Ludmila Caceva discusses the 1970s studies that revealed that the plasma lipid prolife of the Inuit population of Greenland, who had a low incidence of cardiovascular disease, was characterized by low levels of cholesterol, lipoproteins and triglycerides and high levels of omega-3 fatty acids and how these findings shaped dietary guidelines worldwide.
In the setting of myocardial ischaemia-reperfusion injury, ischaemia induces severe myocardial hypoxia, whereas the abrupt reintroduction of oxygen during reperfusion further amplifies tissue injury through redox imbalance. This dynamic stabilizes hypoxia-inducible factors (HIFs), which become transcriptionally active and induce hypoxia-responsive gene networks. In turn, HIF-dependent programmes orchestrate adaptive responses to acute hypoxia, including metabolic reprogramming towards glycolysis, promotion of extracellular adenosine signalling, induction of epidermal growth factor pathways and integration with circadian regulatory circuits. Collectively, these programmes increase myocardial resistance to ischaemic stress and limit ischaemia-reperfusion injury. In this Review, we examine the functional roles of HIFs in cardioprotection, with a particular focus on their contributions to ischaemic preconditioning or remote preconditioning and the HIF-dependent pathways that drive these cardioprotective effects. Given that pharmacological HIF stabilizers are already in clinical use for the treatment of renal anaemia, these insights provide a clear translational framework, positioning HIF activation as a plausible and immediately actionable therapeutic approach to prevent or treat myocardial ischaemia-reperfusion injury.
The introduction of intracoronary imaging (ICI) into clinical practice has been one of the major advances in percutaneous coronary intervention (PCI) for patients with atherosclerotic coronary artery disease. However, because the procedural advantages of ICI in routine clinical practice can be offset by higher costs and longer procedural times, high-quality evidence demonstrating the net clinical benefits of ICI guidance has long been awaited. The publication of eight large (n > 1,000 patients), international, randomized studies (the ILUMIEN IV, IVUS-ACS, IVUS-CHIP, IVUS-XPL, OCCUPI, OCTOBER, RENOVATE-COMPLEX-PCI and ULTIMATE trials) has provided substantial data on the clinical use of ICI guidance to improve the safety and outcomes of patients undergoing PCI. However, the heterogeneity of the study populations, lack of standardized criteria across ICI protocols and the mixed results of randomized trials have left uncertainty about why and when the use of ICI confers a benefit in real-world settings. In this Review, by discussing the study characteristics and procedural aspects that contributed to the consistency and heterogeneity across trials, we provide a practical and comprehensive appraisal of the appropriateness - why, when, how and which - of ICI guidance in the clinical decision-making process for contemporary PCI, with the overall aim of improving clinical outcomes.
In this Tools of the Trade, Ackers-Johnson and Pavlovic describe a Langendorff-free approach to isolate cardiomyocytes without the technical hurdles associated with the conventional Langendorff perfusion procedure.
Adam Goodwill discusses Eric Feigl’s seminal description of coronary physiology and how his paper shaped research into the mechanisms by which coronary blood flow is matched to myocardial metabolism.
Tobacco use and emerging nicotine-delivery systems remain major, preventable drivers of cardiovascular disease worldwide. Although tobacco cigarette smoking has declined in some high-income regions, progress is uneven, with persistently high rates across parts of Europe, alongside rapidly expanding global markets for e-cigarettes, heated-tobacco products and oral nicotine formulations. Youth addiction to nicotine-containing products has emerged as an urgent public health challenge, as engineered e-cigarette devices delivering large nicotine doses facilitate early dependence and might establish lifelong exposure trajectories. Regulatory frameworks have not kept pace with this innovation, allowing new platforms to enter markets faster than safety evidence can mature. Leading cardiovascular societies and regulatory authorities agree that no nicotine-containing product can be safe for the cardiovascular system. Nicotine promotes sympathetic activation, haemodynamic stress, oxidative imbalance and inflammation, and endothelial nitric oxide synthase uncoupling and dysfunction, contributing to atherosclerotic plaque instability in animal models and humans. Studies in humans demonstrate adverse vascular responses across all nicotine-containing products, although interpreting studies requires caution and long-term outcome data are lacking. In this Review, we integrate mechanistic, biomarker, preclinical and clinical data to define a cardiovascular continuum of harm from nicotine-containing products, in which eliminating combustion reduces but does not eliminate vascular toxicity.
The cardiovascular research landscape in China is shaped by a tiered, hospital-centred system, expanding funding opportunities and strong clinical resources. This Comment examines how institutional structures, research pathways and publication expectations influence scientific output and highlights how greater methodological rigour, international collaboration and more effective communication of scientific relevance to global audiences could improve the global visibility and impact of cardiovascular research from China.
Tsiartas and Bennett discuss the discovery that atheroclerotic plaque vulnerability to rupture arises from the interaction between plaque composition and vessel biomechanics.
Two studies published in Science explore how 3D chromatin organization and structure can influence cardiac development and promote heart failure.
