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Implantation of drug eluting stents (DESs) is currently the default approach for percutaneous coronary interventions, but long-term adverse events still exist. An approach with minimal stenting deserves to be assessed in a randomized trial. We studied a novel sirolimus-eluting balloon (SEB) that elutes sirolimus over a 90-day period using a biodegradable polymer microreservoir technology. In a multicenter, open-label, randomized trial, we compared an SEB-based strategy with provisional DES with one of systematic DES for de novo lesions in coronary arteries between 2 and 5 mm in diameter. Subjects were randomized 1:1 before percutaneous coronary intervention. The primary end point was target vessel failure, a composite of cardiac death, target vessel-related myocardial infarction, and clinically driven target vessel revascularization. It was tested for noninferiority at 1 year with the use of an absolute margin equal to 50% of the combined event rate at a significance level of 0.025. The primary analysis population included all randomized subjects with completed or attempted percutaneous revascularization, analyzed according to the intention-to-treat principle. A sensitivity analysis was performed on the per-protocol population. Between August 27, 2021, and July 29, 2024, 3323 participants were randomized and treated in 62 sites. Among 1661 participants in the SEB strategy group, bailout stenting was performed in 343 (20.7%). Target vessel failure occurred over 365 days in 88 (5.3%) and 73 (4.4%) participants in the SEB and the systematic DES strategy groups, respectively (risk difference, 0.91% [95% CI -0.55% to 2.38%]; 1-sided P=0.02 for noninferiority with a 2.44% noninferiority margin). Clinically driven target vessel revascularization occurred more frequently in the SEB strategy group (3.3% versus 2.1%; risk difference, 1.22% [95% CI, 0.11%-2.33%). Safety events, including lesion thrombosis, were low and similar in both groups. Although the results of the per-protocol population (3194 participants, 96%) did not confirm noninferiority (upper boundary of the 95% CI, 2.63; P=0.04), they were similar to the intention-to-treat results in both magnitude and direction. At 1 year, in the primary intention-to-treat analysis population, a strategy of percutaneous coronary intervention with SEB and provisional DES was noninferior to the systematic use of DES for the primary end point of target vessel failure. The per-protocol population sensitivity analysis did not confirm noninferiority. Clinically driven target vessel revascularization occurred more frequently in the SEB strategy group. At 5 years, target vessel failure will be tested again for noninferiority and for superiority if noninferiority is achieved. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04859985.

Although the prognostic utility of positron emission tomography (PET) myocardial flow reserve (MFR) is well established, emerging data suggest that reduced subendocardial flows also predict adverse outcomes. However, the incremental value of subendocardial MFR (MFRSE) beyond transmural MFR (MFRTM) remains unclear. We studied patients in a multicenter PET registry with normal perfusion on stress/rest Rb-82 PET, excluding those with a previous history of coronary artery bypass surgery, heart transplantation, or left ventricular ejection fraction <40%. The optimal MFRSE cutoff for predicting major adverse cardiovascular events (MACEs; death, myocardial infarction [MI], revascularization, or heart failure [HF] hospitalization) was determined using Youden's index. Patients were stratified into 3 groups: concordant-normal (MFRTM ≥2.0; MFRSE ≥2.1), discordant (low-MFRSE, normal MFRTM), and abnormal MFRTM. Clinical outcomes were compared by MFR groups. Among 6603 patients (normal N=4103; discordant N=885; abnormal N=1615) the mean age was 66.3±12.4 years, and 54% were women. Compared with the concordant-normal group, patients with discordant low-MFRSE were older and more likely to have hypertension, diabetes, peripheral artery disease, and previous percutaneous coronary intervention. The median MFRTM for normal, discordant, and abnormal groups were 2.86, 2.15, and 1.72, respectively. Over a median follow-up of 4.9 years, 1661 MACE events occurred. Discordant low-MFRSE patients had a higher risk of MACE (hazard ratio [HR], 1.41; 95% CI, 1.22-1.64) and all-cause mortality (HR, 1.36; 95% CI, 1.14-1.61) compared with concordant-normal patients. The discordant group had an intermediate absolute risk of MACE, with an adjusted annualized event rate of 5.79% (95% CI, 5.10-6.49) compared with 3.99% (95% CI, 3.67-4.30; P<0.001) in the concordant-normal group and 8.35% (95% CI, 7.71-9.00; P<0.001) in the abnormal MFRTM group. Subendocardial MFR reveals clinically meaningful risk heterogeneity among patients with preserved transmural flow reserve, helping refine risk stratification beyond traditional PET metrics.

Atherosclerosis results from cellular and extracellular changes in the arterial wall, preceded by molecular shifts that initiate disease and drive tissue conversion, yet these changes are not yet fully described. More data are needed concerning these early changes in the coronary artery molecular landscape that signify the initiation of atherosclerosis and the subsequent tissue pheno-conversion to atherosclerotic plaque. This report summarizes results from a large biorepository of human coronary artery tissue, applying state-of-the-art omics technology, advanced data analytic methods, and an arterial organoid model system to predict molecular dynamics and identify potential regulatory mechanisms that could interrupt molecular changes that contribute to the earliest stages of disease pathogenesis. The long-term goal of this effort is to identify and develop new therapies to further mitigate the persistently high burden of clinical coronary disease. Mass spectrometry-based proteomic analysis and RNA sequencing (RNASeq) were used to analyse proximal coronary arterial samples from young adults who died of trauma with no ante mortem suspicion of coronary disease [n = 322, mean age (range): 34.1 years (15-59); sex: M-239, F-83; race: W-218, B-88, other-16]. Despite the absence of clinical disease, 56% of samples had morphologic evidence of pre-clinical atherosclerosis. Analyses of the proteomic data (n = 1900 proteins) using state-of-the-art dimensionality reduction and deconvolution techniques generated an estimate of molecular disease progression (e.g. pseudo-time) and identified selected proteomic latent features (LFs) (i.e. large groups of co-ordinated proteins) associated with its initiation and progression. Computational genomics, machine learning models, and multi-omic network mapping of these proteomic LFs and associated mRNA gene transcripts suggested potential transcriptional regulators which were subsequently confirmed in publicly available single-cell coronary artery data. The effects of one of the leading regulatory transcription factors (TFs), MLXIPL, predicted to regulate two LFs, were further validated in a human arterial cell organoid model system. Four proteomic LFs, composed of n = 100 signature proteins/LF, exhibited distinct patterns with respect to disease progression [false discovery rate (FDR) P < .01]. These LFs illuminate the earliest changes in the arterial proteome during tissue pheno-conversion from normal coronary artery to atherosclerotic plaque, including dramatic declines in mitochondrial energy biosynthesis proteins, evidence of vascular unit activation (including pericytes), and neurovascular and neuroimmune modulation (all FDR P < .01). These early changes preceded the expected immune cell recruitment and innate immune response characteristic of atherosclerotic plaque formation. Analysis of transcriptional regulatory networks identified from RNASeq data highlighted both known and novel TFs and master regulators of LF proteins that may drive the initial and early stages of disease progression. Publicly available single-cell RNASeq data from normal and atherosclerotic coronary arteries validated the LFs and several of their likely master transcriptional regulators (all P < .01); and manipulation of the levels of one of top regulatory TFs, MLXIPL, in human arterial cell organoids resulted in the expected changes in expression of the proteins associated with its two targeted LFs (P = .0003 and P < .00001, respectively). The unique nature of this human coronary biorepository with samples ranging from entirely normal to mature pre-clinical atherosclerotic plaque facilitated prediction of molecular disease progression and identification of several potential transcriptional regulators for further evaluation as potential novel targets to interrupt early initiation and progression of atherosclerotic coronary disease.

Atherosclerotic plaques are the leading cause of cardiovascular events. Single-cell approaches have identified diverse human plaque cell phenotypes but their spatial distribution and interactions remain unclear. Here, intercellular communication patterns in human plaque microenvironments were mapped to reveal novel targets to prevent atherosclerotic events. Spatial transcriptomics (Visium, 10x) from 13 carotid plaques, and single-cell transcriptomics (cells = 51 981) were used to analyse cell phenotypes, cell trajectories, and intercellular communications. Cells contributing to plaque stability were explored using deconvolution of plaque bulk RNA-seq data (n = 78), histology, and survival analyses. Key cells and pathways were validated in apolipoprotein E (Apoe)-/- mice and in vitro. Genome-wide association study enrichment analyses were conducted using summary statistics of atherosclerotic diseases. LINCS L1000 data were used to explore drug repurposing. A fibroblast-like vascular smooth muscle cell (VSMC) phenotype associated with extracellular matrix formation pathways (validated in Apoe-/- mice) emerged as a key regulator of intra-plaque ligand-receptor signalling, in particular in the cap region. A higher proportion of fibroblast-like VSMCs was found in asymptomatics, associated with stable plaque features and predicted a lower risk of future events. Genes specific to this VSMC phenotype were enriched in coronary artery disease and myocardial infarction. Finally, compounds, which could induce key marker genes were identified and validated in vitro. This study provides the first comprehensive spatial transcriptomics map of cell communication in human plaque microenvironments. A pivotal role of a fibroblast-like VSMC, orchestrating intraplaque cell signalling and contributing to plaque stability, was identified. Targeting these cells might present promising novel avenues for therapies.

The prevalence and long-term prognostic significance of coronary atherosclerosis detected by coronary computed tomography angiography (CCTA) in young adults remain insufficiently defined. We aimed to evaluate the prevalence of coronary atherosclerosis and its association with long-term cardiovascular outcomes among young adults undergoing clinically indicated CCTA. We performed a retrospective cohort study of consecutive patients undergoing CCTA at two academic centres between 2006 and 2021. Patients with prior coronary artery disease, end-stage renal disease, or malignancy were excluded. Young adults were defined as men ≤50 years and women ≤60 years. Coronary artery disease (CAD) was classified as no CAD, non-obstructive plaque (1-49% stenosis), or obstructive CAD (≥50% stenosis). The primary outcome was a composite of cardiovascular death, non-fatal myocardial infarction, or ischaemic stroke. Associations between CAD severity and outcomes were assessed using cause-specific proportional hazards models with multivariable adjustment. Among 10,247 young adults (median age 47 years; 56% women), 29.0% had non-obstructive plaque and 8.7% had obstructive CAD. Over a median follow-up of 6.7 years (interquartile range 4.2-10.4), the risk of the primary outcome increased stepwise with increasing CAD severity. Compared with no CAD, obstructive CAD was associated with a more than two-fold higher risk of events [adjusted hazard ratio (HR) 2.6, 95% confidence interval (CI) 1.9-3.6], while non-obstructive CAD was associated with a modest, non-significant increase in risk (adjHR 1.2, 95% CI 0.9-1.7). Among patients with non-obstructive CAD, event rates increased with greater plaque extent. In routine clinical practice, approximately 40% of young adults undergoing CCTA demonstrate coronary atherosclerosis, which is independently associated with adverse long-term cardiovascular outcomes. These findings support the role of CCTA in early risk stratification and targeted preventive strategies among younger individuals.

Stable angina pectoris (SAP) is a common risk factor for myocardial infarction and death. The genomic, transcriptomic, and phenomic heterogeneities of SAP require combination therapies. Multi-target drugs with fixed doses are emerging as scalable and promising prevention and therapeutic strategies for SAP. However, the identification of targets and underlying mechanisms of multi-target drugs for optimal clinical efficacy remains insurmountable. Here, we report a modular phenome-wide association study (MoPheWAS) of Danhong Injection (DHI), a clinically proven effective anti-SAP drug. The interrelated multitargets of DHI were divided into 32 On-modules. Eleven clinical SAP phenotypes defined by the Seattle Angina Questionnaire and serum lipids were interactively associated with 14 DHI efficacy-related Phe-modules. The intrinsic polymorphic associations between SAP phenotypes and Phe-modules manifested systematic positive/negative regulation of specific one-to-one as well as complex many-to-many relationships. These Phe-modules were conserved, transformed, or newly emerged modules involving G-protein-coupled receptor signaling and kinase binding. In vitro RNAi analysis confirmed the hub genes GALR1/BCMO1 in Mod-29 as multiple targets for the anti-ischemic effect of DHI. The landscape of modular regulators and polymorphic phenomic associations revealed the multi-target mechanisms underlying the therapeutic heterogeneity of SAP. Therefore, MoPheWAS may provides a novel systematic paradigm for identifying multiple phenomic targets of complex polygenic diseases.

Ischemic heart disease (IHD), the leading cause of death in the US, is predominantly due to modifiable risk factors. Estimates of IHD mortality attributable to risk factors provide evidence for health policy decision-making. To estimate the burden of IHD death attributable to risk factors in the US from 1990-2023. The Global Burden of Disease Study 2023 (GBD 2023) used vital records and a broad set of epidemiologic data to estimate IHD death rates, risk factor exposure, and relative risk curves for risk-outcome pairs for 1990-2023 for the general population. Data analysis was performed from October 2024 to December 2025. Twelve metabolic, behavioral, and environmental risk factors. The primary outcomes were IHD death rates per 100 000 persons, counts, and attributable risks from 1990-2023 by age, sex, and US state. Estimates include 95% uncertainty intervals (UI). IHD death rates were estimated using ensemble modeling methods. Risk exposures were estimated using bayesian meta-regression methods. Relative risks were estimated following the Burden of Proof framework. In 2023, there were 473 000 IHD deaths (95% UI, 414 000-510 000) in the US, a decrease of 58.7% (95% UI, 56.8%-61.0%) in age-standardized rate since 1990. Between 2010 and 2023, there was a 19.0% decrease (95% UI, 15.0%-22.9%) for males and a 24.5% decrease (95% UI, 20.3%-29.7%) for females in IHD death rates. High systolic blood pressure (SBP), dietary risks, and high low-density lipoprotein cholesterol (LDL-C) were the leading risk factors for IHD deaths in 2023, accounting for 47.2% (95% UI, 36.4%-57.0%), 38.6% (95% UI, 17.2%-56.8%), and 28.5% (95% UI, 19.3%-39.6%) of IHD deaths, respectively. Increased exposure to several risk factors substantially increased their attributable burden for IHD deaths in 2023, with high fasting plasma glucose (FPG) increasing 38.8% (95% UI, 11.5%-81.1%) and high body mass index (BMI) increasing 54.5% (95% UI, 41.8%-66.3%) since 1990. Smoking and particulate matter pollution had the greatest decrease in attributable IHD mortality since 1990, at 33.3% (95% UI, 23.6%-41.7%) and 74.9% (95% UI, 46.7%-88.8%), respectively. Per the results of this systematic analysis of GBD 2023, a total of 88.7% (95% UI, 83.4%-92.5%) of IHD deaths were attributable to modifiable risk factors in the US in 2023, with high SBP, dietary risks, and high LDL-C being the greatest contributors. High BMI and high FPG showed the largest attribution increases, while exposure to other risks did not increase significantly for the population.

