Filippo Crea
For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue opens with the first President’s page by Prof. Thomas Lüscher entitled ‘From a group of friends to an esteemed institution: past successes and future challenges for the European Society of Cardiology’ in which the new President of the European Society of Cardiology (ESC) summarizes the key steps that have made ESC one of the largest and most prestigious medical societies in the world.1 He also highlights the main exciting goals that he will pursue during his presidency over the next two years. Then the Editor’s page entitled ‘European Heart Journal: a call to action’ in which the Editors of the European Heart Journal (EHJ) highlight the mission of the Journal, which is not only the dissemination of innovative scientific knowledge but also the promotion of best clinical practice.2 The Editors invite population, clinical, and translational scientists to submit their best manuscripts to EHJ highlighting the opportunities offered by the Journal. The Issue continues with three innovative European Society of Cardiology (ESC) Guidelines: the ‘2024 ESC Guidelines for the management of atrial fibrillation developed in collaboration with the European Association for Cardio-Thoracic Surgery (EACTS)’3, the ‘2024 ESC Guidelines for the management of chronic coronary syndromes’,3 and the ‘2024 ESC Guidelines for the management of peripheral arterial and aortic diseases’.4 The rest of the Issue focuses on arrhythmias and ischaemic heart disease. Ischaemic heart disease remains the number one killer in the world and major efforts are needed to reduce its devastating impact.5–9 In a State of the Art Review article entitled ‘Myocardial ischaemic syndromes: a new nomenclature to harmonize evolving international clinical practice guidelines’, William Boden from the Boston University School of Medicine in the United States, and colleagues note that since the 1960s for chronic stable manifestations of myocardial ischaemia, various classifications have emerged over time, often with conflicting terminology—e.g. ‘stable coronary artery disease’ (CAD), ‘stable ischaemic heart disease’, and ‘chronic coronary syndromes’ (CCS). While the 2019 European guidelines introduced CCS to impart symmetry with ‘acute coronary syndromes’ (ACS), the 2023 American guidelines endorsed the alternative term ‘chronic coronary disease’.10 An unintended consequence of these competing classifications is perpetuation of the restrictive terms ‘coronary’ and ‘disease’, often connoting only a singular obstructive CAD mechanism. It is now important to advance a more broadly inclusive terminology for both obstructive and non-obstructive causes of angina and myocardial ischaemia that fosters conceptual clarity and unifies dyssynchronous nomenclatures across guidelines. The authors therefore propose a new binary classification of ‘acute myocardial ischaemic syndromes’ and ‘non-acute myocardial ischaemic syndromes’, which comprises both obstructive epicardial and non-obstructive pathogenetic mechanisms, including microvascular dysfunction, vasospastic disorders, and non-coronary causes. They herein retain the accepted categories of acute coronary syndrome, ST-segment elevation myocardial infarction (MI), and non-ST-segment elevation MI, as important subsets for which revascularization is of proven clinical benefit, as well as new terms like ischaemia and MI with non-obstructive coronary arteries. Overall, such a more encompassing nomenclature better aligns, unifies, and harmonizes different pathophysiologic causes of myocardial ischaemia and should result in more refined diagnostic and therapeutic approaches targeted to the multiple pathobiological precipitants of angina pectoris, ischaemia, and infarction. Risk stratification and optimal management of atrial fibrillation (AF) remain major targets in cardiovascular medicine.11–18 In the Fast Track Clinical Research article entitled ‘Gender and contemporary risk of adverse events in atrial fibrillation’, Asgher Champsi from the University of Birmingham in the United Kingdom, and colleagues indicate that the role of gender in decision-making for oral anticoagulation in patients with AF remains controversial.19 The population cohort study used electronic healthcare records of more than 16 500 000 patients from UK primary care (2005–2020). Primary (composite of all-cause mortality, ischaemic stroke, or arterial thromboembolism) and secondary outcomes were analysed using Cox hazard ratios (HR), adjusted for age, socioeconomic status, and comorbidities. A total of about 79 000 patients with AF were included, aged 40–75 years, 36% women, no prior stroke, and no prescription of oral anticoagulants. During a total follow-up of 431 086 patient-years, women had a lower adjusted primary outcome rate with HR 0.89 vs. men (P < .001) and HR 0.87 after censoring for