The G protein-coupled receptor GPR18, engaged by pro-resolving and cannabinoid-related lipid ligands, plays a vascular bed-specific protective role in endothelial function. The aim of the present study was to establish the vasoreactivity and passive biomechanical properties of the thoracic aorta and femoral artery of adult GPR18 knockout compared with wildtype mice, using ex vivo myography, arterial morphology, and immunohistochemistry. The results revealed heightened receptor-independent contractility, loss of prostanoid-dependent contractile responses, altered vascular smooth muscle cell (VSMC) calcium handling, and an attenuated stress-tension relationship in the thoracic aorta of GPR18 knockout mice. This phenotype was almost entirely reversed in the femoral artery, with attenuated receptor-independent contractility, unchanged VSMC calcium handling, and a heightened stress-tension relationship in GPR18 knockout mice. These vascular bed-specific differences highlight the need to consider tissue context in the development of GPR18-based vasculoprotective therapies for cardiovascular disease.

BACKGROUND AND AIMS:Calcific aortic valve disease (CAVD) culminates in severe aortic stenosis, currently lacking pharmacological treatment. Intra-leaflet haemorrhage-induced iron overload promotes valvular ferroptosis. This study identifies a druggable ferroptosis pathway and validates its translational relevance across large-scale population cohorts. METHODS:Bulk- and single-cell transcriptomics, whole-mount histology, immunohistochemistry, and primary human valvular interstitial cell (VIC) models of 212 aortic valves from surgical patients were integrated for mechanistic insights. In vivo, valvular ferroptosis and thickness were assessed in a doxorubicin-induced ferroptosis mice model, and a wire injury model with ferroptosis inhibition was utilized to evaluate remodelling and haemodynamic obstruction. A total of 4874 participants of the Swedish CArdioPulmonary bioImage Study (SCAPIS) underwent cardiac computed tomography for aortic valve calcification determination and 273 550 individuals from the UK Biobank were followed for aortic stenosis incidence. RESULTS:Intra-leaflet haemorrhage was prevalent in calcified aortic valves and correlated positively with calcification and circulating ferroptosis biomarker. Bulk transcriptomics and single-cell RNA sequencing identified lipid peroxidation as the dominating valvular ferroptosis pathway centred on arachidonate 5-lipoxygenase (ALOX5). Inducing ferroptosis in VIC triggered lipid peroxidation and calcification while reducing viability, which were reversed by targeting the ALOX5-ACSL4 axis. In vivo, doxorubicin-induced valvular ferroptosis exacerbated valvular thickening in apoE-/- mice through ALOX5-ACSL4 upregulation. ALOX5 inhibition reduced valve thickness and haemodynamically improved valve function in the wire injury model. Arachidonic acid levels independently predicted aortic valve calcification and incident aortic stenosis in SCAPIS and UK Biobank, respectively, and positively correlated with circulating ferroptotic marker. CONCLUSIONS:These findings establish the ALOX5-ACSL4 axis as a critical mediator of ferroptosis in CAVD and promising repurposing target for clinical intervention.

Calcific aortic valve disease (CAVD), culminating in aortic stenosis (AS), is a progressive pathological condition marked by fibrocalcific remodeling of the aortic valve, for which no pharmacological therapies currently exist. Increasing evidence indicates that metabolic alteration of valvular cells is a central driver linking pathological stimuli to fibrocalcific changes. Hemodynamic stress, lipid infiltration, inflammation, and disturbed mineral balance synergistically induce metabolic shifts, characterized by augmented glycolysis, impaired oxidative phosphorylation, and oxidative stress. Beyond serving as a link between inflammation and calcification, metabolic intermediates such as acetyl-CoA and lactate act as epigenetic substrates, stabilizing osteogenic gene expression and perpetuating disease progression. The integration of metabolic and epigenetic signaling positions cellular metabolism as a nexus connecting pathogenic insults to calcification. Therapeutic strategies targeting glycolytic remodeling, mitochondrial dysfunction, and epigenetic modifications, combined with improved diagnostic imaging, physiologically relevant in vitro models, technological innovations, and the discovery of novel targets offer the promise of transforming CAVD management from late-stage surgical intervention to early prevention and precision medicine.

