In this large, real-world cohort of patients with AF and NSTEMI defined according to the 4th UDMI, of whom 81.7% underwent coronary angiography during index hospitalization, we report three major findings.

First, the majority of symptomatic AF patients presenting to the emergency department with NSTEMI were diagnosed as type 1 myocardial infarction and required coronary revascularization at index presentation, predominantly percutaneous coronary intervention (PCI). This finding is particularly noteworthy given that NSTEMI in the presence of AF is frequently assumed to be type 2 MI based on presumed oxygen supply–demand mismatch in the absence of angiographic data [5, 6]. Hence, in cohorts where classification relies primarily on clinical judgment or consensus-based adjudication without systematic angiography, misclassification between type 1 and type 2 MI cannot be excluded [7, 8].

Unlike prior studies reporting coronary angiography rates as low as 10–36% in presumed type 2 MI populations [5, 9], our cohort achieved an angiography rate of 81.7%, among the highest reported in real-world registries. Our cohort enables near-systematic angiographic assessment, thereby minimizing misclassification bias and enhancing mechanistic interpretation. This may reflect how systematic angiography enhances both the recognition of type 1 MI and the delivery of timely revascularization and tailored secondary prevention [20].

From a clinical perspective, the pre-test probability of obstructive coronary artery disease should also be considered when AF patients present with NSTEMI. Traditional atherosclerotic risk factors such as older age, diabetes mellitus, hypercholesterolemia, smoking, prior coronary artery disease or prior MI, together with ischemic symptoms, impaired left ventricular function, and a higher GRACE 2.0 risk score may support a higher-risk ischemic presentation and strengthen suspicion for type 1 MI [1, 7, 11, 21]. In our cohort, several of these characteristics were associated with adverse outcomes, supporting the concept that AF should not automatically be regarded as a sufficient explanation for troponin elevation in symptomatic patients.

Non-invasive coronary diagnostics may have a complementary role in selected patients, particularly when the clinical presentation is equivocal and immediate invasive management is not mandatory. Coronary CT angiography may help identify or exclude relevant coronary artery disease in clinically stable patients with lower or intermediate likelihood of plaque-related ACS, whereas stress imaging may be considered only after stabilization in selected cases [11, 22]. However, in patients with symptoms suggestive of ACS and dynamic troponin changes fulfilling NSTEMI criteria, our data support a low threshold for invasive coronary workup, because reliance on presumed oxygen supply–demand mismatch alone may lead to underdiagnosis of type 1 MI [11].

Importantly, this rate reflects an exceptionally high level of invasive evaluation in routine care and is in line with international benchmarks, considering that 100% adherence is rarely achievable due to unavoidable exclusions such as patient frailty, comorbidities, or advance directives.

Efforts to differentiate type 1 from type 2 MI have included a range of strategies: comparisons of baseline and dynamic cardiac troponin levels, incorporation of additional biomarkers such as fatty acid–binding protein (FABP), myoglobin, C-reactive protein (CRP), and NT-proBNP, as well as comprehensive clinical models with or without biomarkers, and more recently, omics-based classifiers [23,24,25]. More recently, several artificial intelligence (AI) tools have been developed and validated to discriminate type 1 from type 2 MI and hence to overcome limitations of traditional predictive models [26,27,28]. However, their utility remains questionable since the prevalence of type 2 MI may have been systematically overestimated and conversely the prevalence of type 1 MI underestimated as coronary angiography was not obligatory for the definition of type 2 MI in AI-based models [26, 27]. Although some AI models have demonstrated excellent agreement in validation cohorts [28], this may partly reflect the use of standardized UDMI criteria for type 2 MI, which do not require coronary angiography [1]. A second important reason that facilitates high levels of agreement is an established putative but biologically plausible pathomechanism in combination with the commonly applied methodology to reach consensus [23, 29].

Second, type 2 NSTEMI represents a clinically distinct entity that, while sharing key risk factors with type 1 NSTEMI, differs meaningfully in demographic and clinical profile. Patients with type 2 MI were slightly older and similarly distributed by sex, though neither difference was statistically significant. More notably, they had a higher prevalence of arterial hypertension (97.0% vs. 90.4%) and a greater burden of pre-existing cardiovascular disease, including more frequent prior coronary artery disease (63.0% vs. 50.3%) and myocardial infarction (37.0% vs. 25.6%).

Renal function was worse in type 2 MI, with lower median eGFR and higher serum creatinine (both p < 0.05), accompanied by elevated inflammatory and cardiac strain markers (CRP, NT-proBNP), suggesting greater systemic myocardial stress. Despite greater systemic stress, left ventricular function was better preserved, with normal LVEF seen in 30.3% compared to 17.1% in type 1 (p = 0.0306).