Micro- and nanoplastics (MNPs) are emerging risk factors for cardiovascular diseases. The present study aimed to evaluate the burden of MNPs in coronary blood across the spectrum of coronary artery disease (CAD), and their association with air pollution exposure and inflammation. Cross-sectional study, including 61 consecutive patients undergoing coronary angiography for suspected CAD, stratified into: ST-segment elevation myocardial infarction (STEMI, n = 19), chronic coronary syndromes (CCS, n = 20), and controls with normal coronary arteries (n = 22). MNPs were quantified in coronary and peripheral blood using pyrolysis-gas chromatography-mass spectrometry and laser direct infrared spectroscopy. Air pollution exposure data were collected on the day of the invasive procedure (acute exposure) and over the preceding 2 years (chronic exposure). MNPs were detected significantly more frequently in STEMI patients (84.2%) than in CCS (40%) and controls (31.8%) (P = .002), with higher concentration and greater polymer diversity [median of 3 polymers (interquartile range: 2-4), P < .001]. Polyethylene was the predominant polymer (97%). The same polymers were consistently identified in peripheral and coronary blood samples from individual patients, with the highest concentrations in coronary blood (P < .001). STEMI patients showed higher levels of interleukin-6 and tumour necrosis factor-α (P≤.006) and were exposed to higher levels of PM2.5 (P≤.012). MNP detection was more frequent among smokers and patients exposed to PM2.5 > 15 µg/m3 (P = .006), with all patients presenting both factors showing detectable MNPs (P < .001). In multivariable analysis, smoking history emerged as the only independent predictor of MNP presence (odds ratio 5.69, 95% confidence interval 1.33-26.63, P = .023). STEMI patients exhibited a greater burden of MNPs in coronary blood than CCS and controls. MNP detection frequently co-occurred with elevated inflammatory biomarkers, greater PM2.5 exposure, and smoking, suggesting a potential association between environmental exposure and CAD.

The benefits of the Mediterranean diet (MedDiet) are well established. However, one component, wine, remains controversial. This study assessed the association between MedDiet (with or without wine consumption) and major cardiovascular disease (CVD) or all-cause mortality. The PREDIMED trial included 7447 high-risk participants. Adherence to MedDiet was measured using a validated 14-item questionnaire, including one item on wine (cut-off: seven glasses/week). The CVD events were recorded over a 4.8-year follow-up, while all-cause mortality was tracked for 17 years. A younger Spanish cohort (the SUN project), including 23,133 participants followed up for 22 years, was also evaluated. In PREDIMED, compared with poor compliers with MedDiet (excluding wine), good compliers (excluding wine), had a multivariable-adjusted hazard ratio (HR) of 0.84 [95% confidence interval (CI) 0.61-1.15] for CVD. For good compliers with MedDiet (including wine), the HR for CVD was 0.55 (95% CI 0.36-0.83). For all-cause mortality, MedDiet compliers (excluding wine) had HR of 0.77 (95% CI 0.68-0.87), which was 0.67 (95% CI 0.57-0.78) for MedDiet compliers (including wine). In exploratory dose-response analyses, reduced risk for death was not present in PREDIMED participants who drank three or more glasses of wine/day. Additionally, analyses least vulnerable to threats of abstainer bias were not significant and neither were multiplicative interaction terms for the wine item in the questionnaire. In the SUN cohort, no significant associations were observed between MedDiet compliance, wine, and CVD. However, for all-cause mortality, the HR was 0.94 (95% CI 0.71-1.26) for MedDiet compliers (excluding wine) and 0.54 (95% CI 0.28-1.04) for MedDiet compliers (including wine). When pooling both cohorts, wine consumption within the MedDiet was associated with lower all-cause mortality (P = .01). In PREDIMED, moderate wine consumption, as part of the MedDiet, appeared to be associated with lower mortality and CVD risk. Some non-significant associations and interactions advise caution in interpretation of these findings.

This study aims to define the association between severe coronary artery disease and widespread atherosclerosis in younger individuals. Individuals aged 1-50 years with sudden cardiac death (SCD) from 2019 to 2023, autopsy-proven to be due to coronary artery disease, were identified using the state-wide End Unexplained Cardiac Death (EndUCD) registry. Presence of extra-coronary atherosclerosis greater than modified American Heart Association Class III was assessed in four arterial beds (aorta, carotid, renal, and femoral arteries). A total of 3044 individuals experienced SCD; 356 were due to coronary artery disease, and 62 (17.4%) had extra-coronary plaque. Plaque was identified in the aorta (n = 61 patients, 17.1%), carotid arteries (n = 9, 2.5%), iliofemoral arteries (n = 11, 3.1%), and renal arteries (n = 6 patients, 1.7%). Features associated with extra-coronary plaque were older age (median 47.8 vs. 44.4 years, P = 0.0002) and hypertension (30.7 vs. 18.7%, P = 0.035). Patients with extra-coronary plaque had higher rates of cardiomegaly (67.9 vs. 50.7%, P = 0.019), cardiac fibrosis indicative of previous myocardial infarction (46.8 vs. 31.0%, P = 0.017), and multi-vessel coronary disease (71.7 vs. 55.9%, P = 0.024). Fewer than one in five people aged 1-50 years experiencing SCD from a coronary cause exhibited extra-coronary plaque, suggesting that in young people, severe atherosclerosis is not necessarily a concurrent systemic disease. This may limit the utility of screening for carotid or aortic plaque to predict coronary atherosclerosis on an individual level. Individuals with extra-coronary plaque were older with more established coronary disease.

Premature advanced subclinical coronary atherosclerosis among young adults is an under-recognized and unique disease phenotype that has not been well characterized. We used data from 44 047 participants with no prior CVD history (59.8% male) from the Coronary Artery Calcium (CAC) Consortium. We defined advanced disease as CAC ≥ 90th percentile for age, sex, and race and compared the risk factor profile of persons with advanced disease to those without CAC and those with CAC < 90th percentile. Using multivariable-adjusted Cox proportional hazard and competing risks regression, we assessed the association of premature advanced disease with all-cause, cardiovascular, and coronary heart disease (CHD) mortality. Of 44 047 participants, 18 561 (42.2%) had CAC. Among those with CAC, 6680 (36.0%) had CAC ≥ 90th percentile. Notably, 76.4% of those with CAC ≥ 90th percentile had multivessel CAC compared with 40.6% of those with CAC < 90th percentile. After a mean follow-up of 12.5 ± 3.6 years, the incidence per 1000 person-years of all-cause (2.93 vs. 1.85 vs. 1.11), cardiovascular (1.11 vs. 0.39 vs. 0.21), and CHD mortality (0.65 vs. 0.19 vs. 0.08) was highest in the advanced disease group compared with CAC < 90th percentile and the no CAC group. Persons with CAC ≥ 90th percentile had a higher multivariable-adjusted risk of all-cause [HR: 2.17 (1.83-2.57)], cardiovascular [sub-distribution hazard ratios (SHR): 3.89 (2.78-5.44)], and CHD mortality [SHR: 5.45 (3.38-8.78)], compared with those without CAC. In the subgroup analysis, there was no difference in mortality between men and women with advanced CAC. Premature advanced atherosclerosis is a distinct clinical phenotype that strongly predicts all-cause and cause-specific mortality. Among persons with CAC at young age, those with scores ≥90th percentile have the highest risk of early death and should be identified in future guidelines as a focus for aggressive clinical prevention.

The pathogenesis of atherosclerotic cardiovascular disease (ASCVD) is complex, involving a variety of immune and non-immune cells. The rising incidence of ASCVD presents significant challenges for therapeutic strategies. Traditional Chinese Medicine (TCM) and its active constituents demonstrate considerable potential in the treatment of ASCVD, owing to their holistic regulatory characteristics encompassing "multi-component, multi-target" mechanisms. This review systematically summarizes the mechanisms by which TCM and its bioactive ingredients exert anti-ASCVD effects through the modulation of endothelial cells, smooth muscle cells, platelets, cardiomyocytes, fibroblasts, and various immune cells, including T cells, neutrophils, monocytes, macrophages, mast cells, and dendritic cells. Furthermore, it outlines the clinical applications of TCM in managing ASCVD such as acute coronary syndrome, ischemic stroke, and stable coronary heart disease. Current limitations and future research directions are also discussed, offering insights for further investigation into TCM-based interventions for ASCVD.

Atherosclerotic plaque inflammation correlates with risk of rupture, causing myocardial infarction. Lower myocardial infarction risk in young women compared with men abates post-menopause, implicating ERs (estrogen receptors). The ERa (ER alpha) is necessary for estrogen effects on atherosclerosis in mouse models, yet the mechanistic role of ERa in plaque inflammation in both sexes remains unclear. The role of ERa in driving endothelial cell (EC) adhesion molecule expression and inflammation was studied in vitro in primary human ECs and in vivo in mice. LDLR (low-density lipoprotein receptor)-knockout mice with EC-specific ERa knockout were compared with ERa-intact littermates after 12 weeks of high-fat diet. In both sexes, EC-specific ERa knockout increased plaque inflammation and expression of adhesion molecules, including ICAM1 (intracellular adhesion molecule 1). In vitro, primary human ECs from young women expressed more ERa and less ICAM1 versus age-matched cells from men. ERa knockdown in human coronary ECs from both sexes increased adhesion molecules. Because the MR (mineralocorticoid receptor) has been implicated in ICAM1 expression and plaque inflammation in males, the impact of ERa on MR-induced ICAM1 expression was explored. In human ECs, estrogen prevented aldosterone induction of ICAM1 and MR enrichment on the ICAM1 promoter. In vivo, EC-specific MR-knockout and EC-ERa/MR-double-knockout/LDLR-knockout mice were studied as above. In females, EC-specific MR knockout did not impact ICAM1 or plaque inflammation, consistent with ERa inhibiting MR function. In the double-knockout model, the lack of MR prevented the increased inflammation and ICAM1 expression observed with loss of EC-ERa. In males, EC-specific MR knockout alone decreased inflammation and ICAM1. In the double-knockout model, the proinflammatory effects of MR and the anti-inflammatory impact of ERa offset each other. These findings reveal a role for ERa in regulating plaque inflammation in both sexes. In females, estrogen acts via EC-ERa to inhibit MR transcriptional upregulation of ICAM1, attenuating plaque inflammation. In males, ICAM1 expression is driven by the MR and inhibited by ERa.

Coronary atherosclerosis underlies life-threatening conditions such as myocardial infarction and stroke, yet its cellular dynamics remain incompletely understood. Here, through single-cell RNA sequencing of 27,941 cells from 56 human coronary segments, we constructed a disease-stage-resolved cellular atlas, revealing pathological remodelling of endothelial cells (ECs) into a progenitor-like state (EC5SLCO4A1+) with low expression of canonical EC dysfunction signatures. EC5SLCO4A1+ abundance increased with atherosclerotic stage, and its emergence is driven by PRDM15 through direct transcriptional activation. Analysis of the EC5SLCO4A1+ interaction network revealed extensive crosstalk with immune cell types, the interaction between which contributed to atherosclerotic progression. Endothelial overexpression of Prdm15 in vivo exacerbated atherosclerosis, while its suppression ameliorated the disease phenotype, with diminished EC5SLCO4A1+-like cells and immune infiltration. Our findings underscore the central role of EC subtype remodelling in the progression of human coronary atherosclerosis and reveal tractable targets for therapeutic intervention.

Endovascular thrombectomy (EVT) is the standard reperfusion therapy for emergent large-vessel occlusion; however, nearly 20% of EVT-treated patients still die within one year. Although early clinical indicators can help stratify post-EVT prognosis, the baseline neuroinflammatory biology associated with fatal outcomes after EVT remains incompletely characterized. In this prospective study of 148 EVT-treated patients, including 30 patients who died within 1 year, we profiled pre-procedure serum proteins using the Olink 384 Inflammation panel and applied an exploratory clinical-proteomic framework. A clinical-only model was used to define higher-risk and lower-risk clinical strata. We then mapped these strata to baseline proteomic patterns through differential expression and annotation-supported candidate mapping. Higher-risk phenotypes were associated with a candidate inflammation- and immune-receptor-related baseline protein pattern. Lower-risk phenotypes were associated with a candidate adhesion/extracellular-matrix-related baseline protein pattern. These internally derived findings suggest that poor outcomes after EVT are associated with candidate baseline inflammatory and tissue-structure-related proteomic patterns. This study provides a neuroinflammation-focused framework for hypothesis generation and candidate prioritization, but the findings require external validation.

Brain perivascular spaces (PVS) are emerging magnetic resonance imaging markers of microvascular function and waste metabolite clearance. Although PVS enlargement has been linked to aging and vascular risk, it remains unclear whether PVS morphometry reflects shared familial microvascular characteristics and how these are shaped by individual vascular, physiological, and neuropsychiatric factors. We investigated whether PVS morphometry captures these familial characteristics in addition to individual determinants. We analyzed 1183 participants from the Stratifying Depression and Resilience Longitudinally family-based cohort, including 324 individuals with first-degree relatives. Automated magnetic resonance imaging segmentation quantified PVS volume, count, density, and median length in the centrum semiovale and basal ganglia. Linear mixed-effects models assessed associations with age, hypertension, hair cortisol, depressive symptom scores, and hand grip strength while accounting for familial clustering. In 1050 individuals (59.5% female; mean age, 59.3±10.1 years), PVS burden increased with age (PVSvolume%ROI, β=0.18 [95% CI, 0.11-0.26]; P<0.0001), current depressive symptoms across both regions (PVS density: centrum semiovale, β=0.092 [0.023-0.16]; P=0.009; BG, β=0.11 [0.043-0.18], P=0.002; largely robust to false discovery rate correction), and with higher hair cortisol (PVS count β=0.08 [0.003-0.15]; P=0.041; borderline after false discovery rate correction) and weaker grip strength (PVSvolume%ROI β=-0.09 [-0.16 to -0.02]; P=0.013), in the centrum semiovale. Familial clustering was significant for PVS volume (β=0.22 [0.096-0.52]; P=0.013) and median length (β=0.28 [0.16-0.49]; P=0.0003), independent of other factors. PVS morphometry reflects shared familial microvascular phenotypes and neuropsychiatric influences beyond hypertension, highlighting both familial and individual determinants of PVS burden and morphology. These findings support PVS morphometry as a neuroimaging marker of cerebral microvascular health.

