The expanding spectrum of acute coronary syndromes: from STEMI to coronary dissection and Takotsubo syndrome

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. Acute coronary syndromes initially have involved ST-segment myocardial infarction (STEMI), non-STEMI, and unstable angina.1 However, recently it became clear that many patients who fulfil the criteria of an acute coronary syndrome such as chest pain, ECG changes, and a positive troponin actually have other conditions such as Takotsubo syndrome,2 coronary dissection,3 myocarditis, or even the mysterious MINOCA (myocardial infarction with non-obstructive coronary arteries)4,5 syndrome. Some of these, such as Takotsubo syndrome, may actually be manifestations of a brain disease.6 Indeed, Takotsubo syndrome is often triggered by emotional or physical stress.7 Hence, severe activation of the sympathetic nervous system with catecholamine and endothelin release has been attributed to a dysfunctional limbic system.8,9 This hypothesis has now been tested and is reported in the article entitled ‘Altered limbic and autonomic processing supports brain–heart axis in Takotsubo syndrome’ by Christian Templin et al. from the University Hospital Zurich in Switzerland.10 The authors hypothesized that brain regions responsible for autonomic integration and/or limbic processing might be involved, and tested this using functional brain magnetic resonance imaging (MRI) in 15 subjects with Takotsubo syndrome and 39 healthy controls. They found that parasympathetic- and sympathetic-associated subnetworks both showed reduced resting state functional connectivity in Takotsubo syndrome patients. Important brain regions constituting the subnetwork included the amygdala, hippocampus, and insula, as well as cingulate, parietal, temporal, and cerebellar regions. Additionally, the default mode network as well as limbic regions in the whole-brain analysis demonstrated reduced resting state functional connectivity in Takotsubo syndrome, including the hippocampus, and parahippocampal and medial prefrontal regions. Thus, here for the first time they showed that hypoconnectivity of central brain regions is associated with autonomic dysfunctions and dysregulation of the limbic system in Takotsubo syndrome, suggesting that autonomic–limbic dysfunction might play a crucial role in the pathophysiology of Takotsubo syndrome. Another novel acute coronary syndrome is spontaneous coronary artery dissection which was underdiagnosed and poorly understood for decades, but increasingly recognized today, particularly in women.11 In their FAST TRACK ‘Canadian spontaneous coronary artery dissection cohort study: in-hospital and 30-day outcomes’ Jacqueline Saw et al. from the University of British Columbia in Vancouver, Canada assessed the natural history of spontaneous coronary artery dissection in a multicentre, prospective, observational study involving 750 patients.12 The mean age of the patients was 52 years, 89% were women, of which half were post-menopause, and 88% were Caucasian. Emotional stress before the event was reported in half, and physical stress in a third. Predisposing conditions included fibromuscular dysplasia, systemic inflammatory diseases, peripartum, and connective tissue disorders. The vast majority were treated conservatively, while some underwent percutaneous coronary intervention and a few had coronary artery bypass surgery. In-hospital composite major events occurred in 9%. Of note, peripartum dissection patients had higher in-hospital events. Indeed, peripartum dissection and connective tissue disease were independent predictors of 30-day major adverse cardiovascular events (MACE). Thus, spontaneous coronary artery dissection predominantly affects women presenting with myocardial infarction. Despite the majority of patients being treated conservatively, survival is good. However, significant complications occurred within 30 days. These clinically important findings are further discussed in an Editorial by David Adlam from the University of Leicester in the UK.13 Although modern management of STEMI as recommended in the ESC Guidelines14 has markedly improved the outcome of these patients, there remain open questions. Indeed, pre-hospital administration of P2Y12 antagonists in STEMI is supported by guidelines in spite of the lack of definite evidence for its benefit.15–17 In their article entitled ‘Pretreatment with P2Y12 receptor antagonists in ST-elevation myocardial infarction: a report from the Swedish Coronary Angiography and Angioplasty Registry’,18 Elmir Omerovic et al. from the Wallenberg laboratory at Sahlgrenska University in Sweden used data from the Swedish Coronary Angiography and Angioplasty Registry to address this. Of the 44 804 STEMI patients, 58% were treated with clopidogrel, 35% with ticagrelor, and 5% with prasugrel. The vast majority (84.5%) were pre-treated. At 30 days, mortality was 6% and 0.6% had a stent thrombosis. Pre-treatment was not associated with better survival (Figure 1), nor did it reduce occlusion of the infarct-related artery or stent thrombosis. Also, risk of in-hospital bleeding was similar. These important findings are put into context in an informative Editorial by Jeremie Abtan from the Hôpital Bichat – Claude-Bernard in Paris, France.19 Illustration of potential benefits and danger with pretreatment with P2Y12, and the pretreatment-associated propensity score adjusted risks of the primary and secondary endpoints among the 44 804 patients who underwent acute coronary angiography due to ST-elevation myocardial infarction in Sweden between 1 January 2005 and 1 November 2016 (from Redfors B, Dworeck C, Haraldsson I, Angerås O, Odenstedt J, Ioanes D, Petursson P, Völz S, Albertsson P, Råmunddal T, Persson J, Koul S, Erlinge D, Omerovic E. Pretreatment with P2Y12 receptor antagonists in ST-elevation myocardial infarction: a report from the Swedish Coronary Angiography and Angioplasty Registry. See pages 1202–1210). Particularly in STEMI, the time to restoration of coronary blood flow is vital for survival and overall outcome.20 In their article ‘Association between time of hospitalization with acute myocardial infarction