Focus on atherothrombosis mechanisms and ischaemic heart disease management

For the podcast associated with this article, please visit https://academic.oup.com/eurheartj/pages/Podcasts. This Focus Issue on ischaemic heart disease and vascular biology and medicine and brain health contains a State of the Art Review article entitled ‘Ferroptosis in cardiovascular disease: regulatory mechanisms and therapeutic implications’ by Yiheng Zhao from The Second Affiliated Hospital of Nanjing Medical University in China, and colleagues. Their aim was to elucidate the initiating factors and regulatory mechanisms of ferroptosis and to discuss potential therapeutic strategies targeting ferroptosis in various cardiovascular diseases.1 Ferroptosis, an iron-dependent form of regulated cell death, has been identified as a key factor in the pathogenesis and progression of various cardiovascular diseases (CVDs). The molecular basis of ferroptosis involves lipid peroxidation, iron dysregulation, and antioxidant pathways. Accumulating evidence suggests that ferroptosis is associated with various CVDs, including atherosclerosis, myocardial ischaemia–reperfusion injury, cardiac hypertrophy, and diverse cardiomyopathies. In addition to ferroptosis inhibitors, several novel ferroptosis-targeting therapies have emerged, including new uses for existing drugs, plant-derived compounds, and targeted drug delivery. This review synthesizes current knowledge, identifies research gaps to summarize the complex regulatory mechanisms of ferroptosis, and provides an overview of its functions in CVDs. The innovative therapeutic strategies targeting ferroptosis may lead to a paradigm change in the treatment of CVDs (Figure 1). Graphical Abstract1 Atherothrombosis is a complex and progressive disease, and low-grade inflammation plays a key role in all stages up to thrombotic occlusion.2–10 In a State of the Art Review article entitled ‘Distinct inflammatory pathways shape atherosclerosis in different vascular beds’, Oliver Soehnlein from the University of Münster in Germany, and colleagues summarize the current understanding of differences in atherosclerotic lesion biology across vascular beds, paying particular attention to lesional cell composition, potential inflammatory biomarkers, and insights from single-cell sequencing studies.11 Studies suggest varying prevalence of atherosclerotic cardiovascular disease (ASCVD) across arterial beds. Factors such as smoking expedite ASCVD progression in the abdominal aorta, while diabetes accelerates plaque development in lower limb arteries, and hypertension plays a significant role in ASCVD development in the coronary and carotid arteries. Moreover, superficial femoral atherosclerosis advances more slowly compared with atherosclerosis in coronary and carotid arteries. Furthermore, femoral atherosclerosis exhibits higher levels of ossification and calcification, but lower cholesterol concentrations, compared with atherosclerotic lesions of other vascular beds. Such disparities exemplify the diverse progression of ASCVD across arterial beds, pointing towards differential mechanistic pathways in each vascular bed. Hence, this review summarizes the current literature on immune-inflammatory mechanisms in various arterial beds in ASCVD to advance our understanding of this disease in an ageing society with an increased need for vascular bed- and patient-specific treatment options. The CENTURY trial addressed both issues of objective physiological severity of coronary artery disease (CAD) for guiding revascularization and simultaneous comprehensive integrated lifestyle–medical treatment towards risk factor goals. In a Clinical Research article entitled ‘Optimal medical care and coronary flow capacity-guided myocardial revascularization vs usual care for chronic coronary artery disease: the CENTURY trial’, K. Lance Gould from the University of Texas McGovern Medical School in Houston, TX, USA, and colleagues test the hypothesis that a comprehensive strategy integrating intense lifestyle modification and aggressive medical management to goals with revascularization reserved for severely reduced coronary flow capacity (CFC) by positron emission tomography (PET) would reduce risk factors, subsequent revascularization, death, and myocardial infarction (MI) compared with standard of care in chronic stable CAD.12 Participants were randomly assigned to standard or comprehensive care groups. Rest–stress PET quantified CFC for physiological CAD severity at baseline, and 2, 5, and up to 11 years. The comprehensive care group reviewed PET results with frequent clinic visits and open 24/7 phone/email support. Standard care lacked supportive contact, with blinded PET results that were unblinded only for severely reduced CFC with high mortality risk for potential revascularization. Between 2009 and 2017, a total of 515 patients were assigned to comprehensive care and 513 to standard care, and were followed for ≥5 years. Comprehensive vs standard care decreased risk factors and summed 5 year risk score (P < .0001), decreased cumulative 11 year all-cause death (4.7% vs 8.2%; P = .023), death or MI (7.0% vs 11.1%; P = .024), late revascularization (9.5% vs 14.8%; P = .021), and major adverse cardiac events (20.5% vs 29.9%; P = .0006). The authors conclude that the randomized CENTURY trial demonstrates that comprehensive integrated lifestyle modification and medical management towards goals, with revascularization reserved for severely reduced CFC, significantly reduces risk factor scores and improves cardiovascular outcomes. This manuscript is accompanied by an Editorial by Marcelo F. Di Carli and Ron Blankstein from Harvard Medical School in Boston, MA, USA.13 The authors note that the CENTURY trial shows that