Acute coronary syndromes: new guidelines and new light shed on biomarkers and mechanisms of plaque instability

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on acute cardiovascular care contains the ‘2023 ESC Guidelines for the management of acute coronary syndromes: Developed by the task force on the management of acute coronary syndromes of the European Society of Cardiology (ESC)’ by authors from the ESC Scientific Document Group.1 These Guidelines are extremely innovative as for the first time they provide recommendations for the entire spectrum of acute coronary syndromes (ACS) including unstable angina, ST-elevation myocardial infarction (MI), and non-ST-elevation MI. They also provide new recommendations for: antiplatelet and anticoagulant therapy, alternative antithrombotic therapy regimens, in-hospital and out-of-hospital cardiac arrest, technical aspects of invasive strategies, multivessel disease in patients presenting in cardiogenic shock, multivessel disease in haemodynamically stable patients undergoing primary percutaneous coronary intervention, comorbid conditions, long-term management, and patient perspectives. The issue continues with the Special article ‘Perivascular adipose tissue as a source of therapeutic targets and clinical biomarkers: a clinical consensus statement from the European Society of Cardiology Working Group on Coronary Pathophysiology and Micro-circulation’ by Charalambos Antoniades from the University of Oxford in the UK, and colleagues.2 The authors point out that obesity is a modifiable cardiovascular risk factor, but adipose tissue (AT) depots in humans are anatomically, histologically, and functionally heterogeneous.3–8 For example, visceral AT is a pro-atherogenic secretory AT depot, while subcutaneous AT represents a more classical energy storage depot. Perivascular adipose tissue (PVAT) regulates vascular biology via paracrine cross-talk signals. In this position paper, the state-of-the-art knowledge of various AT depots is reviewed providing a consensus definition of PVAT around the coronary arteries, as the AT surrounding the artery up to a distance from its outer wall equal to the luminal diameter of the artery. Special focus is given to the interactions between PVAT and the vascular wall that render PVAT a potential therapeutic target in cardiovascular diseases. This consensus statement also discusses the role of PVAT as a clinically relevant source of diagnostic and prognostic biomarkers of vascular function, which may guide precision medicine in atherosclerosis, hypertension, heart failure, and other cardiovascular diseases. In this article, its role as a ‘biosensor’ of vascular inflammation is highlighted with description of recent imaging technologies that visualize PVAT in clinical practice, allowing non-invasive quantification of coronary inflammation and the related residual cardiovascular inflammatory risk, guiding deployment of therapeutic interventions. Finally, the current and future clinical applicability of artificial intelligence and machine learning technologies is reviewed that integrate PVAT information into prognostic models to provide clinically meaningful information in primary and secondary prevention. In a Fast Track Clinical Research article entitled ‘Intravascular imaging during percutaneous coronary intervention: temporal trends and clinical outcomes in the USA’, Reza Fazel from the Beth Israel Deaconess Medical Center in Boston, MA, USA, and colleagues point out that prior trials have demonstrated that intravascular imaging (IVI)-guided percutaneous coronary intervention (PCI) results in less frequent target lesion revascularization and major adverse cardiovascular events (MACEs) compared with standard angiographic guidance.9 The uptake and associated outcomes of IVI-guided PCI in contemporary clinical practice in the USA remain unclear. In this retrospective cohort study of Medicare beneficiary data from 1 January 2013 through 31 December 2019 were assessed temporal trends and comparative outcomes of IVI-guided PCI as compared with PCI with angiography guidance alone. The primary outcomes were 1-year mortality and MACE, defined as the composite of death, MI, repeat PCI, or coronary artery bypass graft surgery. Secondary outcomes were MI or repeat PCI at 1 year. Multivariable Cox regression was used to estimate the adjusted association between IVI guidance and outcomes. Falsification endpoints (hospitalized pneumonia and hip fracture) were used to assess potential unmeasured confounding. The study population