Background: Aortic valve disease affects vascular and cardiac remodeling and function, with changes observed after cardiac surgery. Ventricular-arterial coupling (VAC), which reflects the interaction between the left ventricle and the arterial system, may be altered by aortic valve replacement (AVR). Therefore, this study aimed to determine changes in VAC and atrial-arterial coupling (AAC) in patients with aortic valve disease before and after AVR. Methods: A total of 41 patients (median age 67 years, interquartile range (IQR) 62-71) undergoing AVR, including 24 (58.5%) with aortic stenosis (AS), were evaluated before and early (3 days) after cardiac surgery. Left atrial reservoir strain (LARS) and left ventricular (LV) global longitudinal strain (GLS) were assessed by echocardiography. Carotid-femoral pulse wave velocity (cfPWV), brachial-ankle-PWV (baPWV), and cardio-ankle vascular index (CAVI) were measured. VAC and AAC were defined as ratios of arterial stiffness to cardiac strain (CAVI/GLS, CAVI/LARS, baPWV/GLS, baPWV/LARS, cfPWV/GLS, cfPWV/LARS). Results: Atrial and ventricular strain and arterial stiffness significantly worsened after surgery. Ventricular-arterial uncoupling was reflected by a substantial increase in arterial stiffness to LV strain ratios (p < 0.001 for each). Moreover, AAC, measured as CAVI/LARS or PWV/LARS, significantly increased after surgery, with p < 0.001 for CAVI/LARS and baPWV/GLS, and p = 0.035 for cfPWV/LARS. Conclusions: Worsened ventricular-arterial uncoupling can be detected early after cardiac surgery using novel measures of VAC, including ratios of peripheral arterial stiffness to cardiac deformation. This study extends these findings by demonstrating atrial-arterial uncoupling, suggesting a generalized cardiac-arterial uncoupling after valve surgery.

AIMS:Inorganic pyrophosphate (PPi) is an endogenous inhibitor of soft tissue calcification. A disturbed equilibrium between pro- and anti-mineralization agents, like extracellular phosphate (Pi) and PPi, has been implicated in the mechanism of aortic valve calcification (AVC). We aimed to investigate the association of the plasma PPi concentration and Pi/PPi ratio with the degree AVC in cardiovascular patients. METHODS AND RESULTS:One hundred and fifty-four patients referred for cardiac computed tomography (CT), including 43 individuals with severe aortic stenosis, were prospectively enrolled. The aortic valve calcium score (AVCS) was measured on non-contrast CT images. Plasma PPi level was determined enzymatically. Of the entire population (age: 67 ± 12 years, 42.5% female), 42% had some degree of AVC (range 9-6641 AU). Plasma PPi showed a significant positive association with plasma Pi and LDL cholesterol (LDL-C) concentration and was inversely related to alkaline phosphatase activity. When controlled for age, female patients had higher PPi levels. In univariate analysis, plasma PPi level did not show an association with AVCS; however, the Pi/PPi ratio was significantly positively associated with the degree of AVC [estimate: 1508.1; standard error (SE) 616.0, P = 0.015], along with age, hypertension, plasma lipoprotein(a) concentration, and statin treatment, whereas estimated glomerular filtration rate and LDL-C level showed significant negative associations. In multivariate analysis, only age and Pi/PPi ratio remained significant determinant of the AVCS (estimate: 1128.6; SE 562.5, P = 0.047). CONCLUSION:This is the first study to investigate the association between PPi homeostasis and AVC in humans. The plasma Pi/PPi ratio was significantly positively associated with the AVC load even after adjustment for traditional risk factors.

Rheumatoid arthritis (RA) confers an elevated cardiovascular disease (CVD) risk through systemic inflammation, arterial stiffness, and myocardial dysfunction. The ratio of carotid-femoral pulse wave velocity (PWV) to left ventricular global longitudinal strain (LV-GLS) has been proposed as a novel index of ventricular-arterial coupling. This study investigated whether a one-year physical activity intervention improves the PWV/LV-GLS ratio in RA patients without known CVD. Eighteen participants with RA from the prospective PARA 2010 study underwent baseline and one-year assessments. PWV was measured by oscillometry, and LV-GLS by speckle-tracking echocardiography. Physical activity was promoted through supervised circuit training and additional moderate-to-vigorous activity. At one year, very active participants [≥ 1,000 metabolic equivalent of task (MET)-minutes/week, n = 10] showed a relative reduction in PWV/LV-GLS ratio compared with baseline, while no change was observed in less active participants (< 1,000 MET-minutes/week, n = 8). Between-group comparison at follow-up demonstrated significantly lower PWV/LV-GLS ratio in very active versus less active patients (p < 0.05). No significant between-group differences were observed when PWV and LV-GLS were analyzed separately. In conclusion, a high level of physical activity was associated with improved ventricular-arterial coupling, reflected by a lower PWV/LV-GLS ratio, in RA patients. These findings support a potential dose-dependent effect of physical activity on subclinical cardiovascular function in RA. The clinical trial was registered at http://www.isrctn.com, unique identifier: ISRCTN88886304.