Ischemic stroke (IS) related to atrial fibrillation (AF) represents a cardio-cerebral comorbidity, whereas diabetes-related IS reflects an advanced manifestation of panvascular disease. We aimed to analyze the burden trends in AF-related and diabetes-related IS, using Global Burden of Diseases 2021 data. To quantify the burdens of AF- and diabetes-related IS, we applied the population-attributable fraction, the proportion of burden preventable by eliminating a risk factor. We calculated population-attributable fractions stratified by time, location, and age group. We analyzed the burdens using joinpoint regression, time-series projection to 2050, and age/sex-stratified. Globally, AF-related IS had a higher age-standardized incidence rate in 1990 but declined steadily (average annual percentage change =-0.81 [95% CI, -0.92 to -0.69]). Conversely, diabetes-related IS, despite a lower initial incidence, exhibited substantial and sustained increases (average annual percentage change=1.10 [95% CI, 1.02-1.18]). Middle-high socio-demographic index regions experienced the greatest burden from both comorbidities. In North America and Eastern Europe, the age-standardized incidence rates of AF-related IS stabilized (average annual percentage change=-1.45 [95% CI, -1.63 to -1.27]; -0.95 [95% CI, -1.06 to -0.84]), whereas the age-standardized incidence rates of diabetes-related IS continued to increase (average annual percentage change=1.18 [95% CI, 1.02-1.34]; 0.72 [95% CI, 0.56-0.88]). High body mass index emerged as a critical shared risk factor for AF, diabetes, and IS. Projections indicate a substantial increase in diabetes-related IS incidence over the next 3 decades, contrasting with minimal growth in AF-related IS. IS remains a critical global health challenge, primarily driven by the rising burden of diabetes-related IS. Our findings highlight the importance of age- and country-specific interventions.

Ischemia-reperfusion injury contributes to continued infarct growth despite successful recanalization. Ischemic postconditioning (IPostC) reduces infarct size in preclinical models, but its therapeutic effect as an adjunct to endovascular thrombectomy remains uncertain. We investigated whether IPostC performed after successful recanalization reduces infarct growth in patients with acute ischemic stroke. This single-center, prospective, randomized, open-label trial with blinded end point assessment was conducted at Tianjin Huanhu Hospital between September 2024 and May 2025. Patients with acute ischemic stroke who underwent endovascular thrombectomy within 24 hours of symptom onset or last known well, had a baseline National Institutes of Health Stroke Scale score ≥6 and a prestroke modified Rankin Scale score ≤2, and achieved successful recanalization after endovascular thrombectomy were randomly assigned to the IPostC or control group. IPostC consisted of 4 cycles of 2-minute balloon inflation followed by 2-minute deflation, with the balloon positioned at the original intracranial arterial occlusion site. The primary outcome was infarct growth from baseline to 48-hour magnetic resonance imaging (MRI). Secondary outcomes included infarct volume on immediate postprocedure MRI (within 2 hours) and on 48-hour MRI; early infarct growth and late infarct growth; serial National Institutes of Health Stroke Scale scores during hospitalization; and modified Rankin Scale score at 90 days. Primary and secondary outcomes were analyzed in the intention-to-treat population using unadjusted between-group comparisons. Sixty patients were enrolled, with 30 randomly assigned to each group. Infarct growth from baseline to 48-hour MRI was lower with IPostC than with control (median difference, -8.7 mL [95% CI, -17.1 to -1.4]; P=0.015). In the serial MRI subgroup (n=30; 15 per group), early infarct growth was also lower with IPostC (median difference, -3.2 mL [95% CI, -8.7 to -0.1]; P=0.045). Patients in the IPostC group had a lower National Institutes of Health Stroke Scale score at 24 hours (median difference, -3.0 [95% CI, -5.0 to -1.0]; P=0.005). The 90-day modified Rankin Scale distribution did not differ significantly between groups (common odds ratio, 1.1 [95% CI, 0.4-2.6]; P=0.921). In this pilot randomized trial, IPostC performed after successful recanalization reduced infarct growth in patients with acute ischemic stroke due to large-vessel occlusion. These findings require confirmation in larger randomized trials. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06545734.

The Fazekas score is widely used to grade white matter hyperintensities (WMHs) in cerebral small vessel disease, yet the equivalent volume of each grade is unclear. We quantified the correspondence between Fazekas scores and WMH volume, normalized ratios, and derived conversion equations across populations. We analyzed 1220 participants from 4 mostly United Kingdom-based cohorts representing different cerebral small vessel disease severities: community-dwelling (LBC1936 [Lothian Birth Cohort 1936]), stroke (MSS2 [Mild Stroke Study 2] and MSS3 [Mild Stroke Study 3]), and a cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy-enriched cohort (INVESTIGATE [Imaging Neuro-Vascular, Endothelial & Structural Integrity in Preparation to Treat Small Vessel Diseases]). WMH burden was quantified as absolute WMH volume and as normalized ratios: WMH volume as a percentage of brain volume and WMH volume as a percentage of intracranial volume. Transition zones were defined as the overlap of WMH volume interquartile ranges between adjacent Fazekas scores. Linear, exponential (nonlinear least squares), and log-linear (ln WMH≈Fazekas score and zeros excluded) models were fitted; model fit was assessed using mean squared error, (pseudo-)R2, and Vuong tests. Periventricular-versus-deep WMH patterns within each total Fazekas score were compared using the Kruskal-Wallis test. The pooled cohort had a mean age of 69.4±8.9 years; 700 of 1227 records (57.1%) were male. WMH burden increased monotonically with a Fazekas score in all cohorts. Adjacent-grade separation was strongest in LBC1936 (all P≤0.002) but weaker at lower grades in MSS2, MSS3, and INVESTIGATE. The widest transition zones occurred between Fazekas grades of 3 to 4 and 4 to 5, whereas a clear WMH volume gap separated grades 5 and 6. Exponential models generally fit better than linear models, with lower mean squared error and supportive Vuong tests in most cohorts. Log-linear sensitivity analyses showed similar fitted trajectories after back-transformation. WMH burden did not differ consistently by periventricular-versus-deep distribution within Fazekas grades. WMH burden followed an exponential trajectory across Fazekas scores, with population-dependent progression. The resulting conversion equations enabled bidirectional translation between visual Fazekas score and quantitative WMH volume, facilitating cross-study comparison, large-scale epidemiology, and might facilitate clinical decision-making in cerebral small vessel disease.

Ischaemic stroke remains a major cause of disability and mortality, with current treatments constrained by a narrow therapeutic time window and the risk of complications such as haemorrhagic transformation and reperfusion injury. This study investigates the role of Dickkopf-related protein 2 (DKK2) in the pathophysiology of ischaemic stroke, exploring its potential as a therapeutic target. Dickkopf-related protein 2 levels were analysed in a murine model of transient middle cerebral artery occlusion (tMCAO) and in stroke patients with large vessel occlusion undergoing endovascular treatment. The causal role of DKK2 was explored using genetic knockout and viral targeting strategies to manipulate its expression, and using pharmacological approaches to assess its therapeutic potential. Mechanistic studies focused on the regulation of DKK2 by retinoid X receptor-alpha (RXRα) and its effects on neuronal injury and blood-brain barrier (BBB) integrity. Dickkopf-related protein 2 was significantly up-regulated in both the brain and serum of mice after tMCAO. Serum DKK2 levels were elevated in stroke patients with larger infarct volumes, ICH, and worse functional outcomes. In murine models, systemic or neuron-specific DKK2 overexpression exacerbated infarction, neurological deficits, and BBB disruption, while genetic ablation or monoclonal antibody-mediated inhibition of DKK2 substantially ameliorated these parameters. Mechanistically, DKK2 was up-regulated in neurons by RXRα under ischaemia/reperfusion conditions both in vitro and in vivo, and this contributed to neuronal death and BBB disruption through suppression of canonical Wnt signalling. Dickkopf-related protein 2 plays a critical role in the progression of ischaemic stroke by modulating neuronal survival and BBB integrity. Targeting DKK2 represents a promising therapeutic approach to ischaemic brain injury, and the observational human data extend experimental findings to human cerebrovascular pathology, suggesting translational potential.

Ischemic stroke and thrombotic vascular occlusion remain leading causes of mortality and disability worldwide, yet current therapies operate largely in an open-loop paradigm, delivering thrombolytics or mechanical intervention without adaptive feedback on clot state or treatment response. This review reframes thrombolysis as a dynamic, controllable biological process and introduces a systems-engineering perspective built around the Sense → Target → Lyse → Report framework for closed-loop nanomedicine. We synthesize advances across nanotechnology, thrombosis biology, and bioresponsive materials to examine how next-generation nanosystems can detect clot-specific biochemical and biomechanical cues, localize to thrombi under physiological flow, actuate controlled lytic activity, and provide real-time reporting of therapeutic progress. We first characterize the thrombus as a heterogeneous, evolving immunothrombotic structure. It comprises platelet-rich shells, red blood cell (RBC)-dense cores, and microdomains enriched in neutrophil extracellular traps (NETs), each presenting distinct molecular and mechanical signatures that can serve as sensing handles. We then analyze emerging stimulus-responsive nanoplatforms activated by thrombin, reactive oxygen species (ROS), shear, or pH, alongside biomimetic and flow-optimized targeting strategies designed to overcome washout and penetration barriers. Particular emphasis is placed on theranostic systems that integrate imaging and therapy, laying the foundation for feedback-guided intervention. To organize this rapidly evolving field, we propose Closed-Loop Readiness Levels (CLRL) as a translational framework that classifies thrombolytic technologies along a five-tier scale. The scale runs from open-loop systems with no feedback (CLRL-0) to fully autonomous, self-regulating nanosystems that adapt therapy in real time and terminate it once reperfusion is achieved (CLRL-4). Across experimental models, closed-loop concepts show promise in improving spatial precision, reducing systemic exposure, and adapting lytic intensity to clot resistance. However, key barriers remain, including hemodynamic complexity, protein corona effects, sensor specificity, and integration of reporting with autonomous control. Intermediate levels capture the progressive integration of stimulus-triggered activation, thrombus targeting, therapeutic actuation, and reporting before full autonomous control is reached. By unifying disparate advances under a control-systems paradigm, this review positions closed-loop thrombolysis as a transformative direction in stroke therapy, with the potential to shift treatment from static dosing toward responsive, intelligent, and patient-specific vascular intervention.

Cerebrovascular and neurodegenerative diseases rank among the leading causes of death worldwide and represent an increasing socioeconomic burden, particularly in aging populations. Pluripotent stem cell (PSC)-based therapies have emerged as promising strategies for replacing lost neurons and restoring neural circuits in disorders of the central nervous system (CNS). However, major barriers remain, including poor survival, limited integration, and variable functional maturation of transplanted cells. These challenges currently limit the reproducibility and clinical translation of PSC-based therapies. Here, we examine these barriers with a particular focus on ischemic stroke and Parkinson's disease, two conditions that represent complementary models of acute and chronic neuronal loss and are among the most advanced indications for PSC-based transplantation. We discuss how programmed cell death signaling contributes not only to neuronal loss in these disorders but also to the limited survival of transplanted PSC-derived grafts. Building on this mechanistic framework, we highlight strategies that may improve graft survival and functional integration. Specifically, we propose an integrated approach that combines modulation of programmed cell death pathways, targeted activation of RAS signaling, optimization of mitochondrial health, and use of biocompatible scaffolds to support neuronal maturation and network integration. Together, these strategies provide a conceptual framework for improving the reliability and therapeutic efficacy of PSC-based cell transplantation therapies and accelerating their translation toward clinical application.Overview of strategies to enhance PSC-derived neural graft survival and integration through modulation of cell death pathways, RAS signaling, mitochondrial function, and extracellular scaffolds. Created in BioRender. Raudzus, F. (2026) https://BioRender.com/blr0ycj.

Acid-sensing ion channels (ASICs) are typically activated by acidic environments and contribute to nociception and synaptic plasticity. ASIC1a is the most abundant subunit in the central nervous system and forms homomeric channels permeable to Na+ and Ca2+, making it a compelling therapeutic target for acidotic pathologies including stroke and traumatic brain injury. However, a complete conformational library of human ASIC1a has yet to be described. Here we show that human ASIC1a adopts six major conformations, resolved by cryo-electron microscopy across a pH range between 8.5 and 5.7 and in the presence of a toxin agonist and a gating-modifying amino acid substitution. These major conformations establish linear transmembrane helices to be associated with an open state, delineate mechanistic differences between proton and toxin activation and demonstrate that desensitization involves unexpected conformational diversity in the transmembrane domain. Together, they provide a three-dimensional framework to integrate previous structure-function studies on ASIC.

Adult hippocampal neurogenesis is altered after cerebral ischemia. Although stroke increases newborn neuron production, many cells display aberrant morphological and positional features that may impair functional integration and contribute to long-term cognitive deficits. Given the clinical heterogeneity of ischemic stroke and limited translational success of preclinical studies relying on single models, it remains unclear whether poststroke neurogenic alterations are conserved across experimental paradigms. This study aimed to identify common and model-specific features of hippocampal neurogenesis across focal ischemia models. We conducted a multicenter, multimodel analysis within the Stroke-IMPaCT consortium using permanent and transient middle cerebral artery occlusion paradigms, including distal middle cerebral artery occlusion under normoxic or hypoxic conditions (distal middle cerebral artery occlusion+hypoxia), and filament-based transient middle cerebral artery occlusion, across 6 sites. Adult C57BL/6J mice were analyzed at 3 days, 7 days, and 2 months after ischemia, sham, or naïve conditions. Hippocampal proliferation (Ki67) and neuroblasts (DCX [doublecortin]) were quantified; morphological maturation of newborn neurons was assessed through high-resolution analyses of dendritic architecture and somatodendritic polarity. Across all stroke models, ischemia induced a robust bilateral increase in hippocampal proliferation, most pronounced at 3 days and still elevated at 7 days, returning to baseline by 2 months. Neuroblast density was similarly increased at 7 days, particularly in the ipsilateral hippocampus, but normalized over time. Despite recovery in cell number, long-term analyses revealed a consistent reduction in apical dendrite length and increased proportion of neurons with aberrant features, including ectopic positioning, polarity defects, and abnormal lateral growth, across models and centers. Aberrant hippocampal neurogenesis represents a robust hallmark of poststroke pathology in mice, independent of ischemia type or surgical approach, despite known differences in the spatial distribution of primary injury across models. Our findings underscore the importance of considering structural quality, and not only quantity, of newborn neurons when evaluating poststroke plasticity and developing therapeutic strategies.