Haemoglobin is a ferrous iron (Fe2+)-containing intracellular protein that is crucial for multiple homeostatic functions, including transport of oxygen and carbon dioxide, acid-base buffering and cellular signalling through nitric oxide oxidation and nitrite reduction. When erythrocyte membranes are disrupted, a process known as haemolysis that is caused by either disease or an exogenous stressor, haemoglobin is liberated into the plasma. This plasma free haemoglobin is highly pathogenic, disrupting a range of physiological processes and causing downstream organ damage through multiple mechanisms, including nitric oxide scavenging, vasoconstriction, generation of reactive oxygen species, activation of innate immune inflammation, disruption of cellular signalling, activation of the coagulation cascade and direct end-organ injury. Haemolysis and an elevated level of plasma free haemoglobin are associated with increased cardiovascular mortality, haemodynamic derangements, renal dysfunction and immune system dysregulation. These injurious pathways are exacerbated as the plasma free haemoglobin concentration and duration of exposure increase and are mitigated by endogenous scavenging pathways. In cardiovascular disease, proliferation of the use of mechanical circulatory support technologies, as well as an ageing population with chronic low levels of haemolysis, has increased exposure to plasma free haemoglobin and its detrimental effects. In this Review, we summarize the relationship between chronic haemolysis and cardiovascular disease and discuss current and future approaches towards the prevention and treatment of haemolytic injury.
Benjamin Dowsing describes the Whitehall studies, which established the inverse relationship between socioeconomic status and the risk of death from coronary heart disease, leading to the concept of social determinants of health.
Ilias Simon and Yohan Santin discuss the study that demonstrated that post-mitotic cardiomyocytes can acquire a senescent phenotype with age.
The nucleus is a highly organized and dynamic organelle, with hierarchical layers ranging from nucleosome positioning to chromatin domains and higher-order 3D genome topology. Viewed over time as the 4D nucleome, this organization enables precise and context-dependent transcriptional control. In the heart, dynamic nuclear architecture orchestrates precise transcriptional programmes that control lineage commitment and the establishment of cardiac cell types crucial not only for heart development, but also for postnatal function and adaptive responses. Correspondingly, transitions between developmental and disease states are accompanied by coordinated changes in genome organization, chromatin accessibility and transcription factor occupancy. These architectural programmes are modulated by mechanical and metabolic inputs, which further shape chromatin organization, nuclear positioning and epigenetic state. Deciphering the 4D nucleome of the heart can potentially provide new insights into disease mechanisms, regenerative strategies and precision cardiovascular medicine. In this Review, we highlight studies that define the fundamental principles of nuclear organization; explore nuclear and chromatin reorganization during cardiac development, disease and ageing; and discuss emerging methods to interrogate nuclear architecture. We also consider how mechanical and metabolic signals shape the 4D epigenome and examine their therapeutic and translational implications for cardiovascular health and disease.
Cardiac glycosides were the cornerstone of heart failure treatment for decades, but their use progressively declined after the introduction of modern prognostic medications. Two clinical trials now report that cardiac glycosides can reduce the risk of worsening heart failure events in patients with heart failure with reduced ejection fraction. These results do not mandate a paradigm shift but support a specific role for cardiac glycosides in selected patients.
In this Journal Club article, Dar describes the first study to report the transcriptional coactivator YAP as a central regulator of cardiac regeneration in mice.
As artificial intelligence (AI), multiomics and human organoids reshape cardiovascular research, calls to replace animal models are accelerating. We argue that understanding complex, multiorgan cardiovascular disease requires an integrated framework in which in vivo, in vitro and computational models each provide complementary biological insights.
With an ageing population and the persistence of unhealthy lifestyle behaviours, health-care systems are challenged by a growing number of individuals living longer with cardiovascular disease and its sequelae. The evolution of cardiac rehabilitation, from a group exercise-based programme to encompassing all aspects of secondary prevention, has led to the ultimate objective of achieving lifelong cardiovascular health for all. In this World Heart Federation Roadmap, we present a united and forward-looking vision to consolidate global and collaborative efforts that enhance equitable access, improve patient outcomes and ensure value-based health care. The Roadmap outlines a reframing of terminology and interconnected solutions founded on unity, person-centredness and being future-focused. The five key roadblocks and widely applicable solutions are interlinked and include having a greater emphasis on lifelong cardiovascular health, better engagement among patients and clinicians, a greater emphasis on new models of care, workforce strengthening and support for strong advocacy and policy. We present a series of practical solutions and successful international case studies. The next steps are to facilitate local and regional implementation and evaluation strategies. A shift to systems, policy and advocacy thinking is crucial for the sector, with a view to long-term investment to meet growing demands. This World Heart Federation Roadmap is endorsed by the International Council of Cardiovascular Prevention and Rehabilitation.
The authors highlight the first report of the measurement of left ventricular ejection fraction in humans, published in 1962 by Roland Folse and Eugene Braunwald.