included about 1 190 000 patients undergoing PCI (38.0% female, 89.8% White, 65.1% with MI). Overall, IVI was used in 10.5% of the PCIs, increasing from 9.5% in 2013 to 15.4% in 2019. IVI use during PCI was associated with significantly lower adjusted hazard rates (aHR) of 1-year mortality (aHR 0.96), MI (aHR 0.97), repeat PCI (aHR 0.74), and MACE (aHR 0.85). There was no association with the falsification endpoint of hospitalized pneumonia (aHR 1.02) or hip fracture (aHR 1.02). The authors conclude that among Medicare beneficiaries undergoing PCI, use of IVI has increased over the previous decade but remains relatively infrequent. IVI-guided PCI is associated with lower risk-adjusted mortality, acute MI, repeat PCI, and MACE. The contribution is accompanied by an Editorial by Ziad Ali and Doosup Shin from the St. Francis Hospital in Brooklyn, NY, USA.10 The authors conclude that the burden of evidence in favour of IVI-guided PCI is reaching critical mass, especially with multiple major randomized controlled trials planned for presentation this year. In this regard, the study by Fazel et al., highlighting the impact of IVI in the real world, makes the glass at least half full. Cardiogenic shock (CS) remains a challenging clinical condition.11–13 Dipeptidyl peptidase 3 (DPP3) is a protease involved in the degradation of angiotensin II, which disturbs peripheral blood pressure regulation and compromises left ventricular function. In a Fast Track Clinical Research article entitled ‘Dipeptidyl peptidase 3 plasma levels predict cardiogenic shock and mortality in acute coronary syndromes’, Florian Wenzl from the University of Zurich in Switzerland, and colleagues examined the relationship of circulating DPP3 (cDPP3) with CS and mortality in patients presenting with ACS.14 Plasma cDPP3 levels were assessed at baseline and 12–24 h after presentation in patients with ACS prospectively enrolled into the multi-centre SPUM-ACS study (n = 4787). Circulating DPP3 levels were associated with in-hospital CS when accounting for established risk factors including the ORBI risk score (per log-2 increase, HR 1.38, P = .021). cDPP3 was an independent predictor of mortality at 30 days (HR 1.87, P < .001) and at 1 year (HR 1.61, P < .001) after adjustment for established risk factors and GRACE 2.0 score. Compared to values within the normal range, persistently elevated cDPP3 levels at 12–24 h were associated with increased 30-day mortality risk (HR 13.42, P < .001) and increased 1-year mortality risk (HR 5.79, P < .001). Results were consistent across various patient subgroups (Figure 1). Circulating dipeptidyl peptidase 3 (cDPP3) was identified as a novel marker of cardiogenic shock (CS) and increased mortality risk in patients with acute coronary syndromes (ACS). Upon ischaemic cell death, the intracellular aminopeptidase DPP3 is released in the circulation where it cleaves angiotensin II (ATII) and exerts negative inotropic effects on the left ventricle. Circulating DPP3 levels were measured at presentation and after 12–24 h in patients enrolled into the multi-centre prospective SPUM-ACS study. High baseline levels of cDPP3 were independently associated with in-hospital CS, mortality risk at 30 days, and mortality risk at 1 year beyond established risk factors. Patients with persistently high cDPP3 levels at 12–24 h displayed substantially increased 30-day and 1-year mortality risk, whereas normalization of initially high cDDP3 levels was associated with a decrease in mortality risk. In a subcohort of patients undergoing cardiac magnetic resonance imaging (MRI), cDPP3 trajectories were associated with infarct size at 30 days of follow-up. Circulating DPP3 provides prognostic information beyond established risk factors in patients with ACS.14 The authors conclude that this study identifies cDPP3 as a novel marker of CS and increased mortality in patients with ACS. Circulating DPP3 offers prognostic information beyond established risk factors and improves early risk assessment. This manuscript is accompanied by an Editorial by Janine Pöss, Holger Thiele, and Petra Büttner from the Heart Center Leipzig at University of Leipzig and Leipzig Heart Institute in Germany.15 The authors highlight that it will be crucial to investigate whether inhibition of cDPP3 improves haemodynamics and outcomes in patients with CS. In an acute heart failure mouse model and a sepsis-induced rat model, treatment with the specific cDPP3 antibody procizumab in an early phase improved haemodynamic and cardiac function, with a reduction in