Nonrapid eye movement sleep (NREMS) is a critical physiological state supporting neural plasticity, memory consolidation, and functional recovery after brain injury. It is characterized by thalamocortical slow-wave (SW) activity (0.5-4 Hz) and spindles (10-16 Hz) that synchronize cortical activity and regulate synaptic strength. Thalamic strokes, though rare, often disrupt sleep-wake cycle architecture, NREMS oscillations, and cognitive and sensory processing. Conventional rodent stroke models lack access to deep brain structures and require anesthesia, restricting investigation of thalamic circuit dysfunction after injury. To address these limitations, we developed an optically guided photothrombotic stroke model that enables focal, anesthesia-free lesions of the mediodorsal thalamus (MD) in freely behaving mice. We tested whether MD stroke impairs thalamocortical oscillations and cognition, and whether sleep-targeted auditory stimulation rescues these deficits. This was a randomized, controlled, interventional study with a within-species design in male C57BL/6JRj mice enrolled at 10 to 16 weeks of age across 8 cohorts (n=8-12/group). Chronic electroencephalogram/electromyogram electrodes and optical fibers targeting the MD were implanted. An optically guided photothrombotic stroke model was induced with intraperitoneal Rose Bengal (10 mg/mL) followed by 532-nm light (10 mW, 6 min) in awake animals; sham controls received no light. Animals with poor electroencephalogram/electromyogram signals, artifacts, or incomplete testing were excluded. Primary outcomes were longitudinal (20 days) sleep-wake features and oscillations, working memory (Y-maze), and pain sensitivity. A subset received daily 1-Hz auditory stimulation (≈1 h/session for 10 days during NREMS-rich periods). Group differences were analyzed using 2-way ANOVA with the Bonferroni post hoc tests, unpaired t tests, and Pearson correlations (99% CIs). Optically guided photothrombotic stroke model induced stable focal MD lesions that increased wake-NREMS-wake transitions, elevated SW activity during wakefulness, and persistently reduced frontal individual SWs and spindles during NREMS compared with shams (P=0.03-P<0.001). These alterations were accompanied by impaired working memory and pain hypersensitivity (P<0.001), recapitulating hallmark features of paramedian thalamic infarcts in humans. Notably, auditory stimulation normalized sleep continuity, restored SW-spindle coupling, and working memory to sham levels (working memory errors were negatively correlated with spindle rate [r=-0.88] and SW-spindle coupling [r=-0.81]) and rescued impaired MD-anterior cingulate cortex connectivity to parvalbumin-positive interneurons. Focal MD lesions disrupt sleep-wake stability, thalamocortical oscillations, and working memory, whereas noninvasive auditory stimulation restores sleep dynamics, cognitive performance, and MD-anterior cingulate cortex synaptic connectivity. Together, our findings establish the optically guided photothrombotic stroke model as a versatile model for dissecting stroke recovery mechanisms and highlight noninvasive stimulations as a promising approach to restore sleep and cognitive function.

Rapid identification of stroke types remains a major clinical challenge, as current diagnostic methods often rely on neuroimaging, which is time-consuming and not always accessible in pre-hospital settings or remote zones. Glial fibrillary acidic protein (GFAP) has emerged as a promising biomarker for distinguishing hemorrhagic from ischemic stroke, paving the way for rapid, quantitative, and portable detection platforms. Here, we report an electrochemical vertical flow immunoassay (eVFIA) as a point-of-care device for the on-site determination of GFAP. The device combines a multilayer paper-based architecture with a screen-printed electrochemical cell, enabling rapid vertical flow immunoassay and electrochemical signal generation within 10 min. Through systematic optimization of assay parameters, the eVFIA offered a detection limit of 85 pg/mL and strong agreement with standard ELISA measurements. The vertical flow format accelerates fluid transport, while the electrochemical readout ensures quantitative, light-independent measurements. This platform thus offers a cost-effective and user-friendly approach to determine biomarkers for stroke type differentiation. Although further large-scale validation is needed, the GFAP-eVFIA demonstrates strong potential for deployment in decentralized healthcare environments, providing clinicians with a rapid and reliable tool for early stroke assessment.

The optimal transfusion strategy in patients with acute myocardial infarction (AMI) and anemia may be influenced by sex differences in pathophysiology and cardiovascular outcomes. The Myocardial Ischemia and Transfusion trial (MINT) randomized patients with AMI and anemia to restrictive or liberal transfusion thresholds, but sex-stratified outcomes remain undefined. The objective was to evaluate whether the clinical effect of restrictive versus liberal red blood cell transfusion strategies differs by sex in patients hospitalized with AMI and anemia. In this prespecified secondary analysis of the MINT trial, we examined outcomes by sex and transfusion strategy. The primary outcome was 30-day composite death or MI. Secondary outcomes included heart failure, stroke, cardiac death, and 180-day mortality. Adjusted relative risks (RRs) and hazard ratios (HRs) were estimated accounting for sex differences at baseline. Interactions between sex and transfusion effects were assessed. There were 3504 study participants, of whom 1593 (45.4%) were women. Women received fewer transfusions on average. Primary outcome occurred in 15.7% of women and 15.7% of men and occurred in 16.5% of women and 17.1% of men in the restrictive arm, versus 14.9% and 14.2% in the liberal arm, respectively. Women had a lower mortality between 30 and 180 days (11.0% versus 13.5%; P=0.04). There were no statistically significant interactions between sex and transfusion strategy for the primary outcome (interaction P=0.60). For 30-day cardiac death, a higher RR in men was observed in the restrictive transfusion arm (RR, 2.34; 95% CI, 1.48-3.70; interaction P=0.05). For MINT patients with anemia and AMI, women comprised nearly half of the study population, and randomization to a restrictive or liberal transfusion strategy resulted in comparable outcomes in women and men. These findings support sex-neutral transfusion thresholds. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02981407.

Patients with acute coronary syndromes (ACS) are at high ischaemic risk to which cholesterol, inflammation, and yet-to-be-identified pathways jointly contribute. The junctional protein associated with coronary artery disease (JCAD) drives incident cardiovascular events by acting on coagulation and fibrinolysis. This study aimed to assess whether JCAD serves as a novel marker of or target to address residual risk. In the discovery cohort (SPUM-ACS; n = 4787), ACS patients at residual lipid risk [RLR; on-statin LDL cholesterol (LDL-c) ≥70 mg/dL or ≥1.8 mmol/L], residual inflammatory risk [RIR; on-statin high-sensitivity C-reactive protein (hs-CRP) ≥2.0 mg/L], or both (RILR; on-statin LDL-c ≥70 mg/dL and hs-CRP ≥2.0 mg/L) were identified and compared with propensity-score matched controls. Contributions of hs-CRP, LDL-c and JCAD to recurrent major adverse cardiovascular events (MACE) were analysed. In an independent cohort (RISK-PPCI study; n = 496), effects of JCAD on endogenous coagulation and fibrinolysis were gauged, and JCAD-MACE associations were externally validated. At 1 year, patients at RLR, RIR, or RILR were at higher MACE risk as compared to controls [hazard ratio (HR), 1.55, 95% confidence interval (CI) 1.08-2.23; HR 1.80, 95% CI 1.24-2.61; and HR 1.75, 95% CI 1.12-2.75, respectively]. In those at RLR, MACE risk rose with increasing hs-CRP and JCAD, respectively, in uni- (HR per log2 increase, 1.17, 95% CI 1.06-1.30; HR 1.29, 95% CI 1.03-1.62) and multivariable-adjusted models [adjusted (a)HR 1.16, 95% CI 1.03-1.30; aHR 1.27, 95% CI 1.01-1.60]. In those at RIR, MACE risk increased 1.28-fold per log2 increase in JCAD (HR 1.28, 95% CI 1.03-1.59), which prevailed in multivariable-adjusted models (aHR 1.31, 95% CI 1.04-1.65). Similarly, in patients at RILR, MACE risk increased almost linearly with increasing JCAD (HR 1.45, 95% CI 1.09-1.92), independently of potential confounders (aHR 1.47, 95% CI 1.11-1.97). Plasma levels of JCAD correlated positively with proxies of impaired endogenous fibrinolysis, with the JCAD-MACE association being similarly observed in the external validation cohort. Acute coronary syndrome patients at RLR, RIR, or both are at high ischaemic risk. By modulating coagulation and endogenous fibrinolysis, JCAD represents a promising candidate to address the high residual risk that persists in ACS patients receiving guideline-recommended care. NCT01000701, NCT02562690.

Standard modifiable cardiovascular risk factors (SMuRFs) and non-SMuRFs are commonly used for risk stratification and therapeutic guidance after ST-elevation myocardial infarction (STEMI) in the general population. Their prognostic relevance with a potential implication for pharmacological and therapeutic management in individuals with established diabetes remains uncertain. This systematic review with meta-analysis aimed to identify prognostic factors associated with mortality in individuals with diabetes and STEMI qualifying for potential therapeutic targets. Studies evaluating prognostic factors for mortality in individuals with diabetes after STEMI were included up to May 3, 2025. Data extraction was performed independently by two reviewers. Certainty of evidence (CoE) was evaluated (GRADE). Thirty-seven studies were included, of which 25 had a high risk of bias. Mortality after STEMI in individuals with diabetes was consistently associated with non-SMuRFs (age, female sex, chronic kidney disease), acute cardiac dysfunction (Killip class III-IV, heart failure, cardiogenic shock), and atherosclerosis extent (anterior infarction, prior myocardial infarction, peripheral vascular disease). Diabetes-specific risk factors, including glycemic control parameters and insulin treatment, were also associated with increased risk of mortality (low to very low CoE). Once diabetes is established, no increased risk of mortality was observed for traditional SMuRFs, such as hypertension, smoking status, dyslipidemia, and obesity. These findings highlight the need for therapeutic strategies beyond conventional risk factor modification, with emphasis on acute hemodynamic management, tailored pharmacotherapy, and optimized glycemic control in this high-risk population. REGISTRATION PROSPERo: CRD42022378193.

Myocardial infarction (MI) remains a major clinical challenge, and early detection is essential to prevent irreversible myocardial damage. However, echocardiography-based MI detection relies heavily on physicians' subjective interpretation, leading to inter-observer variability and suboptimal performance. To address these challenges, we propose SegMotion-Net, an interpretable framework that integrates segmentation-derived anatomical priors with motion representation learning for MI detection. Specifically, a task-specific memory mechanism is employed to aggregate spatiotemporal features across cardiac cycles, providing contextual cues for accurate left ventricular (LV) wall segmentation. To mitigate error accumulation during memory updating, a memory enhancement module refines stored representations using predictive masks. Furthermore, we introduce an LV wall motion dynamics analysis module to capture temporally coherent and region-specific motion patterns associated with MI. On the public HMC-QU dataset, SegMotion-Net achieves a Dice coefficient of 93.5% for LV wall segmentation, and an AUC of 86.7% together with an F1 score of 87.5% for MI classification. External validation across multiple private datasets provides additional evidence of cross-center robustness. Notably, SegMotion-Net achieves performance approaching that of experienced cardiologists under echocardiography-only evaluation settings. By explicitly modeling LV wall segmentation and motion dynamics, the proposed framework provides interpretable and clinically meaningful decision support for MI detection.

To analyse the prevalence of obesity and its impact on long-term cardiovascular outcomes in patients with myocardial infarction (MI). Patients with MI registered in SWEDEHEART between 2010 and 2021 were followed through December 2021 (mean follow-up time 6 years). Associated risk of adverse events in WHO Body mass index (BMI) strata was assessed in adjusted Cox proportional hazards models, stratified by diabetes status (reference: normal BMI without diabetes). Of 124 360 patients, 21% had diabetes. Obesity was more common among patients with diabetes (37% vs. 20%). The highest risk of mortality and major cardiovascular events (MACE; all-cause death, MI, stroke, or heart failure) was observed in those with class 3 obesity and diabetes (HR 2.15 [95% CI 1.88-2.45] and 1.91 [1.73-2.10]), with a lower risk of MACE in class 3 obesity alone (1.29; 1.16-1.45). In patients without diabetes, the risk of MACE and death was present in class 2 and class 3 obesity, but not in those with overweight or class 1 obesity. Regardless of diabetes status, obesity was less associated with atherosclerotic events than heart failure and renal events. The highest risk for heart failure and renal events was for class 3 obesity with diabetes (2.92 [2.57-3.31] and 3.36 [2.87-3.93]). In patients with myocardial infarction, obesity is common and associated with a high risk of mortality, heart failure, and renal events, especially if diabetes is present. There is a need for an increased awareness of this high-risk group with obesity and cardiovascular disease.

An ultrasensitive electrochemiluminescence (ECL) biosensor was developed for the detection of the acute myocardial infarction (AMI) biomarker miRNA-499 by synergistically integrating an iridium-metallized covalent organic framework (Ir@TpBpy) with enzyme-assisted Y-shaped DNA amplification. The Ir@TpBpy COF was synthesized via post-metallization of a bipyridine-rich TpBpy framework with Ir(III) complexes. This design significantly enhances the ECL performance not only through material loading but also via a synergistic optimization strategy: (1) the conjugated framework constructs continuous charge transport pathways to accelerate electron transfer; and (2) the porous architecture induces a guest confinement effect that locally enriches the coreactant triethylamine (TEA), facilitating radical kinetics. Concurrently, a Y-shaped DNA amplification strategy, driven by Klenow fragment and Nt.BbvCl enzymes, facilitated exponential signal enhancement via cascade strand displacement reactions. The generated output strands triggered the displacement of pre-immobilized WO3/CuO quenchers from the electrode surface, thereby restoring the luminescence of Ir@TpBpy and achieving a sensitive "signal-on" readout. Benefiting from this dual-amplification approach, the biosensor achieved an exceptionally low limit of detection (LOD) of 0.81 aM across a linear range from 1 aM to 1 nM in human serum and cellular lysates. Clinical validation using Bland-Altman analysis demonstrated 95% agreement with qRT-PCR results, confirming that this synergy of coordination modulation and guest confinement offers a robust and precise platform for early AMI diagnosis.