oral anticoagulation (P < .001). This was driven by lower mortality in women (HR 0.86; P < .001). No difference was identified between women and men for the secondary outcomes of ischaemic stroke or arterial thromboembolism, any stroke or any thromboembolism, and incident vascular dementia. Clinical risk scores were only modest predictors of outcomes, with CHA2DS2-VA (ignoring gender) superior to CHA2DS2-VASc for primary outcomes in this population (receiver operating characteristic curve area 0.651 vs. 0.639; P < .001) and no interaction with gender (P = .45) (Figure 1). The impact of gender on adverse events in patients with atrial fibrillation (AF) based on a population cohort study using electronic healthcare records from UK primary care (2005–20).19 The authors conclude that removal of gender from clinical risk scoring could simplify the approach to which patients with AF should be offered oral anticoagulation. The contribution is accompanied by an Editorial by Gregory YH Lip and Peter Brønnum Nielsen from the University of Liverpool and Konsta Teppo from the University of Turku in Finland.20 The authors highlight that when ischaemic stroke rates were higher in women compared with men one to two decades ago, and women were undertreated with OACs, the use of the CHA2DS2-VASc score made sense, performing better than a non-sex CHA2DS2-VASc (i.e. CHA2DS2-VA). In more contemporary years, when the sex difference in AF-related stroke risk is less evident, the use of CHA2DS2-VA may offer some degree of simplicity in initial decision-making for stroke prevention. However, rather than undue focus of risk stratification schemes for identifying the somewhat artificial high-, moderate-, or low-risk subgroups, we should promote the initial identification of ‘low-risk’ patients, given the limitations of all clinical risk scores. After all, patients do not fall into three ‘static’ stroke risk categories, especially since risk is dynamic in nature and many stroke risk factors (e.g. blood pressure) represent a continuum of risk. Given the limitations of clinical risk scores in predicting high-risk patients, more emphasis could perhaps be placed on initially identifying the low-risk patients, such that ‘the default is stroke prevention, unless they are low-risk’, with these ‘low-risk’ patients being those with a CHA2DS2-VA score of zero. Patients with high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI) are at increased risk of not only bleeding, but also ischaemic events.21,22 In a Clinical Research article entitled ‘Long-term outcomes of high bleeding risk patients undergoing percutaneous coronary intervention: a Korean nationwide registry’, Jeehoon Kang from the Seoul National University College of Medicine in the Republic of Korea, and colleagues aimed to determine the long-term relative risk of ischaemic and bleeding events in HBR patients.23 This study was a nationwide cohort study, based on the Korean National Health Insurance Review and Assessment Service database. Patients diagnosed with stable angina or acute coronary syndrome and those who underwent PCI in Korea between 2009 and 2018 were included in the analysis. According to the Academic Research Consortium HBR criteria, the total population was divided into HBR and non-HBR groups. The co-primary outcomes were major bleeding events and ischaemic (composite of cardiac death, myocardial infarction, and ischaemic stroke) events. Among a total of more than 325 000 patients who underwent PCI, 20% had HBR. During the follow-up period, HBR patients had a higher risk for major bleeding events (23.9% vs. 8.9%, P < .001) and ischaemic events (33.8% vs. 14.4%, P < .001). The HBR group also exhibited a greater risk of all-cause mortality (HR 3.73, P < .001). The authors conclude that among patients undergoing PCI, those with HBR are at increased long-term risk for both bleeding and ischaemic events, with a greater risk of mortality compared with non-HBR patients. This manuscript is accompanied by an Editorial by Marco Valgimigli and Antonio Landi from the Cardiocentro Ticino Institute, Ente Ospedaliero Cantonale (EOC) in Switzerland.24 The authors conclude that this study adds to the overarching body of literature emphasizing the long-term importance of bleeding risk assessment in patients undergoing PCI. Bleeding first rather than ischaemic risk assessment emerges as the new paradigm for maximizing the net benefit of antithrombotic treatments in HBR patients. The cardiological community used to value the ischaemic risk at the expense of the bleeding risk. Yet, the study by Kang et al. reinforces once more the concept that a Copernican revolution should occur and that the ischaemic risk evolves around the bleeding risk and not vice versa. In a Clinical Research article entitled ‘Atherosclerosis quantification and cardiovascular risk: the ISCHEMIA trial’, Nick Nurmohamed