and in-hospital mortality’ Jianhua Wu and colleagues from the University of Leeds in the UK studied the association between time of hospitalization and in-hospital mortality in 615 035 patients with acute coronary syndromes admitted to 243 hospitals.21 In-hospital deaths occurred in 9%. At night, patients with NSTEMI were more frequently co-morbid, and those with STEMI had longer symptom onset to reperfusion times. For STEMI, in-hospital mortality was highest between 20.00 and 23.59 h compared with 00.00 to 03.59 h, and for NSTEMI it was highest between 12.00 and 15.59 h. However, these differences were only apparent in the earlier years and were attenuated by adjustment for demographics, co-morbidities, and clinical presentation. Differences were not statistically significant after adjustment for the acute clinical treatment provided. Thus, today there is little evidence to support an association between time of hospitalization and in-hospital mortality for acute myocardial infarction. The variation in in-hospital mortality among hospitals may be explained by case mix and the treatments used. The data are further discussed in an Editorial by Gregg W. Stone from the Columbia University Medical Center in New York, USA.22 Once the patient is in the cathlab, the access site needs to be decided. While traditionally the femoral access has been chosen, the radial access showed advantages in a number of trials and registries.23,24 In the Minimizing Adverse Haemorrhagic Events by TRansradial Access Site and Systemic Implementation of angioX (MATRIX) trial, adults with acute coronary syndrome undergoing coronary intervention who were allocated to radial access had a lower risk of bleeding, acute kidney injury, and all-cause mortality as compared with those allocated to femoral access. In their article ‘Association of acute kidney injury and bleeding events with mortality after radial or femoral access in patients with acute coronary syndrome undergoing invasive management: secondary analysis of a randomized clinical trial’ Peter Jüni and colleagues from the University of Toronto in Canada remind us that the mechanism of the mortality benefit of radial access still remains unclear.25 In the MATRIX trial, there were large relative risk reductions in mortality for radial compared with femoral access for the transition from acute kidney injury to death, with a hazard ratio of 0.55, and for the pathway from coronary intervention to acute kidney injury to death with a hazard ratio of 0.49 (Figure 2). Conversely, there was little evidence for a difference between radial and femoral groups for the transition from bleeding to death and the pathway from coronary intervention to bleeding to death. Thus, they conclude that the prevention of acute kidney injury appeared predominantly responsible for the mortality benefit of radial over femoral access in the MATRIX trial. These provocative findings are put into context in an Editorial by Gilles Montalescot from the Pitié-Salpêtrière University Hospital in Paris, France.26 Pathways according to randomization to access site: risk reduction and numbers needed to treat. The risk per 10 000 patients in each arm is estimated using the absolute risk reduction estimated from the competing risk model (Figure 4). Black bars relate to pathways leading to death, while grey boxes relate to non-fatal pathways. Bars on the left side favour radial access and bars on the right side favour femoral access. AKI: acute kidney injury; CA/PCI: coronary angiography and/or percutaneous coronary intervention; CI: confidence interval; P1 to P9: pathways 1 to 9 (from Rothenbühler M, Valgimigli M, Odutayo A, Frigoli E, Leonardi S, Vranckx P, Turturo M, Moretti L, Amico F, Uguccioni L, Contarini M, Gómez-Hospital JA, Mainar V, Creaco M, Petronio AS, Cremonesi A, Tamburino C, Fresco C, Bonmassari R, Díaz Fernández JF, Romagnoli E, Beyersmann J, Heg D, Jüni P. Association of acute kidney injury and bleeding events with mortality after radial or femoral access in patients with acute coronary syndrome undergoing invasivemanagement: secondary analysis of a randomized clinical trial, See pages 1226–1232). This issue also contains a Current Opinion on ‘The learning health system: trial design and participant consent in comparative effectiveness research’ by Mark W.I. Webster from the Auckland City Hospital in New Zealand.27 Most patients undergoing Western medical treatment believe that the important aspects of their care are underpinned by solid scientific evidence. In reality, clinical practice is not strongly evidence based, and treatment choices are often guided by intuition rather than data. In a recent review, only 11% of recommendations were supported by level A evidence, with half based upon expert opinion.28 The evidence deficit is likely to be greater as many aspects of day-to-day care influencing patient outcomes have not been rigorously evaluated and are not considered in the guidelines. There has been recent enthusiasm for developing ‘learning health systems’ as an important strategy to improve evidence-based healthcare. Typically, electronic data from patient records and other databases are collated and analysed as part of quality improvement initiatives, and the findings used to inform continuous improvement. Despite the potential to extend such studies to large, multisite data sets, and new sources of information such as wearable devices, there will always be limitations on the inferences that can be drawn from observational data. This issue is complemented by two Discussion Forum contributions. In a first one entitled ‘Three questions regarding the 2017 ESC STEMI guidelines’, Heiko Baschnegger and colleagues from the Klinikum der Universitat München in Germany comment on the manuscript ‘2017 ESC Guidelines for the management of acute myocardial infarction in patients’.14,29 The authors of the article that is referred to respond in their own comment. Ibanez et al. respond in kind with their comment.30 The editors hope that readers of this issue of the European Heart Journal will find it of interest. With thanks to Amelia Meier-Batschelet for help with compilation of this article.