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This Focus Issue on ischaemic heart disease, vascular biology and medicine, and brain health contains the State of the Art Review entitled ‘Coronary atherosclerosis in athletes: emerging concepts and preventive strategies’ by Guido Claessen from KU Leuven, in Belgium and colleagues.1 It is well recognized that regular physical activity reduces cardiovascular (CV) risk.2–4 Nevertheless, the authors point out that there should be no assumption that an athlete is immune to coronary artery disease (CAD), even when traditional CV risk factors appear to be well managed. Excelling in certain aspects of health does not equate to total CV protection. Recent data from cardiac imaging studies have raised the possibility that long-term, high-volume, high-intensity endurance exercise is associated with coronary atherosclerosis. Whilst the risk of CV events has not been shown to increase with athletic activity, the potential for CAD should not be overlooked as it is the leading cause of sudden cardiac death in athletes >35 years of age (i.e. ‘Masters athletes’). Evaluating both traditional and non-traditional risk factors for CAD is the most important part of pre-participation evaluation in Masters athletes. When managing athletes at risk of CAD it is important to adopt a shared decision-making approach regarding lifestyle adaptation and lipid-lowering treatments. In the great majority of athletes, after excluding the presence of symptoms and inducible ischaemia, this advice should include encouragement to continue exercising, as available data indicate that higher levels of fitness are associated with a markedly attenuated incidence of coronary events regardless of the severity of coronary disease. Future research is needed to establish the relationship between clinically relevant CAD outcomes and coronary artery calcification in Masters athletes, the role of sex, as well as exploration of the mechanisms underpinning these unexpected CV adaptations.
In a State of the Art Review article entitled ‘Carotid artery atherosclerosis: mechanisms of instability and clinical implications’, Luca Saba from the University of Cagliari in Italy, and colleagues point out that CV disease remains a prominent cause of disability and premature death worldwide.5 Within this spectrum, carotid artery atherosclerosis is a complex and multifaceted condition, and a prominent precursor of acute ischaemic stroke and other CV events. The intricate interplay among inflammation, oxidative stress, endothelial dysfunction, lipid metabolism, and immune responses participates in the development of lesions, leading to luminal stenosis and potential plaque instability. Even non-stenotic plaques can precipitate a sudden CV event, regardless of the degree of luminal encroachment. In this context, carotid imaging modalities have proved their efficacy in providing in vivo characterization of plaque features, contributing substantially to patient risk stratification and clinical management. This review emphasizes the importance of identifying high-risk individuals by use of current imaging modalities, biomarkers, and risk stratification tools. Such approaches inform early intervention and the implementation of personalized therapeutic strategies, ultimately enhancing patient outcomes in the realm of CV disease management.
Coronary artery bypass surgery plays a key role in the management of ischaemic heart disease.6–13 In a Hypothesis article entitled ‘Arterial conduits for coronary bypass grafting: the set-point concept’, Antonio Calafiore and Sotirios Prapas from the Henry Dunant Hospital in Athens, Greece along with Mario Gaudino from Weill Cornell Medicine in New York, NY, USA remind us that endothelial cells control the vascular tone of arterial grafts used for coronary artery bypass surgery and react to changes in local shear stress.14 The vascular adaptations induced by endothelial cell activation affect the outcome of surgical grafts and can be predicted based on the set-point theory. In this Hypothesis piece, it is proposed that the set-point concept should inform surgical decision for coronary artery bypass surgery.