Artificial intelligence is now embedded across the scientific research and publishing ecosystem, influencing discovery, analysis, knowledge translation, authorship, peer review, and editorial workflows. In cardiovascular and biomedical sciences, these developments offer substantial opportunities to accelerate knowledge generation, integrate complex datasets, and improve efficiency and consistency. At the same time, they introduce new risks related to bias, transparency, data integrity, and authorship responsibility, potentially endangering trust in the scientific record. This commentary examines the evolving role of AI in biomedical publishing, with particular attention to generative models and machine learning tools. We review both benefits and limitations, highlight risks such as fabricated content, biased outputs, and erosion of accountability, and discuss why traditional detection approaches are insufficient. Instead, we argue for a shift toward transparency, provenance, and enforceable human responsibility as the core principles guiding AI use, ensuring that AI strengthens rather than undermines scientific rigour and public trust. We outline practical expectations for authors, reviewers, editors, and publishers, with emphasis on reporting standards, reproducibility under rapidly evolving model versions, and the conflict-of-interest implications of AI tooling for the editorial process itself.

Single-cell RNA sequencing (scRNA-seq) has revolutionized the study of calcified aortic valve disease (CAVD) by enabling the dissection of cellular heterogeneity, lineage differentiation, and intercellular crosstalk at an unprecedented resolution. It revealed original vistas into the mechanisms of CAVD and novel putative therapeutic targets. This review provides a narrative state-of-the-art overview of scRNA-seq applications in CAVD research, summarizing key findings on valvular cell populations, disease-associated phenotypic transitions, and molecular pathways driving pathological remodeling. Additionally, the translational potential of single-cell technologies in identifying novel therapeutic targets is discussed, as well as the current challenges and future directions in this rapidly evolving field.

Postoperative atrial fibrillation (POAF) affects 38%–63% of patients undergoing surgical replacement for calcific aortic valve stenosis (CAVS), increasing morbidity, stroke risk, and hospital stay. POAF results from an interplay between pre-existing arrhythmogenic substrates, acute surgical triggers, unresolved inflammation, and autonomic nervous system (ANS) imbalance. Specialized pro-resolving mediators (SPMs) orchestrate inflammation resolution and tissue homeostasis; their deficiency may sustain valvular inflammation and promote arrhythmogenesis. Transcutaneous vagus nerve stimulation (tVNS) is a non-invasive approach that enhances parasympathetic tone, restores sympathovagal balance, and modulates inflammatory pathways. While tVNS has been applied postoperatively, its preoperative, preventive use in POAF has not been explored, representing a novel therapeutic strategy. In patients with CAVS, preoperative tVNS could reduce POAF by regulating ANS activity and limiting perioperative inflammation. Mechanistic insights may be gained through perioperative sampling, analysis of excised valvular and atrial tissue, and biomechanical assessments comparing stimulated and control groups. Preoperative tVNS thus offers a promising strategy to prevent POAF while addressing valvular inflammation, bridging translational physiology with clinical cardiology and potentially opening new avenues for the management of CAVS.

Objectives To determine whether preoperative COVID-19 infection before vaccine introduction was associated with postoperative myocardial injury and long-term adverse outcomes after surgical aortic valve replacement. Methods This prospective cohort study included patients undergoing surgical aortic valve replacement between July 2020 and May 2021. Preoperative COVID-19 infection status was determined by antibody testing. Baseline data were collected, and outcomes were identified through structured medical-record review. The primary endpoint was a composite of major adverse cardiovascular events and all-cause mortality. Kaplan–Meier curves, Cox proportional hazards regression and logistic regression were used. Models were adjusted for age, preoperative heart failure, hypertension, diabetes, prior percutaneous coronary intervention and concomitant aneurysm surgery. Postoperative creatine kinase myocardial band within 24 h was analysed in relation to infection status, extracorporeal circulation time and aortic cross-clamp time. Results Ninety-nine patients were included; 15 had prior COVID-19 infection and 84 did not. Median follow-up was 3.4 years. The primary endpoint occurred in 2/15 patients with prior COVID-19 infection (13.3%) and 4/84 patients without prior COVID-19 infection (4.7%; P = .5). Adjusted estimates were numerically higher but non-significant for patients with prior COVID-19 infection (hazard ratio 6.6, 95% confidence interval 0.3-109, P = .1; odds ratio 6.6, 95% confidence interval 0.7-65, P = .3), whereas age was associated with outcome (hazard ratio 1.1/year, 95% confidence interval 1.0-1.4, P = .03). Creatine kinase myocardial band was associated with extracorporeal circulation time (coefficient 0.003/min, 95% confidence interval 0.002-0.004, P < .001) and aortic cross-clamp time (coefficient 0.004/min, 95% confidence interval 0.003-0.005, P < .001), without significant interaction with infection. Conclusions Preoperative COVID-19 infection was not significantly associated with long-term outcome, whereas age was associated with adverse outcome. CK-MB appeared more closely linked to operative ischaemic burden than prior COVID-19 infection.

