Focus on mechanisms and management of acute and non-acute ischaemic syndromes

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on ischaemic heart disease and cardio-oncology contains a Special Article entitled ‘Cardio-oncology rehabilitation and exercise: evidence, priorities, and research standards from the ICOS-CORE working group’ by Scott C. Adams from Cancer Fatigue Services in Toronto, Canada, and colleagues. Cardiac rehabilitation plays an important role in the management of cardiovascular diseases.1–4 This Special Article reviews the current state of literature on the effects of cardio-oncology rehabilitation and exercise (CORE) programmes and provides a roadmap for improving the evidence base to support the implementation of CORE.5 There is an urgent need to reinforce and extend the evidence informing the cardiovascular care of cancer survivors. CORE is an attractive model that is potentially scalable to improve the cardiovascular health of cancer survivors as it leverages many of the existing frameworks developed through decades of delivery of cardiac rehabilitation. However, there are several challenges within this burgeoning field, including limited evidence of the efficacy of this approach in patients with cancer. In this article, a multidisciplinary team of international experts highlights priorities for future research in this field and recommends standards for the conduct of research. Despite advances in research and patient management, mechanisms of acute coronary syndromes (ACS) are not yet fully understood.6–11 In a State of the Art Review article entitled ‘Acute coronary syndromes: mechanisms, challenges, and new opportunities’, Simon Kraler from the University of Zurich, Switzerland, and colleagues provide an update on the mechanisms of acute ACS, delineate the role of previously underappreciated contributors, discuss sex-specific differences, and explore novel tools for contemporary and personalized management of patients with ACS.12 The vast majority of cases of ACS arise from either plaque rupture or erosion, but other mechanisms, including calcific nodules, embolism, spontaneous coronary artery dissection, coronary spasm, and microvascular dysfunction, can also cause ACS. This ACS heterogeneity necessitates a paradigm shift in its management that extends beyond the binary interpretation of electrocardiographic and biomarker data. Indeed, given the evolution in the global risk factor profile, the increasing importance of previously underappreciated mechanisms, the evolving appreciation of sex-specific disease characteristics, and the advent of rapidly evolving technologies, a precision medicine approach is warranted. Beyond mechanistic insights, the review examines evolving imaging techniques, biomarkers, and regression- and machine learning-based approaches for the diagnosis and risk stratification of ACS, along with their implications for future ACS management. A more individualized approach to patients with ACS is advocated, emphasizing the need for innovative studies on emerging technologies, including artificial intelligence, which may collectively facilitate clinical decision-making within a more mechanistic framework, thereby personalizing patient care and potentially improving long-term outcomes. Identifying myocardial infarction (MI) is fundamental to cardiology practice, and troponin measurement plays a key role.13–16 Having a universally agreed definition of MI is so important that it is one of just two topics in cardiology where all major international societies collaborate to publish a consensus document called the universal definition of MI. In a Viewpoint article entitled ‘Age-specific troponin thresholds: considerations for the fifth universal definition of myocardial infarction’, Mark Coyle and John W. McEvoy from Galway University Hospital and University of Galway School of Medicine in Ireland, state that they believe that the use of age-specific high-sensitivity cardiac troponin upper reference limits (URLs) to define myocardial injury could offer major clinical advantages (Figure 1).17 A major update in the fourth universal definition of MI from 2018 was the statement that ‘sex-specific 99th percentile URLs are recommended’ when determining myocardial injury using high-sensitivity cardiac troponin assays. This change stemmed from numerous reports of important differences in 99th percentile high-sensitivity cardiac troponin URLs by sex. Sex-specific URLs are consequently core to contemporary MI diagnosis, since the universal definition of MI requires both acute myocardial injury (determined using serial troponins) and acute myocardial ischaemia (determined using either symptoms, ECG, or imaging) for a diagnosis. While the authors of the fourth universal definition of MI cited data suggesting differences in 99th percentile troponin URLs in adults aged >60 years, they wrote, ‘however, at present, age-dependent cut-off points are not recommended for clinical use’. This specific choice of wording appears to leave open the possibility of reconsidering age-specific URLs with the accrual of new data. Graphical Abstract17 The place of beta-blocker treatment in stable revascularized coronary patients with uncomplicated prior MI without reduced left ventricular ejection fraction (LVEF) is debated. In a Fast Track Clinical Research article entitled ‘Beta-blocker interruption effects on blood pressure and heart rate after myocardial infarction: the AβYSS trial’, Niki Procopi from University Hospitals Pitié Salpêtrière in Paris, France, and colleagues aim to report the effects of beta-blocker interruption on blood pressure (BP) and heart rate (HR) in the AβYSS trial where patients were randomized to interruption or continuation of beta-blocker treatment