Neutrophil extracellular traps (NETs) trigger atherothrombosis during acute myocardial infarction (AMI), but the mechanisms of induction remain unclear. Levels of extracellular vesicles (EVs) carrying oxidation-specific epitopes (OSEs), which are targeted by specific natural immunoglobulin M (IgM), are increased at the culprit site in AMI. In a Fast Track Congress article entitled ‘Malondialdehyde-specific natural IgM inhibit NETosis triggered by culprit site-derived extracellular vesicles from myocardial infarction patients’, Anna Ondracek from the Medical University of Vienna in Austria, and colleagues investigated EVs as inducers of NETosis and assessed the inhibitory effect of natural anti-OSE-IgM in this process.15 Blood from the culprit site and peripheral blood of ST-segment elevation myocardial infarction patients (n = 28) was collected, and myocardial function was assessed by cardiac magnetic resonance imaging (cMRI) 4 days and 195 days post-AMI. Extracellular vesicles were isolated from patient plasma and cell culture supernatants for neutrophil stimulation in vitro and in vivo, in the presence of a malondialdehyde (MDA)-specific IgM or an isotype control. CD45+ MDA + EVs and NET markers were elevated at the culprit site. Extracellular vesicles induced neutrophil activation and NET formation via TLR4 and PAD4, and mice injected with EVs showed increased NETosis. An MDA-specific IgM inhibited EV-induced NET release in vitro and in vivo. CD45+ MDA + EV concentrations inversely correlated with left ventricular ejection fraction post-AMI (Figure 1).
Different subsets of extracellular vesicles (EVs) are released at the culprit site of ST-segment elevation myocardial infarction (STEMI), and a high percentage of leucocyte-derived EVs carry oxidation-specific epitopes (OSEs) such as malondialdehyde (MDA) epitopes (red). Culprit site EVs from ST-segment elevation myocardial infarction (STEMI) patients (MI-EVs) can activate neutrophils and trigger peptidyl-arginine deiminase 4 (PAD4)-dependent formation of neutrophil extracellular traps (NETs) via Toll-like receptor 4 (TLR4) signalling. The presence of the MDA-specific IgM antibody LR04 reduces MI-EV-induced NETosis. ST-segment elevation myocardial infarction patients with high levels of MDA-specific IgM, which have the capacity to balance the activity of proinflammatory NETogenic EVs, present with preserved left ventricular ejection fraction (LVEF)15
The authors conclude that culprit site-derived EVs induce NETosis, while MDA-specific natural IgM inhibits this effect, potentially impacting outcome after AMI. This manuscript is accompanied by an Editorial by Teresa Gerhardt and Ulf Landmesser from the Charité Universitätsmedizin Berlin, Germany.16 The authors note that the present proof-of-concept study identifies OSE-EVs as an important new mechanism stimulating NET formation in AMI and identifies natural anti-OSE-IgM as an endogenous countervailing mechanism that limits myocardial injury during MI. An intriguing question is whether the findings of the present study are equally relevant in different AMI endotypes. A ‘ruptured fibrous cap’ overlying a necrotic core in a vulnerable coronary atherosclerotic plaque and subsequent thrombotic vascular occlusion is the most common cause of AMI in 60%–70% of patients. In 30%–40% of cases of AMI, the causative acute pathology is a distinct, patho-anatomic manifestation called plaque erosion, characterized by loss of the endothelial monolayer and thrombus formation over an ‘intact fibrous cap’. Recent studies have implicated Toll-like receptor 2-mediated neutrophil activation and neutrophil-released matrix metalloproteinase specifically in the pathogenesis of coronary plaque erosion.17,18 It is unknown whether anti-OSE-IgM levels vary in patients with plaque erosion vs. plaque rupture and whether OSE-EV-dependent NETosis could be a relevant mechanism promoting endothelial cell loss-triggered thrombosis in plaque erosion.