Metabolic disorders such as obesity, type 2 diabetes, and dyslipidaemia are major drivers of cardiovascular risk and have reached epidemic levels in Western populations. Recent advances in clinical research have uncovered unexpected and often beneficial effects of pharmacological classes of metabolic drugs on cardiovascular outcomes, revealing complex interactions between metabolism and cardiac pathology. Despite their clinical efficacy, the molecular and cellular mechanisms through which many of these agents act remain only partially understood. This gap in knowledge underscores the urgent need for fundamental research that not only dissects the biology of metabolic disorders and cardiovascular disease but also reveals the mechanistic basis of existing and emerging therapies, thereby enabling rational therapeutic development. This scientific statement, developed by researchers from the European Society of Cardiology (ESC) Council on Basic Cardiovascular Science and several ESC Working Groups, provides a state-of-the-art overview of the emerging molecular and cellular pathways linking metabolic abnormalities with vascular and cardiac disease. By illuminating these critical connections and unresolved questions, this article aims to catalyse innovation in the prevention and management of cardiovascular disease in the context of metabolic dysfunction and to suggest new directions for future research.

Chronic unresolved inflammation is a major driver for the genesis of cardiovascular disease, originating from unhealthy lifestyle interactions with a network of metabolic genes impacting overall immune fitness. Acute inflammation is a host defence response overlapping with safe clearance of inflammation, termed as resolution of inflammation, co-ordinated by nutritionally originated fatty acid's interaction with immune-responsive enzymes. Especially processing of polyunsaturated fatty acids by immune-responsive lipoxygenase and cyclooxygenase orchestrates the biosynthesis of specialized proresolving mediators. In contrast, dysregulation due to an imbalanced lifestyle, such as an unhealthy diet, lack of sleep, and exercise/low physical activity, drives non-resolving inflammation. Overall, the quality of fatty acids, enzymatic processing, on-time biosynthesis of SPMs, and precise activation of SPM-specific receptors operate cardiac repair in heart failure with reduced ejection fraction; however, the dysfunction of specific receptors, such as FPR2, drives obesogenic ageing and heart failure with preserved ejection fraction. Thus, the overlapping inflammation-resolution signalling pathways that are essential for cardiac repair and the prevention of cardiac damage are highly relevant to cardiometabolic disorders and the subsequent development of heart failure. Therefore, future research is warranted to study lifestyle factors that maintain the balance of inflammation-resolution signalling in cardiac health and develop new therapeutic targets for resolution medicine.

BACKGROUND:The role of Helicobacter pylori (H. pylori) screening and eradication on reducing upper gastrointestinal bleeding (UGIB) complications after acute myocardial infarction (MI) is uncertain. The HELicobacter pylori screening to prevent gastrointestinal bleeding in patients with acute MI (HELP-MI SWEDEHEART) trial aims to determine whether systematic H. pylori screening compared to usual care reduces UGIB, mortality, and cardiovascular outcomes after MI. METHODS:A cluster randomized, crossover, registry-based clinical trial using SWEDEHEART as trial platform for study population definition and source for data collection in combination with nationwide Swedish health data registries. Thirty-five Swedish hospitals, organized into 18 clusters based on percutaneous coronary intervention networks, were randomized to either routine H. pylori screening for adults with acute type-1 MI or usual care. After 1 year, a 2-month blanking period was followed by a crossover to the alternate allocation for 1 year. The trial enrolment was concluded after one additional year of registry-based follow-up. The primary endpoint is UGIB. Secondary endpoints include all-cause death, cardiovascular death, readmission for MI, stroke, or heart failure. Endpoints will be reported combined (Net Adverse Clinical Events; Major Adverse Cardiac or Cerebrovascular Events) and separately. The primary analysis will include all available follow-up time corresponding to a maximum follow-up time of 3 years and 2 months. CONCLUSION:HELP-MI SWEDEHEART aims to determine the utility of routine H. pylori screening to reduce UGIB and improve cardiovascular outcomes after MI. By integrating national registry follow-up data with a pragmatic trial design, it has the potential to provide evidence for the effect of the implementation of routine H. pylori screening as part of acute MI care. TRIAL REGISTRATION:ClinicalTrials.gov, NCT05024864.