after an MI.18 Changes in HR and BP from baseline to post-randomization are reported using a linear mixed repeated model, in the 3698 patients of the AβYSS trial with a median follow-up of 3.0 years. Additionally, changes in HR and BP and the impact on the primary endpoint (death, MI, stroke, and hospitalization for a cardiovascular reason) in the pre-specified subgroups of patients with or without a history of hypertension were assessed using linear mixed repeated and adjusted Cox proportional hazards model, respectively. Beta-blocker interruption was associated with a significant increase in systolic BP (+3.7 mmHg, P < .001), diastolic BP (+3.3 mmHg, P < .001), and resting HR (+10 bpm, P < .001) at 6 months that persisted over the duration of follow-up despite an increase in antihypertensive drugs in the beta-blocker interruption group. The effects were observed in both hypertensive (43% of the population) and non-hypertensive patients. Hypertensive patients were at higher risk of events (26% vs. 19%) as compared with patients without hypertension (adjusted hazard ratio 1.18, P = .03). Patients with hypertension had a particularly marked increase in the primary endpoint (risk difference 5.02%, P = .014) when randomized to beta-blocker interruption (Figure 2). Structured Graphical Abstract18 The authors conclude that interruption of beta-blocker treatment after an uncomplicated MI leads to a sustained increase in BP and HR, with potentially deleterious effects on outcomes, especially in patients with a history of hypertension. The manuscript is accompanied by an Editorial by John G.F. Cleland from the University of Glasgow in the UK.19 The author notes that in the aftermath of an MI, patients are at increased risk of arrhythmias, recurrent MI, and heart failure. The best strategy is to initiate all current guideline-recommended therapies in the immediate aftermath of an MI, with clinical re-evaluation 6–12 weeks later. A substantial proportion of patients will have hypertension. The most effective treatment for hypertension after MI is uncertain. It may or may not be a beta-blocker.20 Neoatherosclerosis is a leading cause of late (>1 year) stent failure following drug-eluting stent (DES) implantation. The role of biodegradable polymer vs. durable polymer DES on long-term occurrence of neoatherosclerosis remains unclear. In a Fast Track Clinical Research article entitled ‘Long-term effect of biodegradable vs. durable polymer everolimus-eluting stents on neoatherosclerosis in ST-segment elevation myocardial infarction: the CONNECT trial’, Masanori Taniwaki from Tokorozawa Heart Center in Saitama, Japan, and colleagues test the superiority of biodegradable against durable polymer current-generation thin-strut everolimus-eluting stents (EES) by assessing the frequency of neoatherosclerosis 3 years after primary percutaneous coronary intervention (pPCI) among patients with ST-segment elevation myocardial infarction (STEMI).21 The randomized controlled, multicentre (Japan and Switzerland) CONNECT trial (NCT03440801) randomly (1:1) assigned 239 STEMI patients to pPCI with a biodegradable polymer EES or a durable polymer EES. The primary endpoint was the frequency of neoatherosclerosis assessed by optical coherence tomography (OCT) at 3 years. Neoatherosclerosis was defined as fibroatheroma or fibrocalcific plaque or macrophage accumulation within the neointima. Among 239 STEMI patients randomized, 236 received pPCI with stent implantation (119 biodegradable polymer EES; 117 durable polymer EES). A total of 178 patients underwent OCT assessment at 3 years. Neoatherosclerosis did not differ between the biodegradable polymer EES (11.4%) and durable polymer EES (13.3%, P = .69). There were no differences in the frequency of fibroatheroma (biodegradable polymer EES 9.1% vs. durable polymer EES 11.1%, P = .66) or macrophage accumulation (biodegradable polymer EES 4.5% vs. durable polymer EES 3.3%, P = .68), and no fibrocalcific neoatherosclerosis was observed. Rates of target lesion failure did not differ between groups (biodegradable polymer EES 5.9% vs. durable polymer EES 6.0%, P = .97). The authors conclude that the use of biodegradable polymer EES for pPCI in patients presenting with STEMI is not superior to a durable polymer EES regarding frequency of neoatherosclerosis at 3 years. The manuscript is accompanied by an Editorial by William Wijns and Shengxian Tu from the University of Galway in Ireland and Shanghai Jiao Tong University in China.22 The authors note that the truly striking finding of the study is mentioned in the discussion section and details are given in the supplementary data of the study. There was a strong effect (P = .004) of high-intensity treatment with statins on neo-atherosclerosis at 3 years: 8.5% with high-intensity statin therapy vs. 27.8% without, irrespective of randomization to either stent study arm. The high percentage of patients on high-intensity statin therapy (∼80% at 3 years with no significant difference between stent groups) largely explains the much lower than expected frequency of neo-atherosclerosis in the overall study. This observation illustrates a common limitation of contemporary device-based trials, whereby the study hypothesis entertains the illusion that anything good or bad that happens to PCI patients can be attributed to minute differences in technical features of one or another device that was implanted several years ago. In the current era of good to excellent PCI outcomes with use of one of the many best-in-class DES, pathophysiological mechanisms of the naturally occurring disease are overwhelming potential subtle differences in device-related side effects. As a result, both DES studied in this trial are providing outstanding results, in the