcified plaque with protruding calcification into the lumen |
| Lone thrombus | Presence of thrombus overlying an intact coronary arterial wall, without any visible plaque rupture or erosion |
| Coronary artery spasm | Characterized by intimal bumping with a larger medial area and medial thickness |
| Spontaneous coronary artery dissection | Separation of the intimal layer from the outer vessel wall with a blood column between the two |
Table 10 Observational studies on the efficacy of cardioprotective therapies in myocardial infarction with nonobstructive coronary arteries
| Ref. | Methodology | Results | ||||
| DAPT | Statins | Beta-blockers | ACEI/ARB | CCB | ||
| Lindahl et al[65], 2017 | Observational study on the data from the SWEDEHEART registry collected between July 2003 and June 2013 and followed up to December 2013, involving 9466 cases of MINOCA. Incidence of MACE was measured after a mean follow-up of 4.1 years | Nonsignificant 10% reduction in MACE post-discharge (HR = 0.90; 95%CI: 0.74-1.08) | Significant 23% reduction in MACE (HR = 0.77; 95%CI: 0.68-0.87) | Nonsignificant 14% reduction in MACE (HR = 0.86; 95%CI: 0.74-1.01) | Significant 18% reduction in MACE rate (HR = 0.82; 95%CI: 0.73-0.93) | N/A |
| Paolisso et al[68], 2019 | Study based on the database of Bologna University Hospital between January 2016 and December 2018 involving patients of acute myocardial infarction (including 134 MINOCA cases) undergoing coronary angiography within the first 48 hours of hospitalization. The average follow-up period was 19.35 ± 10.6 months | A nonsignificant reduction in MACE (HR = 0.42; 95%CI: 0.14-1.24) | A nonsignificant reduction in MACE (HR = 0.44; 95%CI: 0.16-1.22) | A nonsignificant reduction in MACE (HR = 0.43; 95%CI: 0.14-1.35) | Significant reduction in MACE (HR = 0.29; 95%CI: 0.10-0.81) | N/A |
| Abdu et al[67], 2020 | Single center retrospective study on 259 MINOCA patients between 2014 to 2018 after a follow-up duration of 2 years | Nonsignificant effect on MACE (HR = 1.53; 95%CI: 0.78-3.01) | Significant decrease in MACE (HR = 0.467; 95%CI: 0.239-0.911) | Nonsignificant effect on MACE (HR = 1.043; 95%CI: 0.547-1.988) | Significant decrease in MACE (HR = 0.486; 95%CI: 0.237-0.996) | N/A |
| Kovach et al[66], 2021 | A propensity-matching study on the data collected from the Veterans Affairs Clinical Assessment, Reporting and Tracking program on troponin-positive patients who had undergone coronary angiography between October 2008 and September 2017. The positive cohort consisted of 1986 cases of MINOCA. The mean follow-up period is 1 year | Nonsignificant effect on MACE with P2Y12 inhibitor (HR = 1.02; 95%CI: 0.58-1.80) | Significant decrease in MACE (HR = 0.34; 95%CI: 0.23-0.51) | Nonsignificant effect on MACE (HR = 1.09; 95%CI: 0.73-1.62) | Significant decrease in MACE with ACEI use (HR = 0.51; 95%CI: 0.33-0.79) | A nonsignificant reduction in MACE (HR = 0.63; 95%CI: 0.38-1.04) |
| Ciliberti et al[71], 2021 | A retrospective multicentric cohort study on 621 patients with MINOCA from 9 Hub Hospitals across Italy between March 2012 and March 2018. The mean follow-up duration is 90 months | Nonsignificant effect on MACE (HR = 2.25; 95%CI: 0.58-8.79) | Nonsignificant effect on MACE (HR = 1.67; 95%CI: 0.91-3.05) | Significant reduction in MACE observed (HR = 0.49; 95%CI: 0.31-0.79) | Nonsignificant effect on MACE (HR = 0.70; 95%CI: 0.40-2.21) | Nonsignificant effect on MACE (HR = 1.41; 95%CI: 0.77-2.50) |
| Bossard et al[64], 2021 | Post hoc analysis of the OASIS 7 trial comparing MACE outcomes among 1599 MINOCA patients with double-strength and standard clopidogrel-based DAPT regimen after a follow-up of 1 year | No additional benefit of double-strength clopidogrel over the standard dose (HR = 3.57; 95%CI: 1.31-9.76) | N/A | N/A | N/A | N/A |
Table 11 Summary of adverse effects associated with myocardial infarction with nonobstructive coronary arteries therapies
| Therapeutic modality | Adverse effects |
| Aspirin (long-term therapy) | Gastrointestinal bleeding, gastric ulceration, dyspepsia, increased hemorrhagic stroke risk, bronchospasm (in aspirin-sensitive asthma), renal dysfunction |
| P2Y12 inhibitors (clopidogrel, ticagrelor, prasugrel) | Bleeding (including gastrointestinal and intracranial), thrombocytopenia, dyspnea (ticagrelor), hypersensitivity reactions |
| Statin therapy | Myopathy, rhabdomyolysis, hepatic dysfunction, new-onset diabetes, cognitive effects (rare), gastrointestinal upset |
| ACE inhibitors/ARBs | Hypotension, cough (ACE inhibitors), angioedema, hyperkalemia, renal dysfunction, dizziness |
| Beta-blockers | Bradycardia, hypotension, fatigue, dizziness, depression, erectile dysfunction, worsening bronchospasm in asthma/COPD |
| Calcium channel blockers | Hypotension, peripheral edema, flushing, headache, constipation (especially with verapamil), dizziness, reflex tachycardia (dihydropyridines) |
| Short-acting nitrates | Headache, hypotension, dizziness, reflex tachycardia, methemoglobinemia (rare), flushing, nitrate tolerance |
| Thrombolytic/anticoagulant therapy | Major bleeding (gastrointestinal, intracranial, retroperitoneal), thrombocytopenia (heparin-induced), hypersensitivity reactions, hematoma at injection site |
| Vitamin K antagonists (Warfarin) | Bleeding complications need regular INR monitoring, skin necrosis (rare), drug interactions, purple toe syndrome |
| Unconventional agents for CMD | Dipyridamole: Headache, dizziness, hypotension, flushing, gastrointestinal discomfort |
| Ranolazine: QT prolongation, dizziness, constipation, nausea, palpitations | |
| Imipramine: Anticholinergic effects, drowsiness, dry mouth, urinary retention | |
| Aminophylline: Arrhythmias, CNS stimulation, nausea, tremors, seizures (at high doses) | |
| Dual antiplatelet therapy | Increased bleeding risk, anemia, epistaxis, easy bruising, dyspepsia |
| Invasive interventions (PCI/stenting) | Iatrogenic vessel injury, stent thrombosis, restenosis, arterial dissection, contrast-induced nephropathy, procedural bleeding, coronary spasm |
| Non-pharmacological approaches (cardiac rehabilitation, lifestyle modifications) | Minimal direct risks, but unsupervised activity may lead to musculoskeletal injury or cardiovascular events in high-risk individuals |
- Citation: Seshadri H, Gunasekaran D, Mohammad A, Rachoori S, Rajakumar HK. Myocardial ischemia in nonobstructive coronary arteries: A review of diagnostic dilemmas, current perspectives, and emerging therapeutic innovations. World J Cardiol 2025; 17(5): 106541
- URL: https://www.wjgnet.com/1949-8462/full/v17/i5/106541.htm
- DOI: https://dx.doi.org/10.4330/wjc.v17.i5.106541