G protein-coupled receptor (GPR) 18 is the receptor for the specialized pro-resolving lipid mediator (SPM) RvD2, which has proven efficacy in preventing atherosclerosis in mice. The aim of the present study was to establish direct vascular effects of GPR18 signaling. GPR18 knockout (KO) and wildtype (WT) mice underwent magnetic resonance imaging (MRI) for in vivo determination of endothelial function, and continuous 24 h telemetry for in vivo blood pressure monitoring. Isolated vessels derived from GPR18 KO and wildtype mice were used for determinations of ex vivo vascular reactivity and immunofluorescent quantifications. GPR18 KO mice exhibited endothelial dysfunction in the femoral arterial segment measured by MRI in vivo and in isolated arteries ex vivo as impaired ACh-induced vasodilatation, whereas the sensitivity to exogenous NO was unchanged. Endothelial function was not significantly different in the thoracic aortic segment between GPR18 KO and WT mice, demonstrating vascular bed-specific endothelial dysfunction as a result of GPR18 deletion. A significantly reduced eNOS expression and a larger indomethacin-sensitive component in ACh-induced relaxations observed in femoral arteries derived from GPR18 KO compared with WT mice suggest that the dysfunctional eNOS-mediated femoral endothelial function may be partly compensated by increased relaxant prostanoid modulation. Finally, conscious mean arterial blood pressure recorded by telemetry was significantly higher daytime compared with wildtype mice at 24 h telemetry measures, whereas young mice did not exhibit any significant differences in day- and night-time blood pressure. These observations linking GPR18 to vascular bed-specific endothelial dysfunction and age-dependent hypertension point to beneficial pro-resolving cardiovascular effects through GPR18 during aging.

Background:Cardiovascular autonomic dysfunction is a major complication in a large proportion of patients with long coronavirus disease (LC). As one of the most typical phenotypes of cardiovascular autonomic dysfunction, postural orthostatic tachycardia syndrome (POTS) is commonly observed as a sequelae of coronavirus disease infection. Objective:This study aimed to develop and test a 24-hour electrocardiogram (ECG) recording to direct the clinical suspicion toward the diagnosis of POTS. Methods:Consecutive patients referred to the Karolinska University Hospital in Stockholm from April 2021 to April 2022 were included. Patients with POTS were compared with patients with LC without POTS (verified by active standing tests) and control healthy subjects according to 3 specific analyses based on 24-hour ECG recording: (1) heart rate (HR) spikes of > 30 beats per minute, (2) awakening HR increase, and (3) HR variability (root mean square of successive difference). The control group consisted of healthy subjects from the database of the University Hospital of Saint-Etienne. Results:A total of 100 patients with LC (mean age, 42.54 ± 10.45 years; 92% women) and 100 healthy subjects (41.40 ± 7.21 years; 96% women) were included. LC POTS (n = 45) was associated with (1) a higher number of HR spikes/h (1.47 ± 0.84 vs 0.68 ± 0.50 and 0.40 ± 0.28/h; P < .01), (2) an abrupt and sustained increase in HR after awakening (P < .05), and (3) a reduction of HR variability: mean root mean square of successive difference of 34.90 ± 12.48 vs 30.47 ± 19.15 and 43.35 ± 21.10 ms (P < .01) compared with patients with LC without POTS (n = 55) and healthy subjects. Conclusion:A triple analysis of 24-hour ECG recordings could reveal a characteristic POTS signature in LC. More research in other populations is needed to draw any firm conclusions about its generalizability.

Early vascular aging plays a central role in chronic kidney disease (CKD), but its molecular causes remain unclear. Somatic mutations accumulate in various cells with age, yet their functional contribution to aging tissues is not well understood. Here we found progerin, the protein responsible for the premature aging disease Hutchinson-Gilford progeria syndrome, steadily recurring in vascular smooth muscle cells of patients with CKD. Notably, the most common progeria-causing mutation, LMNA c.1824C>T, was identified as a somatic mutation in CKD arteries. Clusters of proliferative progerin-expressing cells in CKD arteries and in vivo lineage-tracing in mice revealed clonal expansion capacity of mutant cells. Mosaic progerin expression contributed to genomic damage, endoplasmic reticulum stress and senescence in CKD arteries and resulted in vascular aging phenotypes in vivo. These findings suggest that certain somatic mutations may be clonally expanded in the arterial wall, contributing to the disease-related functional decline of the tissue.