context of contemporary best of medical care. There is growing interest in angina/ischaemia and non-obstructive coronary arteries (ANOCA/INOCA). Exercise electrocardiography stress testing (EST) may be diagnostically useful in patients with ANOCA/INOCA. In a Rapid Communications article entitled ‘Exercise electrocardiography stress testing in suspected angina and non-obstructive coronary arteries’, Robert Sykes from NHS Golden Jubilee National Hospital in Glasgow, UK, and colleagues assess the diagnostic accuracy of exercise EST for identifying endotypes (microvascular angina, vasospastic angina, or both) in a community-dwelling population with suspected ANOCA/INOCA according to invasive functional testing (coronary flow reserve, index of microvascular resistance, and acetylcholine vasomotor responses) as a reference.23 Outpatients referred for coronary computed tomography angiography (cCTA) in three regional hospitals in Scotland were prospectively screened. Exercise EST involved the Bruce treadmill protocol, with myocardial ischaemia defined as ≥0.1 mV ST-segment depression 60 ms from the J-point (ischaemic group). Participants with suspected ANOCA/INOCA underwent functional coronary angiography involving guidewire-based coronary thermodilution at rest and during adenosine hyperaemia and intracoronary infusion of acetylcholine. The Rose Angina Questionnaire and the Seattle Angina Questionnaire (SAQ) were prospectively recorded. A cohort of 163 participants (mean age 55 years, 63% women) underwent endotyping and follow-up (median 20.5 months). Compared with patients with negative EST, in patients with positive exercise EST, the SAQ angina stability was lower (worse) (48 vs. 55; P = .034). Following invasive endotyping, 51% participants had microvascular angina, 12% had vasospastic angina, and 8.6% had both. The response to exercise EST had moderate specificity (72%) to detect microvascular dysfunction (defined as coronary flow reserve <2.5, index of microvascular resistance ≥25, and microvascular spasm by acetylcholine) but low sensitivity (30%). The negative predictive value of the exercise EST for microvascular endotypes was high (range 0.814–0.941). The authors conclude that given the high negative predictive value, a cCTA/exercise EST strategy is diagnostically useful to rule-out microvascular endotypes in patients with suspected ANOCA/INOCA. Radiotherapy (RT) is known to reduce the rate of disease recurrence following breast-conserving surgery in patients with breast cancer, but also entails irradiation of the heart, which can lead to cardiotoxicity and vascular injury, specifically through sustained inflammation. In a Rapid Communications article entitled ‘Coronary inflammation and cardiovascular risk in breast cancer after radiotherapy’, Christos P. Kotanidis from the University of Oxford, UK, and colleagues explore the evolution of coronary inflammation and residual inflammatory risk 2 years after RT in women with breast cancer.24 It has previously been hypothesized that RT for breast cancer leads to inflammatory damage of the coronary arteries (due to direct radiation exposure of the heart) which results in higher future cardiovascular risk. In this Rapid Communication, the authors have now analysed coronary CT angiograms to assess coronary inflammation and calcium burden in women with breast cancer, before and 2 years after RT. Using validated advanced AI imaging techniques, they measured coronary inflammation utilizing the perivascular fat attenuation index (FAI) score and calculated the 8 year cardiac mortality risk using the AI-Risk prognostic model. These women had strikingly elevated coronary artery inflammation and unexpectantly AI-Risk at baseline, even before they received RT. Two years later, calcification in the coronary arteries increased, but both the extent of coronary inflammation and the inflammatory risk were significantly reduced, suggesting that the increased calcification was a sign of stabilization of atherosclerotic disease, rather than a sign of increased cardiovascular risk. There was no difference in the coronary inflammatory burden between the coronary arteries exposed and not exposed to RT. The authors conclude that the high inflammatory burden of the coronary arteries before RT may be driven by tumour-related systemic inflammatory signals, while treating the tumour with RT leads to reduced coronary inflammation (and higher coronary calcification as plaques are stabilized). This hypothesis-generating study may lead to a paradigm shift in cardio-oncology and will certainly trigger larger longitudinal studies to test the impact of RT on cardiovascular risk. The issue is also complemented by three Discussion Forum contributions. In a commentary entitled ‘Addressing sample overlap and meta-analysis imbalances in Mendelian randomization: a critical appraisal of protein targets for myocardial infarction’, Junhao Chen, Junxian Zhao, and Shi Fu from the Second Affiliated Hospital of Kunming Medical University and 920th Hospital of Joint Logistic Support Force in Yunnan, China, comment on the recent publication ‘Plasma proteome and incident myocardial infarction: sex-specific differences’ by Olga Titova from the Uppsala University in Sweden, and colleagues.25,26 Titova and colleagues respond in a separate contribution.27 This issue also contains a Discussion Forum reply entitled ‘Erythritol and xylitol and cardiovascular disease risk: a growing concern’ by Marco Witkowski from the German Heart Center of Charité in Berlin, Germany, and Stanley L Hazen from the Cleveland Clinic in Ohio, USA.28 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 Lindsay Washington, Johanna Huggler, Amelia Meier-Batschelet, and Martin Meyer for help with compilation of this article