Acute coronary syndrome stratification: is it time to go beyond the ECG?

The past is always tense, the future perfect Zadie Smith Acute coronary syndromes (ACS), including ST-segment elevation myocardial infarction (STEMI) and non-ST-segment elevation acute coronary syndromes (NSTE-ACS), are leading causes of morbidity and mortality worldwide.1,2 It is well established that accurate and prompt identification of the infarct-related artery (IRA), the so-called culprit lesion, in patients with ACS is crucial for an appropriate management, with significant therapeutic and prognostic implications, especially in the case of total coronary occlusion (TCO).3 While angiography is the gold standard for identifying sites of coronary obstruction or occlusion, the initial and pivotal diagnostic tool for ACS is obviously the 12-lead electrocardiogram (ECG). Despite its age, ECG remains an indispensable tool in the diagnosis and risk stratification of ACS, with ST-segment elevation being a key indicator of TCO, even though this does not always hold true. Indeed, in many healthcare settings, such as ours in Latina, Italy, ECGs are already performed at the patient’s home or in the ambulance to save precious minutes. Indeed, the key premise is that ECG is necessary to differentiate between STEMI and NSTE-ACS, with the prompt requirement of primary percutaneous coronary intervention (pPCI) for STEMI patients, whereas the indication for invasive management in NSTE-ACS depends on individual risk stratification.4 Indeed, in most cases, patients with NSTE-ACS must be approached in a comprehensive fashion, in which emergent or urgent coronary angiography may be indicated, but only when carefully weighed. However, the ECG findings at presentation may not always accurately reflect the presence of TCO, especially in NSTE-ACS cases.5 Moreover, the impact of IRA location on major cardiovascular events (MACE), such as death, stroke, myocardial infarction, or repeat revascularization, remains unclear in unselected ACS populations, particularly in the NSTE-ACS subgroup. In this context, we welcome the work by Brunoet al.,6 which aims to delineate the clinical characteristics and outcomes of NSTE-ACS patients stratified by the location of the IRA and the presence of TCO. In addition, among the possible clinical predictors evaluated, systemic inflammation markers have emerged as possible independent predictors of TCO, irrespective of ECG presentation. This retrospective analysis of the SPUM-ACS registry data included 4412 ACS patients, with 56.0% presenting with STEMI and 44.0% with NSTE-ACS. The primary outcome was MACE (in such a specific case, a composite of all-cause death, non-fatal myocardial infarction, and non-fatal stroke at one year). In this cohort of patients, the IRA and the incidence of TCO varied across different locations. Interestingly, among NSTE-ACS patients, TCO was more frequently observed in left circumflex (LCx) and right coronary artery (RCA) compared with the left anterior descending (LAD) coronary artery. Notably, in patients diagnosed with NSTE-ACS, occlusion of the LCx was associated with a higher risk of MACE within the first year following the ACS episode. One of the hot topics in cardiovascular research regards myocardial infarction with non-obstructive coronary arteries (MINOCA), which can mimic a STEMI ECG pattern very often but without an obstructive coronary disease.1 However, it should be borne in mind the flip side: These findings highlight the importance of considering TCO even in the absence of ST-segment elevation in NSTE-ACS patients. Rephrased, in the ECG-coronarography relationship, we must carefully consider the grey areas, and not just pre-established schemes. Bruno and colleagues suggest that IRA location is a crucial factor to consider when assessing the risk of adverse outcomes in NSTE-ACS patients. Identifying high-risk individuals with LCx involvement may facilitate targeted interventions and improve patient outcomes. Intriguingly, the study by Bruno et al. also investigated the role of systemic inflammation in predicting TCO, regardless of ECG presentation. Indeed, high lymphocyte and neutrophil counts, higher levels of high-sensitivity C-reactive protein (hs-CRP), and high-sensitivity troponin T (hs-TnT) were associated with TCO in NSTE-ACS patients. Thus, systemic inflammation markers might serve as valuable adjuncts in detecting TCO and risk-stratifying NSTE-ACS patients beyond the traditional ECG-based approach. This finding corroborates what is becoming always clearer about the complex interplay between inflammation, ACS, and heart failure: oxidative stress and autophagy, damage-associated molecular patterns, and the adaptive immune system play a key role in the setting of ACS and heart failure, which may be driven by an increased bowel permeability that modulates gut microbiota.7 However, these findings are speculative and should be considered mainly hypothesis-generating. Further research is warranted to validate these results in independent cohorts of NSTE-ACS patients. It is worth noting that a significant limitation of the study protocol is the lack of a centralized ECG core lab to differentiate between STEMI and NSTE-ACS. Having a central core lab and maintaining an archive of admission ECGs could have facilitated the development of novel ECG parameters for predicting acute coronary occlusion in patients with NSTE-ACS. Insight from SPUM-ACS registry data. NSTEMI = non-ST-elevation myocardial infarction; STEMI = ST-elevation myocardial infarction; Hs-CRP = high-sensitivity C-reactive protein. In conclusion, this study, confirming once again that TCO can also occur in NSTE-ACS patients, challenges the notion that ST-elevation is the sole determinant of coronary occlusion.8,9 Moreover, understanding the clinical characteristics associated with different IRA locations and the occurrence of TCO also in NSTE-ACS patients is vital for risk stratification and appropriate management: Rapid identification of NSTE-ACS with TCO enables prompt and appropriate management, including timely invasive intervention with PCI. Accordingly, the findings from this study could have significant clinical implications. By elucidating the impact of IRA location on long-term outcomes, physicians can be guided in risk stratification and individualized treatment decisions for ACS patients. With this research, Bruno et al. significantly advance our understanding of clinical features and outcomes associated with different IRA locations in ACS patients, especially in NSTE-ACS. Identifying high-risk subsets of NSTE-ACS, such as those with TCO involving LCx or RCA, and also leveraging machine learning methods would provide an immediate risk stratification and consequently an early revascularization strategy that could improve the outcomes of many acute MI patients, as underscored by current guidelines indications.10 Future studies should also further investigate the underlying mechanisms linking systemic inflammation to TCO and explore potential therapeutic strategies targeting inflammation in ACS. Research leading to these results has received funding from the European Union—NextGenerationEU, through the Italian Ministry of University and Research, under PNRR—M4C2-I1.3 Project PE_00000019 ‘HEAL ITALIA’ to Giuseppe Biondi-Zoccai CUP B53C22004000006 Sapienza University of Rome. The views and opinions expressed are those of the authors only and do not necessarily reflect those of the European Union or the European Commission. Neither the European Union nor the European Commission can be held responsible for them. Conflict of interest: Giuseppe Biondi-Zoccai has consulted for Amarin, Balmed, Cardionovum, Crannmedical, Endocore Lab, Eukon, Innovheart, Guidotti, Meditrial, Microport, Opsens Medical, Replycare, Teleflex, and Terumo. All other authors report no conflicts of interest.