The importance of risk stratification in patients with chest pain extends beyond diagnosis and immediate treatment. In a Clinical Research article entitled ‘Electrocardiogram-based machine learning for risk stratification of patients with suspected acute coronary syndrome’, Zeineb Bouzid from the University of Pittsburgh in Pittsburgh, PA, USA, and colleagues sought to evaluate the prognostic value of electrocardiogram (ECG) feature-based machine learning models to risk-stratify all-cause mortality in those with chest pain.19 This was a prospective observational cohort study of consecutive, non-traumatic patients with chest pain. All-cause death was ascertained from multiple sources, including the CDC National Death Index registry. Six machine learning models were trained for survival analysis using 73 morphological ECG features, followed by a variational Bayesian–Gaussian mixture model to define distinct risk groups. The resulting classification performance was compared against the HEART score. The derivation cohort included >4000 patients (mean age 59 years, 47% women). The mortality rate was 20% after a median follow-up period of 3 years. This model outperformed the HEART score, reducing the rate of missed events by >90%, with a negative predictive value and sensitivity of 93.4% and 85.9%, compared with 89.0% and 75.0%, respectively. In an independent external testing cohort, patients in the moderate- (odds ratio 3.62) and high- (odds ratio 6.12) risk groups had significantly higher odds of mortality compared with those in the low-risk group (Figure 2).
The model achieved a very good classification performance, and the derived risk groups adequately defined distinct risk trajectories of time-to-event data. These risk clusters outperformed the classification performance of the HEART score, with a significant gain in recall, precision, and negative predictive value. This performance generalized well to data from an external clinical site. ML, machine learning; ECG, electrocardiogram; HEART, History, ECG, Age, Risk factors, Troponin; NPV, negative predictive value; OR, odds ratio. Created with BioRender.com (credit to Z.B.)19
The authors conclude that the externally validated machine learning-based model, exclusively utilizing features from the 12-lead eECG, outperforms the HEART score in stratifying the mortality risk of patients with acute chest pain. This may have the potential to impact the precision of care delivery and the allocation of resources to those at highest risk of adverse events. The contribution is accompanied by an Editorial by Zachi Attia and Paul Friedman from the Mayo Clinic Minnesota in Rochester, MN, USA.20 The authors conclude that as artificial intelligence (AI) technologies continue to evolve, integrating them with robust, randomized clinical trials will not only confirm their utility but will also expand their applicability in real-world scenarios. The future of cardiac care lies in the ability to seamlessly blend cutting-edge AI tools with clinical expertise, ensuring that predictions are not only scientifically sound but also clinically relevant. Prediction is difficult, but the authors predict that clinical trials demonstrating the improved power of our diagnostic tests afforded by AI will lead to better clinical outcomes and new disease insights—ultimately revolutionizing the landscape of acute cardiac care.
Marfan syndrome (MFS) is a hereditary disorder primarily caused by mutations in the FBN1 gene.21 Its critical cardiovascular manifestation is thoracic aortic aneurysm (TAA), which poses life-threatening risks. Owing to the lack of effective pharmacological therapies, surgical intervention continues to be the current definitive treatment. In a Translational Research article entitled ‘PIEZO1 attenuates Marfan syndrome aneurysm development through TGF-β signaling pathway inhibition via TGFBR2’, Peiwen Yang from the Huazhong University of Science and Technology in Wuhan, China, and colleagues investigated the role of Piezo-type mechanosensitive ion channel component 1 (PIEZO1) in MFS and identified the activation of PIEZO1 as a potential treatment for MFS.22 PIEZO1 expression was detected in MFS mice (Fbn1C1041G/+) and patients. PIEZO1 conditional knockout mice in vascular smooth muscle cells of MFS mice (MFS × CKO) were generated, and bioinformatic analysis and experiments in vitro and in vivo were performed to investigate the role of PIEZO1 in MFS. PIEZO1 expression decreased in the aortas of MFS mice; MFS × CKO mice showed aggravated TAA, inflammation, extracellular matrix remodelling, and transforming growth factor-β (TGF-β) pathway activation compared with MFS mice. Mechanistically, PIEZO1 knockout exacerbated the activation of the TGF-β signalling pathway by inhibiting the endocytosis and autophagy of TGF-β receptor 2 mediated by Rab GTPase 3C. Additionally, the pharmacological activation of PIEZO1 through Yoda1 prevented TGF-β signalling pathway activation and reversed TAA in MFS mice.