Anatomically, type 2 MI was associated with less extensive coronary artery disease: 16.0% had no significant lesions (vs. 0% in type 1), and only 53.0% had three-vessel disease (vs. 71.5%, p < 0.001). Medication use mirrored these differences, with markedly lower rates of antiplatelet therapy in type 2 MI.

Taken together, these findings reinforce that type 2 NSTEMI is not a milder variant but a distinct clinical syndrome, often driven by systemic triggers and non-obstructive coronary pathology. This distinction is crucial for guiding diagnostic workup, revascularization decisions, and individualized antithrombotic strategies. In addition, patients with type 2 MI who exhibit impaired left ventricular function or clinical heart failure should receive guideline-directed medical therapy analogous to patients with type 1 MI, including beta-blockers, renin–angiotensin system inhibition, mineralocorticoid receptor antagonists, and sodium–glucose cotransporter-2 inhibitors, as recently emphasized in expert consensus statements. Although randomized data are lacking, the myocardial injury and subsequent remodeling risk are not fundamentally different, and omission of heart failure therapy in this setting may represent a missed opportunity for secondary prevention [30].

Lastly, we identified a small but high-risk subgroup of patients classified as having acute myocardial injury. Although these individuals did not meet the clinical criteria for NSTEMI, they exhibited dynamic troponin elevations and were ultimately found to have diverse underlying etiologies, including infection, cardiomyopathy, pulmonary embolism, and valvular heart disease. Notably, this group demonstrated the highest unadjusted rates of both composite adverse events (65.4%) and all-cause mortality (57.7%), exceeding those observed in either NSTEMI subtype. Despite the absence of ischemic symptoms, nearly 70% had angiographically confirmed CAD, and 42.3% had three-vessel disease.

These findings highlight a critical diagnostic blind spot: patients with non-ischemic troponin elevations may still harbor significant coronary pathology and carry all-cause mortality rates approaching 60% during follow-up. Their heterogeneity and disproportionately poor outcomes underscore the need for more refined diagnostic tools and perhaps a re-evaluation of how this category is clinically managed. Further studies are needed to assess whether selected patients with acute myocardial injury, particularly those with underlying CAD or major systemic stressors, may benefit from invasive evaluation and tailored secondary prevention.

This study’s retrospective, observational design limits causal inference and renders findings vulnerable to residual confounding. Although myocardial infarction type was adjudicated using 4th UDMI criteria and considered only patients who underwent CA during index hospitalization, a misclassification between type 1 and type 2 MI cannot be fully ruled out, particularly because the spatial resolution of CA is not high enough to allow clear visualization of small erosion, fissure, or dissection of coronary plaque and intracoronary thrombi [31]. Importantly, during the recruitment period (2009–2020), intravascular imaging with optical coherence tomography (OCT) or intravascular ultrasound (IVUS) was not performed, especially in the setting of acute myocardial infarction. For this purpose, systematic evaluation with intravascular imaging including IVUS and OCT would be required in forthcoming studies.

Second, although 81.7% of eligible AF patients with NSTEMI underwent coronary angiography—a rate among the highest reported in the literature—this may still introduce a degree of selection bias. However, at the University hospital of Heidelberg, all patients who fulfill the criteria for NSTEMI are considered for coronary angiography unless there are relevant comorbidities such as severe cognitive impairment or severe dementia, advanced cancer with reduced life expectancy, concomitant severe sepsis or septic shock, or upon patients’ request. Therefore, our cohort reflects a nearly unselected, real-world population of patients undergoing early invasive evaluation. Overall rates of coronary angiography and myocardial revascularization were the highest among international PCI centers [32,33,34,35]. We also lacked data on exact symptom onset because patients frequently cannot reliably recall exact time of symptom onset. Moreover, coronary anatomy was described only semi-quantitatively, based on the presence and estimated severity of coronary stenosis based on a 50% luminal obstruction threshold, but lacked information on plaque characteristics, plaque composition, lesion complexity or functional significance of the culprit lesion. However, all coronary angiographies were re-evaluated by experienced invasive cardiologists for the presence of either visible plaque rupture, erosion, fissure or dissection, for visible intracoronary thrombus or for reduced TIMI flow.

Despite these limitations, the strength of this study lies in the large number of patients presenting with AF to an ED of a single academic center with established invasive protocols and who systematically underwent CA when the criteria of NSTEMI were present. Such a strategy provides for the first time a transparent estimation of the true rates of type 1 and type 2 MI in AF.