from Amsterdam UMC in the Netherlands, and colleagues sought to determine the prognostic value of coronary computed tomography angiography (CCTA)-derived atherosclerotic plaque analysis in ISCHEMIA.25 Atherosclerosis imaging quantitative computed tomography (AI-QCT) was performed on all available baseline CCTAs to quantify plaque volume, composition, and distribution. Multivariable Cox regression was used to examine the association between baseline risk factors (age, sex, smoking, diabetes, hypertension, ejection fraction, prior coronary disease, estimated glomerular filtration rate, and statin use), number of diseased vessels, atherosclerotic plaque characteristics determined by AI-QCT, and a composite primary outcome of cardiovascular death or MI over a median follow-up of 3.3 years. The predictive value of plaque quantification over risk factors was compared in an area under the curve (AUC) analysis. Analysable CCTA data were available from 3711 participants (79% with multivessel CAD). Amongst the AI-QCT variables, total plaque volume was most strongly associated with the primary outcome (adjusted HR 1.56; P = .001). The addition of AI-QCT plaque quantification and characterization to baseline risk factors improved the model’s predictive value for the primary outcome at 6 months (AUC 0.688 vs. 0.637; P = .006), at 2 years (AUC 0.660 vs. 0.617; P = .003), and at 4 years of follow-up (AUC 0.654 vs. 0.608; P = .002) (Figure 2). The findings were similar for the other reported outcomes. Study design and main outcomes of the current study. AI-QCT, atherosclerosis imaging quantitative computed tomography; AUC, area under the curve; CAD, coronary artery disease; CCTA, coronary computed tomography angiography; CV, cardiovascular; FU, follow-up; MI, myocardial infarction; NRI, net reclassification improvement.25 The authors conclude that in the ISCHEMIA trial, total plaque volume is associated with cardiovascular death or MI. In this highly diseased, high-risk population, enhanced assessment of the atherosclerotic burden using AI-QCT-derived measures of plaque volume and composition modestly improve event prediction. The contribution is accompanied by an Editorial by Noel Bairey Merz from the Cedars-Sinai Medical Center in Los Angeles, CA (USA).26 Bairey Merz notes that the ISCHEMIA trial’s Guidelines-directed medical treatment (GDMT) adherence protocol worked well and could be replicated in systems. What would these protocols cost? On average, investments in secondary prevention interventions can yield a return of $10 for every $1 invested. Utilization of AI might reduce the costs. As we look to the future of targeted secondary prevention of cardiovascular disease related to the development of deep learning image analysis platforms and novel therapeutics, let’s not forget to invest in what we already know and ensure we deploy GDMT and adherence enhancers first. Type 1 long QT syndrome (LQT1) is caused by pathogenic variants in the KCNQ1-encoded Kv7.1 potassium channels, which pathologically prolong ventricular action potential duration (APD). In a Translational Research article entitled ‘KCNQ1 suppression-replacement gene therapy in transgenic rabbits with type 1 long QT syndrome’, Sahej Bains from the Mayo Clinic in Rochester, MN (USA), and colleagues rescued the pathologic phenotype in transgenic LQT1 rabbits using a novel KCNQ1 suppression-replacement (SupRep) gene therapy.27KCNQ1-SupRep gene therapy was developed by combining into a single construct a KCNQ1 shRNA (suppression) and an shRNA-immune KCNQ1 cDNA (replacement), packaged into adeno-associated virus serotype 9, and delivered in vivo via an intra-aortic root injection. To ascertain the efficacy of SupRep, 12-lead electrocardiograms were assessed in adult LQT1 and wild-type (WT) rabbits and patch-clamp experiments were performed on isolated ventricular cardiomyocytes. KCNQ1-SupRep treatment of LQT1 rabbits resulted in significant shortening of the pathologically prolonged QT index (QTi) towards WT levels. Ventricular cardiomyocytes isolated from treated LQT1 rabbits demonstrated pronounced shortening of APD compared with LQT1 controls, leading to levels like WT. Under β-adrenergic stimulation with isoproterenol, SupRep-treated rabbits demonstrated a WT-like physiological QTi and APD90 behaviour. The authors conclude that this study provides the first animal model, proof-of-concept gene therapy for correction of LQT1. In LQT1 rabbits, treatment with KCNQ1-SupRep gene therapy normalizes the clinical QTi and cellular APD90 to near WT levels both at baseline and after isoproterenol. If similar QT/APD correction can be achieved with intravenous administration of KCNQ1-SupRep gene therapy in LQT1 rabbits, these encouraging data should compel continued development of this gene therapy for patients with LQT1. 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.