physiology-based risk assessment, when paired with comprehensive medical and lifestyle management, leads to sustained improvements in outcomes for patients with stable CAD. Future work should explore how to translate this comprehensive approach into scalable, pragmatic frameworks—potentially using telehealth to promote patient education and review of imaging test results, regional imaging hubs, and digital educational and engagement tools to democratize access. This trial suggests that by leveraging the power of quantitative imaging, integrating best practice, and supporting patients through systems designed for sustained engagement, it is possible to achieve durable clinical benefits. Structured Graphical Abstract16 Adverse pregnancy outcomes (APO) are important sex-specific risk factors for both the mother and the offspring.14,15 During their reproductive years, up to 30% of all women experience a major APO (pre-term delivery, small for gestational age, pre-eclampsia, other hypertensive disorders of pregnancy, or gestational diabetes). In a Clinical Research article entitled ‘Adverse pregnancy outcomes and long-term risk of stroke: a Swedish nationwide co-sibling study’, Casey Crump from the University of Texas Health Science Center in Houston, TX, USA, and colleagues examine five major APO and long-term risk of stroke in a large population-based cohort.16 A national cohort study was conducted of all (>2 000 000) women with a singleton delivery in Sweden during 1973–2015, followed up for stroke through 2018. Cox regression was used to determine hazard ratios (HRs) for stroke associated with pre-term delivery, small for gestational age, pre-eclampsia, other hypertensive disorders, and gestational diabetes, adjusting for other maternal factors. Co-sibling analyses assessed for potential confounding by shared familial (genetic or environmental) factors. In 48 million person-years of follow-up, 30% of women experienced an APO and 1.6% of women were diagnosed with stroke. All five APOs were independently associated with long-term increased risks of stroke. With up to 46 years of follow-up, adjusted HRs for stroke associated with specific APO were: 1.86 for gestational diabetes; 1.82 for other hypertensive disorders; 1.40 for pre-term delivery; 1.36 for pre-eclampsia; and 1.26 for small for gestational age. These findings were only partially explained by shared familial factors (Figure 2). The authors conclude that women with any of five APO have increased risks of stroke up to 46 years after delivery. Women with APO need early preventive actions and long-term follow-up to reduce their lifelong risk of stroke. The manuscript is accompanied by an Editorial by Abbi D. Lane from the University of Michigan in Ann Arbor, MI, USA.17 The author highlights that a model for improving lifestyle behaviours after a cardiovascular event already exists—traditional cardiac rehabilitation programmes address most or all stroke risk factors. They include supervised or home-based exercise and counselling to support smoking cessation, improvements in diet, and stress management. In other patient groups, outpatient cardiac rehabilitation is delivered in tandem with regular contact with healthcare providers. In women with a recent APO, the provider contact might include review of home-measured blood pressure and supportive medication titration. Because poor mental health is associated with poor medication and cardiac rehabilitation adherence in other populations, the inclusion of a mental health component/treatment would be likely to promote success in blood pressure management as well as behavioural goals in individuals with recent APOs. Delivery methods for any post-partum intervention could include home-based or virtual sessions to reduce child care or travel burden, and improve feasibility. As APO occur in ∼30% of parous people, and stroke is ∼90% preventable, implementing a multicomponent, preventive intervention aimed at modifiable stroke risk factors soon after delivery seems like an obvious win. Thoracic aortic aneurysms are silent but deadly diseases, causing aortic dissection leading to rupture. These events can be prevented by timely aortic root surgery.18,19 In a Rapid Communication article entitled ‘Family history of aortic dissection in fibrillin-1 pathogenic variant’, Maria Tchitchinadze from Bichat-Claude Bernard Hospital in Paris, France, and colleagues evaluate the personal risk of aortic dissection in FBN1 carriers according to a family history of aortic dissection.20 This retrospective study compares two groups of patients with a pathogenic FBN1 variant: a group of patients with a family history of aortic dissection (n = 481) and a group of patients without a family history of aortic dissection (n = 1219). The incidence of aortic dissection, aortic surgery, age at aortic dissection, and age at aortic surgery were similar in the two groups. Of note the presence of a family history of aortic dissection was associated with a greater number of affected relatives. The authors conclude that a family history of aortic dissection cannot be used as a risk marker for aortic dissection in patients with a pathogenic FBN1 variant. The issue is also complemented by two Discussion Forum contributions. In a commentary entitled ‘Potential measures to enhance understanding of coffee-drinking timing and mortality’, Guo-Sheng Li, Hua-Fu Zhou, and Nuo Yang from The First Affiliated Hospital of Guangxi Medical University in China comment on the recently published paper entitled ‘Coffee drinking timing and mortality in US adults’ by Xuan Wang et al. from Tulane University in New Orleans, LA, USA. Lu Qi from Tulane University replies in a separate contribution.20–22 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.