Acute Coronary Syndrome
Acute coronary syndrome (ACS) is a spectrum of life-threatening conditions caused by a sudden reduction in blood flow to the heart muscle due to acute obstruction of a coronary artery[^c1]. It encompasses ST-elevation myocardial infarction (STEMI), non-ST-elevation myocardial infarction (NSTEMI), and unstable angina, which are distinguished by the presence and extent of myocardial necrosis and characteristic electrocardiographic findings[^c2]. NSTEMI has become the predominant manifestation of ACS globally, driven by population aging, the widespread use of high-sensitivity cardiac troponins, and improved survival after prior coronary events[^c11]. ACS represents the acute manifestation of coronary artery disease and remains a leading cause of morbidity and mortality worldwide. Cardiovascular diseases caused an estimated 19.8 million deaths globally in 2022, with heart attacks and strokes accounting for 85% of these fatalities[^c4]. In the United States, approximately 805,000 individuals experience a myocardial infarction each year[^c7].
The most common underlying cause of ACS is acute thrombus formation over a ruptured or eroded atherosclerotic plaque in a coronary artery[^c3]. Inflammation plays a central role in plaque destabilization: activated immune cells weaken the fibrous cap of the plaque, predisposing it to rupture[^c5]. Once the thrombogenic core is exposed, platelets are activated and the coagulation cascade is triggered, leading to partial or complete coronary occlusion. In more than half of cases, the pre-event stenosis is less than 40%, highlighting that plaque biology, rather than the degree of luminal narrowing, determines the risk of acute events[^c6]. Recent advances have confirmed the inflammatory hypothesis of atherosclerosis therapeutically: agents targeting the NLRP3 inflammasome/interleukin-1β/interleukin-6 pathway reduce major adverse cardiovascular events, while broad immunosuppression does not[^c9]. A phase-2 study of the IL-6 ligand inhibitor ziltivekimab has shown reductions in inflammatory biomarkers such as hs-CRP and the neutrophil-to-lymphocyte ratio without the severe infections observed with canakinumab[^c26]. Clonal hematopoiesis of indeterminate potential (CHIP), involving mutations in TET2 and ASXL1, has emerged as a mechanism linking aging to cardiovascular risk through macrophage hyperreactivity and increased plaque vulnerability[^c10].
Diagnosis of ACS rests on clinical presentation, electrocardiography, and cardiac biomarkers. The 2025 ACC/AHA/ACEP/NAEMSP/SCAI guideline unified STEMI and NSTEMI management into a single comprehensive document, replacing the separate guidelines from 2013 and 2014; the 2023 ESC guideline likewise consolidated recommendations for the entire spectrum of ACS into one document for the first time[^c17]. The updated ACC/AHA guidance emphasizes rapid and accurate risk assessment using high-sensitivity troponin assays and clinical decision tools to improve early diagnosis and avoid unnecessary treatment delays[^c21]. Complete revascularization of non-culprit arteries received a Class I recommendation for both STEMI and NSTE-ACS[^c13], and intracoronary imaging (IVUS or OCT) was upgraded to Class I for guiding PCI in complex coronary lesions. High-sensitivity troponin-based risk stratification has made emergency department rule-out pathways faster and safer: implementation reduced length of stay and increased discharge directly from the emergency department in both low- and intermediate-risk patients[^c18]. In the prehospital setting, HEART-derived clinical risk scores combined with point-of-care troponin identify low-risk patients with high sensitivity (91.8–93.2%) and negative predictive values (97.2–99.8%) for 30-day mortality and major adverse cardiac events[^c19]. An AI-enhanced GRACE 3.0 scoring system validated across 609,063 patients in 10 countries now offers improved prediction of both in-hospital mortality (AUC 0.90) and 1-year mortality, along with individualized treatment effect estimates to identify patients who benefit most from early invasive management[^c12]. The CB-ACS multi-biomarker risk score, integrating NT-proBNP, D-dimer, GDF-15, and other routine variables, predicted 10-year cardiovascular death or myocardial infarction with a C-index of 0.79 in development and 0.77 in validation, outperforming GRACE 2.0[^c22]. Emerging biomarkers include the long non-coding RNA NORAD, which added diagnostic value beyond traditional risk factors (AUC 0.700 vs 0.763) in a study of 156 ACS patients[^c23]. In the SECURE trial presented at EuroPCR 2026, index of microcirculatory resistance (IMR)-guided early discharge after primary PCI for STEMI shortened hospital stay by at least 24 hours without affecting three-month left ventricular function[^c24].
Despite advances in care, ACS carries a significant burden of complications. The SCAI shock staging classification (Stage A through E) provides validated risk stratification for cardiogenic shock, with stepwise in-hospital mortality ranging from 4.0% at Stage A to 40.2% at Stage E. In a prospective study of 1,166 ACS patients, 7.4% developed cardiogenic shock and 51% of those died; reduced 24-hour urine output and cool extremities were independent predictors of mortality[^c25]. In a nationwide study of 1.56 million survivors, cardiovascular mortality reached 9.37% at four years, with non-cardiovascular causes accounting for a growing proportion of deaths over time[^c8]. Bleeding risk assessment using tools such as the PRECISE-DAPT score—derived from 14,963 patients and validated in the PLATO trial (c-index 0.70)—helps guide the intensity and duration of antithrombotic therapy, with a score of 25 or more identifying patients in whom abbreviated DAPT reduces harm without loss of ischemic protection[^c16]. The TARGET-Type 2 pilot is the first completed randomized controlled trial in type 2 myocardial infarction, demonstrating the feasibility of recruiting and randomising these patients to an imaging-guided investigation strategy[^c20].
Long-term secondary prevention through lifestyle modification, cardiac rehabilitation, and pharmacotherapy is essential for reducing recurrent events. The CROS-II meta-analysis of 228,337 patients confirmed that comprehensive cardiac rehabilitation participation after ACS is associated with a substantial reduction in total mortality (HR 0.37 in prospective cohort studies)[^c15]. The 2025 Australian guideline introduced a more stringent LDL-C target of less than 1.4 mmol/L (approximately 55 mg/dL) and emphasized tailored DAPT duration, limited beta-blocker use in preserved ejection fraction, and the emerging role of GLP-1 analogues and SGLT2 inhibitors in secondary prevention[^c14].