oxidative stress and/or inflammation. A first-in-human study with this agent is planned: the results will shed more light on this highly exciting topic. The present acute MI (AMI) rule-out strategies are challenged by the late temporal release of cardiac troponin.16–20 Copeptin is a non-specific biomarker of endogenous stress and rises early in AMI, covering the early period where troponin is still normal. In a Clinical Research article entitled ‘Accelerated ­rule-out of acute myocardial infarction using prehospital copeptin and in-hospital troponin: the AROMI study’, Claus Kjær Pedersen from the Aarhus University Hospital in Denmark, and colleagues indicate that an accelerated dual-marker rule-out strategy combining prehospital copeptin and in-hospital high-sensitivity troponin T could reduce length of hospital stay and thus the burden on the health-care systems worldwide.21 The AROMI trial aimed to evaluate whether the accelerated dual-marker rule-out strategy could safely reduce length of stay in patients discharged after early rule-out of AMI. Patients with suspected AMI transported to hospital by ambulance were randomized 1:1 to either accelerated rule-out using copeptin measured in a prehospital blood sample and high-sensitivity troponin T measured at arrival to hospital or to standard rule-out using a 0 h/3 h rule-out strategy. The AROMI study included 4351 patients with suspected AMI. The accelerated dual-marker rule-out strategy reduced mean length of stay by 0.9 h in patients discharged after rule-out of AMI and was non-inferior regarding 30-day major adverse cardiac events when compared to standard rule-out (absolute risk difference −0.4%; P-value for non-inferiority = 0.013). Pederson et al. conclude that accelerated dual marker rule-out of AMI, using a combination of prehospital copeptin and first-in-hospital high-sensitivity troponin T, reduces length of hospital stay without increasing the rate of 30-day major adverse cardiac events as compared to using a 0 h/3 h rule-out strategy. The contribution is accompanied by an Editorial by Goaris Aarts, Niels van Royen, and Cyril Camaro from the Radboud University Medical Centre in Nijmegen, the Netherlands.22 The authors note that improvement of the diagnostic pathway of chest pain patients could reduce emergency department overcrowding. Efficiency can be improved in both the pre-hospital triage and the in-hospital evaluation, so we must pursue a combined approach, reducing the number of chest pain patients in the hospital and reducing the time patients spend at the hospital. The recently introduced 0 h/1 h algorithm has permitted rapid rule-out of AMI in hospital. The use of pre-hospital retrieved copeptin in a −1 h/0 h strategy can further reduce the length of stay. Even a 1 h reduction, as shown in the AROMI study, can have massive implications on costs and availability of emergency care services, simply by the sheer number of patients. Finally, rapid rule-out of AMI outside the hospital is on the horizon, and the results of the AROMI study have certainly brought us closer. In one-third of patients with ACS, thrombosis occurs despite an intact fibrous cap (IFC) (IFC-ACS, ‘plaque erosion’). In a Translational Research article entitled ‘Toll-like receptor 2, hyaluronan, and neutrophils play a key role in plaque erosion: the OPTICO–ACS study’, Denitsa Meteva from the Charité – Universitätsmedizin Berlin in Germany, and colleagues remind us that recent studies emphasize neutrophils as the immediate inflammatory response in this pathology, but their exact molecular activation patterns are still poorly understood and may represent future therapeutic targets.23 Thirty-two patients with IFC-ACS and matched patients with ACS with ruptured fibrous cap (RFC) (RFC-ACS) from the OPTICO–ACS study were included, and blood samples were collected from the local site of the culprit lesion and the systemic circulation. Neutrophil surface marker expression was quantified by flow cytometry. Neutrophil cytotoxicity towards endothelial cells was examined in an ex vivo co-culture assay. Secretion of active matrix metalloproteinase 9 (MMP9) by neutrophils was evaluated using zymography in supernatants and in plasma samples. Optical coherence tomography (OCT)-embedded thrombi were used for immunofluorescence analysis. Toll-like receptor 2 (TLR2) expression was higher on neutrophils from IFC-ACS than RFC-ACS patients. TLR2 stimulation increased the release of active MMP9 from local IFC-ACS-derived neutrophils, which also aggravated endothelial cell death