Mechanosensitive nuclear signaling contributes to myocardial ischemia-reperfusion injury, but the substrates and mechanisms of NUAK1 (AMPK-related kinase 5) remain unclear. We investigated whether NUAK1 regulates SYNE1 (Nesprin-1)/linker of nucleoskeleton and cytoskeleton-dependent nuclear gating of YAP1 (Yes-associated protein 1) during hypoxia/reoxygenation and ischemia-reperfusion injury. We integrated quantitative phosphoproteomics, biochemical assays, phosphosite-mutant analyses, subcellular fractionation, atomic force microscopy, and genetic or pharmacological NUAK1 inhibition in neonatal mouse ventricular myocytes and mouse models of ischemia-reperfusion injury to define the NUAK1-SYNE1-YAP1 axis. Quantitative phosphoproteomics identified a conserved NUAK1-dependent phosphorylation site in Nesprin1-α2/SYNE1 (S434; S8284 in nesprin-1 giant), and biochemical assays supported direct SYNE1 phosphorylation by NUAK1. NUAK1 inhibition reduced apoptotic signaling and SYNE1 stability, enhanced YAP1 nuclear localization, and altered nuclear YAP1 dynamics. SYNE1 phosphosite-mutant and fractionation analyses indicated that NUAK1-SYNE1 restrains stress-induced YAP1 nuclear accumulation. Atomic force microscopy linked this pathway to nuclear mechanical remodeling. In mouse models of ischemia-reperfusion injury, NUAK1 inhibition reduced acute myocardial damage and improved remodeling indices. NUAK1-dependent SYNE1 phosphorylation shapes nuclear mechanosignaling during ischemic stress. NUAK1 downregulation promotes cardiomyocyte YAP1 nuclear activity and attenuates injury responses.

Designing robust, fully synthetic receptors capable of selective protein detection remains critical for advanced clinical diagnostics. Molecularly imprinted polymers (MIPs) are a promising alternative to antibodies, but their application is often limited by empirical epitope selection and incomplete integration into functional assays. Here, we present an end-to-end platform combining data-driven epitope selection with polynorepinephrine-based molecular imprinting to produce fully synthetic protein receptors. The Python script "Epitope Selection Rational Approach" (ESRA), integrating physicochemical descriptor analysis and supervised machine learning, was developed and applied to human myoglobin (MYG) to identify effective imprintable peptide epitopes in the pre-analytical stage. Five selected epitopes were used to fabricate molecularly imprinted PNE nanofilms (MIPNE-NFs) and nanoparticles (MIPNE-NPs), targeting distinct regions of MYG. Systematic kinetic and affinity characterization by surface plasmon resonance (SPR) revealed pronounced epitope- and format-dependent recognition, underscoring the need for parallel evaluation of nanofilm and nanoparticle architectures. The optimal NF/NP combination, exploited as a capturing probe and a signal enhancer, respectively, was implemented in a fully antibody-free SPR sandwich assay. This configuration achieved sensitive detection over 4-125 ng mL-1, with a limit of detection of 0.9 ± 0.5 ng mL-1 in buffer and 0.70 ± 0.02 ng mL-1 in 1/200 diluted serum, covering the clinically relevant range for acute myocardial infarction, rhabdomyolysis, and muscle injury. This work establishes a generalizable workflow, from rational epitope selection to imprinting, kinetic validation, and assay integration, demonstrating that MIPNE can provide robust, antibody-free alternatives for sensitive protein detection in complex biological matrices.

Myocardial infarction, characterized by irreversible cardiomyocyte loss, progressive cardiac fibrosis and subsequent deteriorated heart function, constitute an intractable global health burden. Promoting endogenous cardiomyocyte proliferation to achieve functional cardiac regeneration represents an available foreground for combatting heart failure. Based on extensive preclinical evidence, researchers have characterized the cellular and molecular mechanisms governing cardiomyocyte proliferation and elucidated the modulatory influence of the metabolic factors and extracellular matrix. Insights from various studies have facilitated the development of regenerative approaches that reprogramming terminally differentiated cardiomyocytes toward a more metabolic plastic and fetal-like state, thereby enhancing the proliferative and reparative potential. Integration of metabolic and mechanical signals has emerged as a critical determinant of successful cardiomyocyte reactivation, providing a mechanistic rationale for combinatorial therapeutic strategies. Nevertheless, despite remarkable progression in mechanistic understanding and proof-of-concept studies, cardiac regeneration protocols advanced to robust clinical validation or pharmacal application have yet to be developed. This review provides a historical and biologically grounded synthesis of preclinical advances in cardiac repair, regeneration and cardiomyocyte reprogramming, with particular emphasis on translational feasibility and clinical applicability. Current strategies and preclinical trial outcomes are summarized to construct a readiness framework that maps the developmental maturity of each approach. Finally, the review highlights existing biological and technical barriers, as well as emerging opportunities poised to shape the future of cardiac regenerative medicine.

Myocardial infarction (MI) is a major contributor to cardiovascular diseases (CVDs), creating an urgent demand for wireless, real-time, and continuous electrocardiogram (ECG) monitoring. However, conventional hospital-based instruments are bulky and operator-dependent, limiting accessibility and continuous pre-hospital monitoring of MI. Herein, we propose an interfacial welding strategy to fabricate seamlessly integrated point-of-care electronics for ECG monitoring towards pre-hospital diagnosis of MI. The interfacial welding is realized using a covalently-adaptive polymer containing dynamic disulfide bonds, which enables seamless interlocking of polymer layers to fabricate portable and integrated wearable electronics (PIWE). The PIWE can wirelessly record stable and high-quality ECG signals which reflect different stages of MI development. Furthermore, machine learning models are successfully established to analyse and classify the collected ECG signals, achieving accurate prediction of a certain stage of MI; it will greatly benefit pre-hospital ECG monitoring and MI diagnosis for people who are exposed to high-risk factors of CVDs. Overall, this work demonstrates an interface welding strategy based on dynamic chemistry, which enables facile fabrication of integrated electronics, offering great significance for smart healthcare once combined with machine learning, typically the pre-hospital monitoring of MI.

Designing a temporal regulation system for responsive stem cell delivery that simultaneously addresses micro-environmental improvement in the infarcted area and electromechanical coupling compensation through synergistic stem cell therapy continues to pose substantial research challenges. We present a micro-environmentally induced smart temporal regulation composite conductive hydrogel for myocardial infarction therapy. Adipose derived stem cells (ADSC) were seeded on alginate (Alg)/gelatin (GT) composite microspheres (Alg/GT), which were encapsulated into reactive oxygen species (ROS) responsive conductive hydrogels (HGB) based on hyaluronic acid functionalized with phenylboronic acid (HA-PBA), dopamine-modified GT (GT-DA), and borate-functionalized polyaniline (BPA). Alg/GT microspheres exhibit excellent carrying capacity for ADSC and promoting ADSC paracrine effects. Besides the smart controlled release properties, the optimised hydrogel (HGB3) possesses a variety of functional properties including injectability, appropriate mechanical strength and electrical conductivity, anti-inflammatory and antioxidant properties. Together, these properties contribute to micro-environmental enhancement and electromechanical coupling restoration in the infarcted myocardial region. When the composite system was injected into the infarcted myocardifm, it achieved benign remodeling of the infarcted myocardium through regulation of inflammation, inhibition of fibrosis and promotion of vascular regeneration. This micro-environmentally induced smart temporal regulation composite conductive hydrogel system offers a novel therapeutic strategy for the management of acute myocardial infarction.

Cardiac sarcoidosis is a granulomatous myocarditis, classified by some authorities as an infiltrative cardiomyopathy and by others as an inflammatory cardiomyopathy, that carries an elevated risk of life-threatening arrhythmias, heart failure, and sudden cardiac death. Despite its clinical importance, diagnosis remains challenging. No single modality achieves both high sensitivity and specificity, and the 4 major consensus documents-comprising expert consensus statements, clinical practice guidelines, and a scientific statement-differ in diagnostic thresholds and can yield discordant diagnoses when applied to the same patient. Genetic cardiomyopathies account for a meaningful fraction of patients diagnosed with presumed isolated cardiac sarcoidosis. This primer organizes the diagnostic approach around 2 clinical contexts: de novo cardiac presentation with unexplained atrioventricular block, ventricular arrhythmia, or heart failure without previous sarcoidosis; and cardiac screening in patients with established extracardiac sarcoidosis. In nonurgent presentations, concordant cardiac magnetic resonance imaging and 18F-fluorodeoxyglucose positron emission tomography abnormalities are accepted as sufficient for diagnosis; endomyocardial biopsy is indicated when imaging is inconclusive or giant cell myocarditis must be excluded. Advanced imaging should precede permanent device implantation in all de novo presentations. Isolated cardiac sarcoidosis represents the most diagnostically challenging phenotype. A 5-step pathway is presented that integrates advanced imaging, tissue acquisition when it would change management, and genetic evaluation. Expert opinion on histologic confirmation in nonurgent presentations is divided, and no diagnostic approach has been prospectively validated.

Pathophysiological features of hypertrophic cardiomyopathy include left ventricular hypertrophy, myocardial fibrosis, and myocardial energy deficiency. Depletion of cardiomyocyte copper I ions leads to impaired mitochondrial function, a state associated with left ventricular hypertrophy. Unbound or loosely bound copper II ions activate profibrotic pathways. Trientine dihydrochloride improves intracellular copper I ion trafficking and availability, and chelates copper II ions. In preclinical studies, trientine improved myocardial mitochondrial function and reduced left ventricular hypertrophy and fibrosis. The efficacy and safety of trientine in persons with hypertrophic cardiomyopathy are unknown. In this multicentre, placebo-controlled phase 2 trial, adults with hypertrophic cardiomyopathy, a left ventricular wall thickness of 15 mm or greater, and who were in New York Heart Association class I to III were randomly assigned to receive trientine 400 mg twice daily or placebo for 52 weeks. Patients with any left ventricular outflow tract (LVOT) gradient were eligible. The primary endpoint was the change in left ventricular mass indexed to body surface area measured using cardiovascular magnetic resonance. A total of 154 patients underwent randomization. The mean age was 53.4 years, median maximum left ventricular wall thickness was 20.0 mm, median maximum LVOT gradient was 6.0 mmHg, 18.6% of patients had a resting LVOT gradient ≥30 mmHg, and 61.7% were in New York Heart Association class I. At 52 weeks, the mean change in the left ventricular mass indexed to body surface area was -4.4 ± 7.7 g/m2 in the trientine group and -1.5 ± 6.1 g/m2 in the placebo group (between-group difference -3.2 g/m2; 95% confidence interval -5.6 to -0.8; P = .009). The efficacy of trientine increased at higher levels of baseline left ventricular mass (baseline left ventricular mass indexed to body surface area by treatment allocation interaction P = .015). The effect of trientine was mediated via a reduction in myocardial cellular mass (average causal mediated effect -3.9 g/m2; 95% confidence interval -6.8 to -0.9). The incidence of adverse events was similar in the two groups. Among patients with hypertrophic cardiomyopathy, treatment with trientine resulted in a significantly greater reduction in left ventricular mass indexed to body surface area than placebo. (Funded by NIHR; TEMPEST ClinicalTrials.gov number, NCT04706429).

Hypertrophic cardiomyopathy (HCM) is characterized by left ventricular hypertrophy along with (micro)vascular abnormalities. These include cardiac and peripheral vascular dysfunction, as well as structural vascular changes. This review summarizes the modalities for assessing (micro)vascular function and explores how vascular changes relate to disease progression, including structural remodeling, fibrosis, and clinical outcomes. A systematic search of multiple databases was conducted to identify studies investigating vascular changes in patients with HCM, varying in disease severity. Human studies were included without time restrictions and studies involving hypertrophy secondary to other conditions (e.g., hypertension, aortic stenosis) were excluded.A total of 130 studies were included. Vascular changes were assessed with Positron Emission Tomography (n = 24), Cardiac Magnetic Resonance Imaging (n = 21), angiography (n = 18), scintigraphy and Single Photon Emission Computed Tomography (n = 30), peripheral measures (n = 12), and histology (n = 29). Perfusion abnormalities were common in HCM. While resting myocardial blood flow appears to be similar between HCM patients and controls, myocardial perfusion reserve is consistently reduced, correlating with early disease features, structural remodeling, and adverse outcomes. Peripheral vascular dysfunction is also frequently observed, though findings vary and mechanisms remain unclear. Vascular abnormalities play a key role in the pathophysiology of HCM, and are closely linked to disease progression and prognosis. Data are limited regarding the role of vascular dysfunction in genotype-positive/phenotype-negative individuals and individuals with early or mild disease. Future research should focus on evaluating cardiac and peripheral vascular function across the disease spectrum to better understand underlying mechanisms and potential targets for intervention.

Metabolic adaptation and maladaptation are hallmarks of the failing heart and may be a target for therapeutic interventions. For example, sustained glucose oxidation during cardiac stress is associated with increased activity and abundance of ACL (ATP-dependent citrate lyase, Acly), which produces acetyl-coenzyme A (CoA) from citrate and CoA and supports de novo lipid synthesis. However, our understanding of how ACL supports cardiac metabolic adaptation and its potential to modulate disease pathophysiology has not yet been investigated. We used human heart tissue samples from healthy donors and patients with nonischemic cardiomyopathy. Next, we used CRISPR (clustered, regularly interspaced short palindromic repeats)/Cas9 (CRISPR-associated 9) gene editing to inactivate Acly in cardiomyocytes of Myh6-Cas9 mice. In vivo positron emission tomography and ex vivo stable isotope tracer labeling were used to quantify metabolic flux changes in response to Acly knockdown. We conducted a multi-omics analysis using RNA sequencing and mass spectrometry-based metabolomics and proteomics. Experimental data were integrated into computational modeling using the metabolic network CardioNet to identify significantly dysregulated metabolic processes at a systems level. We observed reduced ACL abundance and activity in human heart tissue samples from patients with nonischemic cardiomyopathy, which correlated with decreased abundance of Krebs cycle intermediates. Using CRISPR/Cas9 gene editing, we found that cardiac-specific loss of ACL reduces acetyl-CoA synthesis, leading to altered cardiac metabolism characterized by increased glucose uptake and oxidation, impaired energy flux, and elevated AMP to ATP ratios, which collectively promote left ventricular dysfunction. Transcriptomic and mass spectrometry-based metabolomics, as well as proteomic data, reveal compensatory cardiac lipid remodeling and reduced histone 3 acetylation. This metabolic stress promotes activation of AMPK (AMP kinase) and PKA (protein kinase A), which in turn mediates YAP (Yes-associated protein) inhibition through phosphorylation. Stable isotope tracer studies combined with CardioNet simulations demonstrated that increased IDH1 (isocitrate dehydrogenase 1) activity prevents allosteric inhibition of glycolysis from cytosolic citrate accumulation. AAV9-mediated cardiac Idh1 deletion improved cardiac function and energy provision, reducing YAP phosphorylation and restoring downstream YAP signaling. Our findings suggest that ACL plays a pivotal role in cardiac metabolism through regulating lipid synthesis and cardiac function. Exploiting compensatory pathways of citrate metabolism may improve cardiac function during heart failure.