The authors conclude that PIEZO1 deficiency aggravates MFS aneurysms by promoting TGF-β signalling pathway activation via TGF-β receptor 2 endocytosis and a decrease in autophagy. These data suggest that PIEZO1 may be a potential therapeutic target for MFS treatment. The manuscript is accompanied by an Editorial by Jin Komuro from Keio University School of Medicine in Tokyo, Japan, and Norifumi Takeda and Issei Komuro from the The University of Tokyo in Japan.23 The authors note that as new therapeutic targets for MFS are being sought, this study reveals for the first time the role of PIEZO1 in the pathophysiology of TAA in MFS mice. Interestingly, in this study, TGF-β signalling was not completely suppressed, but remained to some extent. This partial modulation of the enhanced TGF-β signalling pathway may balance its activity and have beneficial effects on the pathophysiology of TAA in MFS. The results of this research are novel and interesting, but at the same time leave many important issues to be addressed in the future. The reduction of PIEZO1 levels in MFS is a key finding, but the exact mechanism of its down-regulation is unknown. Since PIEZO1 is a mechanosensitive ion channel, not only its expression level but also its activity as an ion channel should be important. It would be interesting to know whether the various effects achieved by the activation of PIEZO1 by Yoda1 are due to suppression of TGF-β signalling or some other pathways. Many important questions remain, and resolving these questions could lead to an even better understanding of the pathophysiology of MFS and better treatments.
In a Rapid Communications contribution entitled ‘Functional coronary assessment in angina with intermediate coronary stenosis: the #FullPhysiology approach’, Antonio Maria Leone from the Gemelli-Isola Hospital, Università Cattolica del Sacro Cuore in Rome, Italy, and colleagues indicate that recent studies and Guidelines24 support the role of a comprehensive invasive functional approach in patients showing angina with non-obstructive CAD.25 In this regard, the authors recently proposed the #FullPhysiology (#FP) algorithm, which recommends the measurement of the coronary flow reserve and index of microcirculatory resistance using the bolus-thermodilution technique and vasoreactivity testing with acetylcholine on top of a conventional epicardial assessment. The authors tested this approach in patients with intermediate epicardial stenoses, enrolling consecutive patients with the following inclusion criteria: (i) chronic coronary syndromes exhibiting angina severity Canadian Cardiovascular Society class ≥1 and/or evidence of myocardial ischaemia at non-invasive testing; and (ii) a physiologically non-significant single-vessel disease. Then, the study population was allocated to two consecutives cohorts according to the date of implementation of the #FP approach. The first cohort included patients undergoing only conventional physiological assessment of the epicardial disease by fractional flow reserve (conventional physiology, CP). The second cohort included patients undergoing a comprehensive physiological assessment according to the #FP approach, from 2020 to May 2023. A total of 751 patients (543 in the CP and 208 in the #FP group) were included. Patients undergoing #FP had a lower rate of the primary endpoint at 1 year follow-up (P = .01) as compared with patients undergoing CP. In addition, patients undergoing #FP exhibited a significant reduction in anginal symptoms (P < .01) and recurrent ischaemia tests (P < .01). Notably, the clinical advantage observed in the #FP group also translated into a substantial reduction in healthcare costs (P < .01).
The authors conclude that these findings support the notion that in anginal patients with chronic coronary syndrome and intermediate stenoses, a treatment guided by the #FP approach may improve clinical outcomes and reduce healthcare costs.
The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘What truly drives the significant reduction in major adverse cardiac events after switching to electronic cigarettes following percutaneous coronary intervention?’, Yuqin Zhao from the The First People’s Hospital of Kunshan in China and colleagues comment on the recent publication ‘Prognosis after switching to electronic cigarettes following percutaneous coronary intervention: a Korean nationwide study’ by Danbee Kang from the Sungkyunkwan University School of Medicine in Seoul, Republic of Korea.26,27 Kang et al. respond in a separate comment.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, enarini outside the submitted work.
With thanks to Amelia Meier-Batschelet, Johanna Huggler, and MartinMeyer for help with compilation of this article.