independently of TLR2. Thrombi of IFC-ACS patients exhibited more hyaluronidase 2 with concomitant increase in local plasma levels of hyaluronic acid, a TLR2 ligand. The authors conclude by noting that the current study provides first-in-human evidence for distinct TLR2-mediated neutrophil activation in IFC-ACS, presumably triggered by elevated soluble hyaluronic acid (Figure 2). Together with disturbed flow conditions, neutrophil-released MMP9 might be promoting endothelial cell loss-triggered thrombosis and therefore providing a potential future target for a phenotype-specific secondary therapeutic approach in IFC-ACS. The manuscript is accompanied by an Editorial by Grégory Franck from the Université Paris Cité and Université Sorbonne Paris Nord in France, and colleagues.24 Franck note that understanding the precise cascade of events leading to plaque erosion is imperative for identifying potential therapeutic targets. By describing a novel interaction between thrombus, plaque composition, and a specific innate immune response, the study by Meteva et al. sheds new light on this possible cascade. By recognizing the unique characteristics of thrombi associated with plaque erosion, the study highlights the importance of future interventions tailored specifically for this subset of ACS patients. Continued research in this area holds the potential to improve the understanding, management, and treatment of IFC-ACS, ultimately reducing the burden of this manifestation. TLR2, Toll-like receptor 2; HA, hyaluronic acid; MMP9, matrix metalloproteinase 9; HYAL2, hyaluronidase 2.23 As noted above RFC and erosion of IFC are the two predominant mechanisms causing ACS.25 In a Translational Research article entitled ‘Culprit plaque morphology determines inflammatory risk and clinical outcomes in acute coronary syndrome’, Teresa Gerhardt from the Deutsches Herzzentrum der Charité in Berlin, Germany notes that it is uncertain whether clinical outcomes are different following RFC-ACS vs. IFC-ACS and whether this is affected by a specific inflammatory response.26 This analysis included 398 consecutive ACS patients, of whom 62% had RFC-ACS and 25% had IFC-ACS. The primary endpoint was a composite of cardiac death, recurrent ACS, hospitalization for unstable angina, and target vessel revascularization at 2 years [major adverse cardiovascular events (MACE)]. Inflammatory profiling was performed at baseline and after 90 days. Patients with IFC-ACS had lower rates of MACE than those with RFC-ACS (14.3% vs. 26.7%, P = 0.02). In 368-plex proteomic analyses, patients with IFC-ACS showed lower inflammatory proteome expression compared with those with RFC-ACS, including interleukin-6 and proteins associated with the response to interleukin-1β. Circulating plasma levels of interleukin-1β decreased from baseline to 3 months following IFC-ACS (P < 0.001) while they remained stable following RFC-ACS (P = 0.25). Interleukin-6 levels decreased in patients with RFC-ACS free of MACE (P = 0.01) but persisted high in those with MACE. The authors point out that this study demonstrates a distinct inflammatory response and a lower risk of MACE following IFC-ACS. These findings advance our understanding of inflammatory cascades associated with different mechanisms of plaque disruption and provide hypothesis-generating data for personalized anti-inflammatory therapeutic, a strategy that merits evaluation in future clinical trials. The contribution is accompanied by an Editorial by Steven E. Nissen from the Cleveland Clinic Coordinating Center for Clinical Research, USA.27 The author note that the current study represents an extraordinary effort and a valuable preliminary study of plaque morphology in AMI. However, cautious and tempered interpretation is required. The current study is most useful as a ‘hypothesis-generating’ scientific study of plaque morphology and inflammatory markers in ACS but it does not provide a reliable roadmap to guide treatment of patients after an acute event. Further observational studies should compare inflammatory biomarkers and the frequency of hard MACE events in patients with differing plaque morphologies matched for similar characteristics including infarct size. The editors hope that this issue of the European Heart Journal will be of interest to its readers. Dr. Crea reports speaker fees from Abbott, Amgen, Astra Zeneca, BMS, Chiesi, Daiichi Sankyo, Menarini outside the submitted work. With thanks to Amelia Meier-Batschelet, Johanna Huggler, and Martin Meyer for help with compilation of this article.