In non-muscle cells, actin filaments exhibit variable lengths and rapid turnover, with subunits adding primarily at the barbed end. The situation is strikingly different in striated muscle sarcomeres, where despite rapid turnover, actin thin filaments exhibit uniform length and exchange subunits primarily at the pointed end. This filament length uniformity is tightly regulated by several proteins, including the molecular ruler nebulin in skeletal muscle and the barbed- and pointed-end capping proteins CapZ and tropomodulin (Tmod) in both skeletal and cardiac muscles. Recent studies in cells and animal models have identified leiomodin-2 (Lmod2) as an additional regulator proposed to promote pointed-end elongation to maintain thin filament length. This activity would make leiomodin the only known eukaryotic factor to drive pointed-end elongation, yet its molecular mechanism remains unresolved. Here, we present a series of cryo-electron microscopy structures that support a stepwise elongation mechanism in which two Lmod2 molecules alternate at the pointed end while recruiting actin monomers. These findings establish the molecular basis of pointed-end elongation in muscle sarcomeres and provide a framework for understanding mutations in Lmod2 that cause dilated cardiomyopathy.

The actin cytoskeleton drives essential processes like cell migration and muscle contraction. While barbed-end polymerization is well-established, pointed-end elongation was long considered impossible in vivo. Here, we demonstrate that Leiomodin 2 (Lmod2), which localizes to thin-filament pointed ends in striated muscle cells, functions as an actin polymerase for pointed-end elongation. Single-molecule and single-filament imaging reveal that Lmod2 remains processively bound to pointed ends in vitro, enabling elongation even in the presence of high profilin concentrations found in the cytoplasm that otherwise would cause depolymerization of free pointed ends. Kinetic analysis indicates that Lmod2-mediated elongation proceeds through a linked two-step mechanism, in which monomer addition is followed by a first-order transition at the Lmod2-bound pointed end that limits elongation at high actin concentrations. Lmod2's activity also persists in the presence of tropomyosin, underscoring its physiological relevance. Both processivity and elongation rate of Lmod2 are dependent on its WH2 domain. Remarkably, human dilated cardiomyopathy-associated mutations in Lmod2 greatly reduce Lmod2's pointed-end elongation activity, providing a potential mechanism for disease progression and supporting a role for Lmod2-mediated polymerization in the formation and maintenance of muscle sarcomeres.

Cardiac hypertrophy, a significant pathological response to various stressors, often culminates in heart failure and necessitates the identification of novel regulatory targets for developing effective therapeutic strategies. In our study, an integrated transcriptomic and proteomic analysis revealed that deubiquitinating enzyme 13 (USP13) was significantly downregulated during cardiac hypertrophy. Subsequent functional experiments confirmed that USP13 overexpression markedly ameliorated transverse aortic constriction-induced cardiac dysfunction and attenuated cardiomyocyte hypertrophy, indicating that USP13 functions as a potential suppressor of this pathological condition. Mechanistic studies demonstrated that USP13 binds to and deubiquitinates sorting nexin 13 (SNX13), thereby stabilizing the SNX13 protein. SNX13 promotes nuclear accumulation of Nrf2, upregulating key ferroptosis-related genes including SLC7A11 and GPX4, thereby attenuating ferroptosis and ameliorating cardiac hypertrophy. Additionally, the m6A reader YTHDF2 was found to bind m6A-modified USP13 mRNA, facilitating its degradation and subsequent reduction in USP13 expression. We also established that the palmitoyltransferase ZDHHC18 enhances YTHDF2 stability by mediating YTHDF2 S-palmitoylation, specifically at Cys468. This study identifies a functional ZDHHC18/YTHDF2/USP13/SNX13/Nrf2/ferroptosis signaling axis in cardiac hypertrophy, highlighting its potential as a therapeutic target.

Pathological cardiac hypertrophy, a key precursor to heart failure (HF), can be triggered by external stimuli such as pressure overload or increased sympathetic activity. While liquid-liquid phase separation (LLPS) is a fundamental mechanism for cellular stress response and is implicated in various diseases, its role in HF remains unclear. Of particular interest are paraspeckles, membraneless organelles formed through the long non-coding RNA Neat1 via LLPS. Therefore, this study aims to investigate the contribution of this specific RNA-mediated LLPS pathway to the development of cardiac hypertrophy and HF. RNA fluorescence in situ hybridization (FISH) was employed to evaluate the presence and abundance of paraspeckles in cardiomyocytes under pathological stress-including isoproterenol (ISO) treatment and transverse aortic constriction (TAC) surgery-as well as in heart tissue from patients with HF. Neat1 expression in human HF samples was quantified to establish the association between Neat1 and HF. The functional role of paraspeckles was assessed using Neat1 knockout mice. Subsequent in vivo and in vitro loss-of-function experiments, involving both Neat1 knockout and knockdown models, were conducted to elucidate the underlying mechanisms. Finally, the therapeutic potential of targeting paraspeckles was explored using a viral delivery strategy to disrupt paraspeckle formation in mice subjected to TAC. Paraspeckles were present in cardiomyocytes, and their formation, mediated by lncRNA Neat1, was significantly up-regulated in cardiomyocytes in response to ISO stimulation, pressure overload, and in heart tissue from patients with HF. Functionally, disrupting paraspeckle formation attenuated ISO-induced cardiomyocyte remodelling, whereas genetic ablation of Neat1 prevented pressure overload-induced cardiac dysfunction and hypertrophy. Mechanistically, increased paraspeckle formation drove myocardial remodelling by promoting cardiomyocyte ferroptosis, achieved through the nuclear sequestration of Fth1 mRNA. Importantly, AAV9-mediated cardiomyocyte-specific knockdown of Neat1_2 (the long isoform of Neat1) effectively prevented the development of TAC-induced HF. These findings revealed that LLPS driven by lncRNA Neat1 promotes pressure-overload cardiac remodelling by regulating iron homeostasis. Targeting this process presents a novel RNA-based therapeutic avenue for preventing pathological cardiac remodelling and HF.

Mutations in the splice-regulator RBM20 cause heart failure with reduced ejection fraction (HFrEF), typically manifesting as dilated cardiomyopathy (DCM). Mutations at position 634 in the RS-domain cause DCM with (R634L) or without (R634W) left ventricular non-compaction (LVNC). However, the mechanisms underlying phenotype variability and personalized therapy beyond HFrEF remain unclear. We generated induced pluripotent stem cell-derived cardiomyocytes (iPSC-CM), 3D-cardiospheres and engineered myocardial tissues from patients with RBM20 mutations R634L (LVNC) or R634W (DCM). Using CRISPR/Cas9, we created isogenic rescue and mutation-insertion lines, identifying RBM20 mis-localization, splicing errors in TTN and RYR2, and sarcomere irregularities in both. DCM-CM showed increased resting Ca2+ leak and reduced Ca2+ transient amplitude, typical of HFrEF, and spatial disorganization of sarcoplasmic reticulum and mitochondria. In contrast, LVNC-CM exhibited elevated Ca2+ transient amplitude with faster kinetics, driven by elevated cAMP and mis-spliced, hyperactive CAMK2D, leading to PLN-hyperphosphorylation and increased metabolic respiration. Further, LVNC showed desmosomal derangement potentially from mis-splicing of Junction plakoglobin and reduced 3D cardiosphere compaction. Despite distinct mechanisms, contractile force was reduced in both. Isogenic controls confirm mutation causality. Drug intervention with verapamil partially improved selected abnormal Ca2+ handling and contractile phenotypes in LVNC- and DCM-CM, whereas the CAMK2D inhibitor AIP improved systolic Ca2+ handling predominantly in LVNC-CM. In conclusion, different amino acid substitutions at the same RBM20-residue induce opposing Ca2+-handling and structural phenotypes. While DCM features impaired Ca2+ handling, LVNC shows defective cell-cell coupling and activated Ca2+ handling and metabolism, yet insufficient to compensate for organ-level dysfunction. This supports personalized pharmacological therapies in early HF, and potential CRISPR/Cas9 repair for RBM20 cardiomyopathy.

Bisphenol F (BPF) is a common substitute for bisphenol A and the most prevalent bisphenol compound in diverse plastic manufacturing applications. However, the potential toxicity of BPF remains largely unexplored. This study investigates the effects of BPF on the cardiovascular system and intestinal barrier. Germ-free mouse models and fecal microbiota transplantation techniques were used to confirm the role of gut microbiota in BPF-induced cardiovascular injury. Untargeted metabolomics and spatial metabolomics were used to identify the in vivo metabolic products of BPF. Single-cell sequencing was used to identify which cardiac cell types were damaged by BPF exposure. BPF was detected in 90.5% of 285 human urine samples (median, 1.16 ng/μg creatinine). BPF exposure induced cardiomyocyte hypertrophy, cardiac dysfunction, and intestinal barrier damage, effects contingent on the presence of gut microbiota. Metabolomic analysis identified the microbial conversion of BPF to N-acetylputrescine (NAP). Mechanistically, we found that BPF stimulated intestinal epithelial cells to secrete spermidine/spermine N1-acetyltransferase 1 (Sat1), which catalyzed this conversion. Furthermore, NAP impaired the intestinal barrier by disrupting the Golgi-mitochondria axis and caused cardiac hypertrophy by activating the p53 pathway and inhibiting glycolysis in cardiomyocytes. Supplementation with Akkermansia muciniphila or its metabolite tryptophol mitigated BPF-induced cardiac and intestinal injuries by downregulating the Sat1-NAP axis. Clinical analysis further showed elevated serum NAP levels in patients with inflammatory bowel disease, positively correlating with cardiac injury markers. BPF disrupts intestinal barrier function through microbial metabolism involving the tryptophol/Sat1 pathway, leading to NAP production. NAP damages intestinal organelles and enters circulation, inducing cardiac p53 activation and hypertrophy. This study delineates a novel gut microbiota-Sat1-NAP pathway underlying BPF-induced cardiotoxicity, offering new insights for risk assessment and therapeutic intervention.

At a time when there was no unifying hypothesis and no broadly effective treatments for heart failure with a preserved ejection fraction (HFpEF), it was proposed that HFpEF represented a multitude of different disorders. Accordingly, characterization of phenotypic heterogeneity was envisioned as a means of identifying novel causal pathways that could lead to new treatments while simultaneously discerning patients who would selectively benefit from a specific therapy. However, efforts over the past decade to characterize phenotypic diversity in diverse and complex ways have not achieved these goals. Subgroup analyses of neutral HFpEF trials have failed to reliably identify responders to treatments. Neither proteomics nor unsupervised cluster analysis across multiple phenotypic domains has yielded reproducible results (even in the same dataset), elucidated novel mechanistic pathways for new drug development, or identified patients most likely to benefit from treatment. In marked contrast to these efforts to characterize phenotypic heterogeneity, large-scale trials in HFpEF enrolled patients using broad eligibility criteria, and they established the benefits of sodium-glucose cotransporter 2 inhibitors and mineralocorticoid receptor antagonists without evidence for subgroup effects. However, it is noteworthy that patients enrolled in recent large-scale HFpEF trials were characterized by general uniformity with respect to the presence of excess adiposity, with central obesity being a feature of the vast majority of enrolled participants. Of note, patients with obesity showed particularly large benefits when treated with effective drugs for HFpEF. These observations raise the possibility that, if these trials had permitted the participation of patients with class III obesity or with lower natriuretic peptide levels, the magnitude of the observed treatment effects might have been greater than originally reported. These findings are consistent with a central role for visceral adiposity (and the secretion of an altered suite of adipokines) in the pathogenesis of HFpEF. Therefore, because the field of HFpEF has a unifying hypothesis (applicable to the large majority of patients), enrolled a broad population of patients in large-scale trials without subgroup interactions, and has several broadly applicable effective treatments (as is true for heart failure with a reduced ejection fraction), the motivation to characterize phenotypic heterogeneity in HFpEF in complex ways may no longer be supported or needed.

Efforts to improve heart failure (HF) outcomes have focused on prescribing guideline-directed medical therapy at hospital discharge. Whether new prescriptions translate to sustained medication use after HF hospitalization is largely unknown. To characterize medication-use patterns following HF hospitalizations. A cohort study of patients in a regional US health system discharged home after an HF hospitalization between July 1, 2017, and March 30, 2023. Data were analyzed from August 2024 to February 2026. Medications of interest included β-blockers, renin-angiotensin system inhibitors (RASis), mineralocorticoid receptor antagonists (MRAs), and sodium-glucose co-transporter 2 inhibitors (SGLT2is). New prescriptions were identified by in-hospital administration or discharge medication orders. Using electronic health records linked to pharmacy dispensation records, medication initiation (prescription dispensation) and primary nonadherence (discharge prescriptions that were not filled) were assessed at 7 and 90 days postdischarge. Adherence (proportion of days covered ≥80%) and persistence (continuous days' supply) were assessed over 6 months postdischarge. This cohort study included 6111 patients with HF hospitalizations (mean [SD] age, 69.9 [13.6] years; 37.3% female [2277]) of whom 51% of were prescribed at least 1 new HF medication at discharge. At admission, 58.1% of patients were prescribed β-blockers (3549), 41.4% RASis (2530), 16.3% MRAs (997), and 4.9% SGLT2is (299); and at discharge, use increased to 73.3% (4481), 52.9% (3232), 28.5% (1740), and 9.0% (548), respectively. Primary nonadherence was observed in 51% (972 of 1904) of new prescriptions for β-blockers, 48% (659 of 1361) for RASis, 39% (482 of 1225) for MRAs, and 35% (134 of 383) for SGLT2is. Thus, of 4873 new discharge prescriptions, only 54% (2626) were initiated within 7 days of discharge and an additional 20% (954) had delayed initiation, between 7 and 90 days postdischarge. At 6 months, persistence to β-blockers was 70% (3127 of 4481), for RASis was 60% (1952 of 3232), for MRAs was 55% (961 of 1740), and for SGLT2is was 56% (306 of 548). As a result, at 6 months, only 42% (2188 of 5183) of patients were adherent and 51% (2620 of 5183) were persistent to all HF medications used at discharge. This cohort study found that following HF hospitalization, most new guideline-directed medical therapy prescriptions went unfilled. Moreover, most newly initiated prescriptions did not persist at 6 months, suggesting a need to develop interventions to support patients' medication use beyond the initial prescription at discharge.

Heart failure remains a major global health challenge. Emerging evidence highlights the gut microbiome's role in its pathogenesis and progression. This systematic review analyzed 32 studies involving 5825 patients to evaluate gut microbiota alterations and microbial metabolites in heart failure. Findings on alpha diversity were inconsistent, but beta diversity showed more agreement. A common pattern included depletion of short-chain fatty acid (SCFA)-producing bacteria and enrichment of pathogenic taxa such as Escherichia and Shigella. Heart failure patients also exhibited elevated levels of harmful metabolites like trimethylamine-N-oxide (TMAO) and phenylacetylglutamine. The dysbiotic profile was marked by increased Proteobacteria and decreased Firmicutes, linked to reduced cardioprotective metabolite production and heightened inflammation. These shifts may worsen heart failure prognosis and contribute to systemic inflammation. The results support the potential of microbiome-targeted therapies, such as probiotics, as adjunctive strategies in heart failure management.

To assess the cost-effectiveness of guideline-directed medical treatments for heart failure with reduced ejection fraction (HFrEF) by performing a network meta-analysis (NMA) of randomized controlled trials (RCTs) feeding a subsequent cost-effectiveness analysis. A random-effects NMA of RCTs was conducted. The primary analysis included only RCTs evaluating drugs in the clinical settings as recommended in the 2021 European Society of Cardiology HF guidelines. Main efficacy outcomes included all-cause mortality (ACM) and total HF hospitalizations (HFH). A decision tree-Markov model was populated with NMA-derived efficacy estimates, quality-of-life data, and costs from United Kingdom (UK, main analysis), as well as Sweden and United States (US) (scenario analyses) healthcare perspectives. 47 RCTs (75,978 patients) were included. The risk of ACM and total HFH decreased with increasing number of pharmacological treatments. In the main (UK) analysis, the greatest benefit was observed with a quadruple therapy including angiotensin receptor-neprilysin inhibitor (ARNI) + β-blocker (BB) + mineralocorticoid receptor antagonist (MRA) + sodium-glucose cotransporter 2 inhibitors (SGLT2i), which resulted as the most cost-effective strategy (12.31 quality-adjusted life-years; net monetary benefit of £338,460; UK perspective). Findings were consistent in Sweden and US. Quadruple therapy with ARNI+BB+MRA+SGLT2i had the highest probability of being the most cost-effective strategy. Our findings might inform future health economic policies and reimbursement decisions, while also considering affordability, budget impact, and implementation feasibility.

Early identification of poor diuretic response is central to acute heart failure (AHF) care, yet the recommended post-diuretic urine sodium (uNa+) thresholds are neither prospectively derived nor validated. We aimed to derive and validate clinically actionable urinary biomarker thresholds to identify poor diuretic response. In this prospective derivation-validation study, 336 AHF patients formed the derivation cohort, and 141 patients formed the validation cohort. Spot urinary biomarkers were measured 2h after loop diuretic administration. Diuretic resistance was defined as urine output <500 mL/6 h, and insufficient diuretic response as <1000 mL/6 h. In the derivation cohort, optimal uNa thresholds were <60 mmol/L and <90 mmol/L, respectively. For diuretic resistance, uNa+ <60 mmol/L showed 0.80 (95%CI: 0.65 -0.90) sensitivity, 0.94 (95%CI: 0.90-0.96) specificity, and an area under the curve (AUC) of 0.93 (95%CI: 0.90-0.97). For insufficient diuretic response, uNa+ <90 mmol/L showed 0.80 (95%CI: 0.69-0.86) sensitivity, 0.84 (95%CI: 0.787-0.878) specificity, and an AUC of 0.86 (95%CI: 0.83-0.93). In the validation cohort, uNa+ <60 mmol/L had numerically higher sensitivity than uNa+ <50 mmol/L (0.87 (95%CI: 062 -0.98) vs. 0.73 (95%CI: 0.48- 0.89)), with similar specificity (0.94 (95%CI: 0.89 -0.97) vs. 0.97 (95%CI: 0.92-0.99)) for diuretic resistance. For insufficient diuretic response, uNa+ <90 mmol/L had higher sensitivity: 0.86 (95%CI: 0.71-0.94) than lower thresholds, with specificity: 0.83 (95%CI: 0.75 -0.89). In AHF, data-derived post-diuretic uNa+ thresholds of <60 mmol/L and <90 mmol/L identify diuretic resistance and insufficient diuretic response, respectively. Further research and broad external validation are needed.

Tricuspid regurgitation (TR) rarely exists as an isolated condition and is most frequently secondary due to heart failure (HF), or atrial fibrillation, with prevalent extracardiac comorbidities. Morphological assessment of the anatomy and severity of TR, together with evaluation of symptoms, currently drives interventional approaches, yet a more holistic integration of causal and contributing comorbid conditions might further improve outcomes. The present review explores such a pathophysiology-driven holistic approach to interpret functional changes and symptomatic burden in patients with TR. It focuses on acknowledging the dynamic nature of TR, but most importantly the bidirectional crosstalk between TR and HF, as well as other organ systems that might drive symptoms and prognosis, but also TR progression. Assessment of TR is ideally performed after optimizing the treatment of interfering comorbidities and correcting volume overload to isolate the true effects of the TR itself. Invasive hemodynamic assessment, portal vein Doppler, and liver stiffness measurements may offer useful information in clinical decision-making. When TR is identified as the primary driver of disease, or if it is strongly interacting with concomitant diseases, more aggressive therapeutic approaches may be pursued. In contrast, when it is more a consequence of the underlying HF, the right expectations in terms of symptomatic improvement and prognosis should be set. This framework may help to identify patients who are the most likely to benefit from TR interventions, while acknowledging the complexity of their clinical picture in the context of HF.

Myocardial injury is a hallmark of heart failure (HF). It is unknown whether established (e.g. troponin) or novel biomarkers of myocardial injury [e.g. cardiac myosin-binding protein C (cMyBP-C)] provide additive diagnostic value beyond natriuretic peptides in community patients with suspected HF. Community-based patients with suspected HF and elevated NT-proBNP levels were recruited into a multicentre, prospective, observational study at five sites (NCT04724200). Venous blood sampling was performed at the time of echocardiography. HF was classified according to left ventricular ejection fraction: HF with reduced ejection fraction (HFrEF) = ≤40%, HF with mildly reduced ejection (HFmrEF) = 41-49%, and HF with preserved ejection fraction (HFpEF) = ≥50% with HFA-PEFF score ≥5. NT-proBNP (Roche Elecsys® assay), high-sensitivity cardiac troponin T (hs-cTnT, Roche Elecsys® assay) and cMyBP-C (Roche precommercial assay) were measured. Diagnostic accuracy of each biomarker alone and in combination was examined using the area under the receiver operating characteristic curve (AUROC). Of 867 patients, 751 (87%) had measurable left ventricular ejection fraction and available biomarker data. Of these, 43 (6%) had HFrEF, 75 (10%) HFmrEF, and 278 (37%) HFpEF. NT-proBNP levels were highest in patients with HFrEF, with similar patterns observed for hsTnT and cMyBP-C. For the diagnosis of HF versus no HF, the combination of NT-proBNP and cMyBP-C had the highest AUROC of 0.77 (95%CI 0.73-0.80) versus NT-proBNP alone [0.74 (0.71-0.78); P = .003]. For detection of HFrEF versus no HF, the AUROC was 0.90 (0.86-0.95) for the combination of NT-proBNP and cMyBP-C compared with 0.85 (0.80-0.90) for NT-proBNP alone (P = .006). Measurement of cMyBP-C improved the diagnostic accuracy of NT-proBNP in community-based patients with suspected HF, with greatest additive value for identifying HFrEF, and may help in the prioritization of echocardiography.

SIRT5 (sirtuin 5) is a member of the sirtuin family known to regulate cardiac metabolism, aging, and function. However, its role in cardiac fibroblast (CFB) metabolism, activation, and fibrosis remains elusive. Expression changes of SIRT5 in CFBs from cardiac tissue of human and mouse with heart failure were determined. The functional role of SIRT5 in cardiac fibrosis was evaluated through CFB-specific knockout and overexpression of Sirt5 in mice. The involvement of succinylation of lysine 489 (Lys489) on PCK2 (phosphoenolpyruvate carboxykinase 2) in SIRT5-mediated regulation of cardiac fibrosis was assessed by introducing the Lys489-to-arginine mutation of PCK2 in Sirt5-deficient CFBs and in CFB-specific Sirt5 knockout mice. SIRT5 expression was markedly reduced in CFBs from humans and mice with heart failure and showed a negative correlation with cardiac fibrosis severity. Loss of Sirt5 in CFBs exacerbated left ventricular dysfunction, cardiac hypertrophy, and cardiac fibrosis in mice subjected to transverse aortic constriction, whereas overexpression of Sirt5 in CFBs significantly attenuated these pathological changes. Sirt5 deficiency promoted CFB activation by driving a metabolic shift from oxidative phosphorylation to glycolysis. Mechanistically, Sirt5 deficiency increased the succinylation of PCK2 at Lys489, a key enzyme linking glycolysis and the tricarboxylic acid cycle, which consequently inhibited this enzyme activity in CFBs. Importantly, this specific modification at the Lys489 mutation that prevents succinylation effectively reversed both the metabolic reprogramming and the hyperactivation of CFBs induced by Sirt5 knockout. In vivo, introducing the Pck2 K489R mutation fully rescued the exacerbated cardiac fibrosis and dysfunction observed in Sirt5-deficient mice after transverse aortic constriction. By desuccinylating PCK2 at Lys489, SIRT5 prevents the metabolic reprogramming and subsequent activation of CFBs, protecting against cardiac fibrosis.

Heart failure with preserved ejection fraction (HFpEF) is increasingly acknowledged as a major public health concern due to its complex pathophysiology, which involves neuroinflammation and sympathetic activation. The crosstalk between the heart and hypothalamic microglia in HFpEF, particularly the role of small extracellular vesicles (sEVs), remains insufficiently explored. We constructed an HFpEF model in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor l-NAME (N[ω]-nitro-l-arginine methyl ester). These mice exhibited microglial activation and hypothalamic inflammation. Microglial depletion with PLX3397 suppressed sympathetic activity and improved cardiac dysfunction in HFpEF. sEVs derived from the myocardium of HFpEF mice induced a proinflammatory M1 phenotype in microglia, leading to hypothalamic inflammation and sympathetic activation. Intraperitoneal injection of the sEV biogenesis inhibitor GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglia treated with sEVs isolated from palmitic acid-treated HL-1 cardiomyocytes. Bioinformatic and RT-qPCR analyses revealed a notable upregulation of miR-200c-3p in sEVs derived from both HFpEF myocardial tissue and palmitic acid-treated HL-1 cardiomyocytes, as well as in microglia. A cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation, and sympathetic activation in HFpEF mice. Conversely, a miR-200c-3p mimic exacerbated proinflammatory responses in BV2 cells, while a miR-200c-3p inhibitor prevented the transition to a proinflammatory phenotype. The antiinflammatory protein DUSP1 (dual-specificity phosphatase 1) was validated as a potential downstream target of miR-200c-3p in microglia. Our study reveals that HFpEF prompts cardiomyocytes to release sEVs enriched with miR-200c-3p, leading to hypothalamic inflammation and evoking sympathetic outflow, which in turn exacerbates cardiac dysfunction. Focusing on sEV-mediated communication between cardiomyocytes and microglia may offer a new therapeutic approach for HFpEF.

The prognosis for heart failure (HF) with preserved ejection fraction (HFpEF) remains poor, with treatment evidence and studies at the human cellular level limited. Here, we aimed to model HFpEF-associated diastolic dysfunction in vitro by generating human engineered heart tissues (hEHTs) using human induced pluripotent stem cells and culturing the tissues under high fatty acid and L-NG-nitroarginine methyl ester supplementation. Medium-loaded hEHTs showed a marked reduction in relaxation function while preserving contraction function; secreted high levels of the HF marker, BNP; exhibited abnormal calcium transients; and showed structural and functional features of HF. After treatment with several existing HF drugs, a sodium-glucose cotransporter 2 inhibitor (SGLT2i) improved the decline in relaxation function and contributed to an improvement in the diastolic dysfunction phenotype. This mechanism exhibited an anti-inflammatory effect mediated by the recovery of the eNOS-NO-cGMP-PKG signaling pathway. These findings serve as a basis for elucidating the pathogenesis and mechanisms of improvement in HFpEF.

Preterm birth poses a global health challenge, frequently resulting in complex infant multimorbidity. While the adverse effects of maternal hypertensive disorders of pregnancy (HDP) on offspring are well recognized, their specific impact on distinct multimorbidity patterns in very preterm infants remains underexplored. In this multicenter cohort study, we utilize the Sino-northern Neonatal Network (SNN) database to systematically characterize these profiles. Here we show distinct patterns, including extrauterine growth restriction (EUGR) complicated by parenteral nutrition-associated cholestasis (EUGR-PNAC), congenital hypothyroidism (EUGR-CH), retinopathy of prematurity (EUGR-ROP), and bronchopulmonary dysplasia (EUGR-BPD). Notably, maternal HDP significantly increases the risk of developing these specific patterns. By elucidating these clinical consequences, our study advances the current understanding of the impact of adverse intrauterine exposures on offspring health. Ultimately, these insights highlight the critical need for multidisciplinary screening and management in this high-risk population, providing a crucial foundation for improving long-term neonatal outcomes.

The classical renin-angiotensin-aldosterone system (RAAS) remains one of the most important pharmacological targets in the treatment of cardiorenovascular diseases, including hypertension, heart failure, and chronic kidney disease. Pharmacological modulation of the RAAS has transformed clinical practice over the past decades. The earliest agents targeting this pathway were mineralocorticoid receptor antagonists, which were followed by ACE (angiotensin-converting enzyme) inhibitors, Ang (angiotensin) AT1R (AT1 receptor) blockers, and direct renin inhibitors. These drug classes continue to represent the cornerstone of guideline-directed therapy, and newer compounds within these categories are being developed to enhance efficacy, improve organ protection, and minimize adverse effects such as hyperkalemia, hypotension, and renal dysfunction. In addition to established therapies, innovative strategies targeting the classical RAAS are emerging. These include RNA-based therapeutics designed to suppress hepatic angiotensinogen synthesis and small-molecule inhibitors of aldosterone synthase. Such approaches may offer improved cardiovascular and renal outcomes by intervening earlier, more sustainably, or selectively in the RAAS cascade. Beyond the classical axis, increasing attention is being directed toward the so-called protective or alternative renin-angiotensin system (RAS). This pathway centers on ACE2, Ang-(1-7), alamandine, and their associated receptors, including Mas, MrgD (Mas-related G-protein-coupled receptor D), and the Ang AT2R (AT2 receptor). Activation of this axis exerts vasodilatory, anti-inflammatory, antifibrotic, and cardioprotective effects, thereby counterbalancing the deleterious actions of the classical RAAS. Growing experimental and clinical evidence supports its therapeutic potential not only in cardiovascular disease but also in metabolic, fibrotic, and inflammatory disorders. This review summarizes the current state of pharmacological interventions targeting both the classical and protective RAAS and highlights emerging therapeutic directions that may shape the next generation of cardiovascular treatments.

Hypertension prevalence rises dramatically with advancing age, is not well controlled with current therapy, and contributes substantially to cardiovascular, renal, and neurological disorders that are common in the elderly. The renin-angiotensin-aldosterone system is a hormonal pathway with multiorgan involvement critical to controlling blood pressure. The production of the steroid hormone aldosterone and the activation state of its MR (mineralocorticoid receptor) are important clinical targets for hypertension treatment and cardiorenal disease prevention. This review summarizes studies demonstrating that aging is associated with (1) dysregulation of adrenal aldosterone production by autonomous aldosterone-producing adrenal cells and, when comorbid with obesity, by factors released from adipose tissue that promote adrenal aldosterone production; (2) increased expression of the MR due to oxidative stress-activated and inflammation-activated transcription factors; and (3) aldosterone-independent MR activation by oxidative stress-activated Rac1 (Ras-related C3 botulinum toxin substrate 1), angiotensin II signaling, and declining expression of the cortisol-inactivating enzyme 11β-HSD2 (11-beta-hydroxysteroid dehydrogenase type 2). Together, these data support the concept that elderly individuals are at high risk for mineralocorticoid-driven hypertension and associated cardiovascular, renal, and neurological disease. The review further describes the different classes of agents that inhibit this pathway, including traditional steroidal MR antagonists, newer nonsteroidal MR antagonists, and aldosterone synthase inhibitors, comparing their modes of action. The steroidal MR antagonists and nonsteroidal MR antagonists have different degrees of MR selectivity and potency, yet they all block MR activation by aldosterone, cortisol, and ligand-independent mechanisms. The aldosterone synthase inhibitors block aldosterone production in the adrenal gland and attenuate aldosterone-mediated MR effects. All 3 drug classes raise potassium proportional to the degree of renal MR inhibition. Trials are summarized showing efficacy of the new agents in reducing MR activation, aldosterone production, blood pressure, and adverse cardiorenal outcomes. Head-to-head studies in older individuals are needed to determine the relative efficacy of aldosterone synthase versus MR inhibition for blood pressure control to improve outcomes in the elderly and very old.

GLP-1R (glucagon-like peptide-1 receptor) agonists are transforming therapeutic strategies in hypertension and cardiometabolic syndrome by shifting the focus from merely controlling individual risk factors to modifying the vascular-metabolic biology that underpins these conditions. In addition to promoting weight loss and improved glycemic control, growing clinical and experimental evidence indicates their beneficial effects on endothelial dysfunction, vascular inflammation, leukocyte recruitment, atherosclerotic plaque composition, and cardiorenal pathways involved in sodium regulation and neurohumoral balance, key processes in cardiometabolic-related hypertension and associated heart failure. This review integrates rapid clinical advancements in GLP-1R agonists with emerging mechanistic insights, clarifying which findings are well-established and which remain inferential, and identifying significant translational gaps that would provide deeper insight into cardiometabolic diseases. Key priorities include determining which benefits reflect direct GLP-1R signaling within cardiovascular/renal tissues versus secondary cardiometabolic changes, establishing cell type-resolved GLP-1R localization in human heart and kidney, and developing response biomarkers for cardiovascular and heart failure outcomes. Addressing these issues through detailed trial phenotyping, advanced mechanistic imaging, and relevant experimental models will facilitate personalized application of existing therapies and inform the development of next-generation incretin-based strategies aimed at durable vascular protection and blood pressure regulation for better cardiovascular health.

Dementia is the fifth leading cause of death globally and currently has no cure. The evidence on the associations of hypertension, internet use, physical activity (PA) and dementia remains sparse. This study examined whether internet use and PA mediate the hypertension-dementia link, assessed their interactive and joint effects with hypertension, and evaluated the direct, indirect, and total associations among these factors. This multinational cohort study used data from four nationally representative surveys across 31 countries (2011-2024). We included participants aged 50 years or older with data on hypertension, PA, internet use, and at least two assessments, excluding those with baseline dementia or memory disease, missing dementia or covariate data, or lost to follow-up. The analytical sample comprised 57,912 participants with a mean follow-up of 7 years, during which 4,945 dementia endpoint events were recorded. We used Cox proportional hazards models to examine the hypertension-dementia association, and did subgroup analyses to explore the variation. Furthermore, we conducted interaction, longitudinal mediation, and joint effect analyses to assess relationships among hypertension, PA, internet use, and dementia risk. Finally, we pooled results using random-effects meta-analysis. Hypertension was associated with increased dementia risk (hazard ratio[HR] 1.21 [1.11-1.31]). A significant multiplicative interaction existed between hypertension and internet use (HR 1.21 [1.06-1.38]). Longitudinal mediation analysis estimated indirect associations via PA (HR 1.06 [1.04-1.08]) and internet use (HR 1.21 [1.03-1.42]), with mediated proportions of 4.95% and 11.27%, respectively. Participants with hypertension, physical inactivity, and no internet use had a higher risk of dementia (HR 3.61 [3.21-4.06]). All associations were statistically significant (P < 0.05). PA and internet use only partially mediate hypertension and dementia, indicating additional interventions may also be needed to reduce dementia risk in older adults. Furthermore, their joint effects with hypertension suggest the potential value of combined strategies to alleviate the global dementia burden.

Obesity is a major risk factor for hypertension, but most evidence relies on single weight measurements. We examined associations between weight change and short-term risk of incident hypertension across body mass index (BMI) categories. We conducted a retrospective cohort study in the Danish Blood Donor Study of 81,954 participants aged 18-79 with at least two questionnaires (2010-2025). Weight change was the percentage difference between consecutive self-reported weights, grouped as stable, 2.5-5, 5-10, or more than 10% loss or gain. Incident hypertension was defined as first redemption of antihypertensive drugs. Associations were estimated using multivariable Cox models. During a median follow-up of 1.66 years (IQR 0.79-2.88; maximum 3 years), 5,503 participants initiated antihypertensive treatment. In BMI-stratified analyses, weight gain was associated with higher risk of initiation in all BMI categories, while weight loss was associated with lower risk only in overweight or obesity relative to stable weight. Across BMI categories using stable normal weight as reference, associations were stronger at higher BMI. More than 10% weight gain was associated with hazard ratios of 1.60 (95% CI 1.30-1.96) in normal weight, 2.44 (2.02-2.96) in overweight and 4.51 (3.57-5.70) in obesity. Hazard ratios were comparable across sex and age groups, although higher in younger men with obesity, while rates were highest in older participants. Weight gain was associated with higher risk of antihypertensive treatment across BMI categories compared with stable weight, whereas weight loss was inversely associated with initiation among adults with overweight or obesity.

This study estimates long-term effects of air pollution and greenness on the incidence of pre-/hypertension in children and adolescents. Exposures to particulate matter <2.5 µm (PM2.5), black carbon (BC), and nitrogen dioxide (NO2) at the residential addresses of 2385 children and adolescents of the IDEFICS/I.Family cohort were estimated using land use regression models; environmental greenness was assessed using the Normalized Difference Vegetation Index (NDVI). Applying g-computation, we estimated the effects of hypothetical reductions of PM2.5, BC, NO2, and increases of NDVI on the incidence of pre-/hypertension over a 6-year period compared with no intervention. The observed risk of developing pre-/hypertension was 14.4%. We found a dose-dependent relationship showing higher risk reductions when imposing lower hypothetical levels or larger percental reductions for the air pollutants. The largest effects were observed for PM2.5, e.g. reducing PM2.5 to ≤10 μg/m3 lowered the risk of developing pre-/hypertension by -10.7 [-14.1, -5.7; 95% bootstrap CI] percentage points compared with no intervention. Effects of BC reductions were less strong, e.g. -5.3 [-10.2, 1.7] when reducing BC to ≤0.8 × 10-5/m and small (non-significant) effects were found for NO2. Hypothetically increasing NDVI to ≥0.6 lowered the pre-/hypertension risk by -1.5 [-2.9, -0.4]. Sensitivity analyses suggested effects of air pollution mainly on systolic (SBP) but not diastolic blood pressure. Adherence to recommended levels of air pollutants and increased greenness can help to prevent hypertension among children and adolescents. Efforts to reduce air pollution could thus reduce the cardiovascular disease burden in later life.

The present study aimed to evaluate the association between body mass index (BMI) during childhood and puberty and blood pressure and hypertension in midlife and to explore midlife BMI as a potential mediator of these associations. We linked the BMI Epidemiology Study Gothenburg with developmental BMI, with the Swedish CArdioPulmonary bioImage Study (SCAPIS) with blood pressure and hypertension in midlife (n = 2394). The associations between childhood BMI (7-8 years) and pubertal BMI change (young adult BMI minus childhood BMI), and blood pressure and hypertension in midlife, were evaluated using linear or logistic regression models. Mediation analysis was conducted to evaluate the indirect effect, via midlife BMI, and the direct effect on blood pressure and hypertension. The analyses were adjusted for birth year and smoking. The pubertal BMI change was positively associated with systolic and diastolic blood pressures and hypertension in midlife, independent of childhood BMI, in both men and women (P < 0.01). For men but not for women, childhood BMI was positively associated with systolic and diastolic blood pressures in midlife, independent of the pubertal BMI change (P < 0.01). No significant independent association was observed for childhood BMI with hypertension. Mediation analyses for the association between the pubertal BMI change and blood pressure and hypertension in midlife indicate that these associations were largely mediated by BMI in midlife. These findings indicate that high blood pressure may originate in early life. A life-course approach for targeted prevention, starting already during the developmental years, could reduce the risk of high blood pressure.

Endothelium-derived NO is an important vasodilator essential for maintaining vascular homeostasis. However, how eNOS (endothelial nitric oxide synthase) is regulated in hypertension conditions is not yet fully understood. In this study, we describe a critical role of the GLRA2 (α2 subunit of glycine receptor) in modulating eNOS signaling and blood pressure regulation. Endothelial-specific Glra2-deficient mice and the adeno-associated viral-transfected mice were generated to assess the role of GLRA2 in hypertension models. Endothelium-dependent relaxation response and whole-cell patch clamp recording were determined. We first demonstrated selective expression of GLRA2 in arterial endothelial cells. Activation of GLRA2 by its ligand, glycine, effectively counteracts hypertension in a GLRA2-dependent manner. Our patient study indicated a negative correlation between plasma levels of glycine and blood pressure. Furthermore, we showed that endothelial GLRA2 regulates vasodilation by promoting NO production, rather than functioning solely as a chloride channel. Mechanistically, GLRA2 facilitates the phosphorylation of glycogen synthase kinase-3β at Ser9 (serine 9), which activates the AKT (protein kinase B)/eNOS signaling pathway in the endothelium, leading to increased NO release. This study discovers that a novel endothelial GLRA2 pathway holds significant potential for developing new strategies to control hypertension.

Large language models (LLMs) show considerable potential for atrial fibrillation (AF) management, yet current clinical applications frequently remain suboptimal due to accuracy limitations. To address these limitations, this study developed PULSE (Potentiated User-friendly LLM-driven Search Engine), a novel knowledge-enhanced, domain-aware LLM agent specifically designed to improve AF patient self-management across the entire care continuum. The proposed framework integrates multimodal inputs, meticulously curated clinical knowledge bases, optimized prompt engineering, and retrieval-augmented generation within an agent-based architecture. Performance was rigorously evaluated against four leading base LLMs using response quality (clinical accuracy, content integrity, practical utility, and patient safety) and readability (clarity, conciseness, and empathy). Comprehensive clinical validation was subsequently conducted through blinded expert assessment of 75 real-world AF-related patient queries. The results demonstrated that PULSE improved clinical accuracy, content integrity, utility, and safety (P < 0.05) across all tested models. Furthermore, it substantially enhanced empathy and clarity while maintaining comparable conciseness. Overall, PULSE improves both the factual accuracy and readability of patient-facing medical outputs, highlighting the immense clinical potential of agent-driven LLM systems to advance chronic disease self-management and improve long-term patient outcomes.

Many patients with heart failure (HF) have or develop atrial fibrillation (AF), which may contribute to worsening symptoms, hospitalisations and mortality. Whether catheter ablation improves outcomes in patients with HF and AF receiving guideline-recommended pharmacological therapy (GRPT) is controversial. A systematic review and meta-analysis of relevant randomised controlled trials (RCT)s on the role of catheter ablation in patients with AF and HF. Public databases for trials published prior to 17th March 2025 and investigating the effects of catheter ablation on morbidity and mortality in patients with HF and AF were searched. Outcomes of interest were all-cause and cardiovascular mortality, adverse events due to HF or AF, changes in left ventricular ejection fraction (LVEF), 6-Minute Walking Distance (6-MWD) and Minnesota Living With Heart Failure Questionnaire (MLWHFQ) scores. Altogether, thirteen RCTs including 2,490 patients (predominantly aged <65 years; of whom 73% were men and 79% reported persistent AF) were identified. Blinding of intervention was not attempted. Only three RCTs assessed the effect of catheter ablation in patients with preserved LVEF. Overall, compared to GRPT alone, catheter ablation was associated with lower all-cause mortality (hazard ratio [HR]: 0.58; 95% confidence interval [CI]: 0.44-0.76), cardiovascular death (HR: 0.52; 95% CI: 0.36-0.74) and adverse events related to HF or AF (HR: 0.69; 95% CI: 0.53-089). In addition, catheter ablation improved LVEF (+6% mean difference (MD)[95% CI: +4% to +9%]) and MLWHFQ (-12 points MD [95% CI: -18 points to -6 points]), with a trend to enhanced 6-MWD (+18 meters MD [95% CI: -1 meter to +38 meters]). For a selected group of patients with chronic HF and AF enrolled in un-blinded RCTs, catheter ablation improved cardiac function, wellbeing and outcomes, including all-cause mortality. Further RCTs are required to determine whether the benefits of catheter ablation extend to a broader population of patients at higher risk of procedural failure and recurrent AF.

Oral anticoagulants may reduce risk of hepatic decompensation in patients with compensated cirrhosis, but well-powered randomized trials are missing. We aimed to estimate the effect of oral anticoagulants on risk of hepatic decompensation and major bleeding in patients with compensated cirrhosis and atrial fibrillation. Observational data from Swedish healthcare registers 2011-2022 were used to emulate a target trial of oral anticoagulants in patients with compensated cirrhosis and newly diagnosed atrial fibrillation. Inverse-probability weighted marginal structural models were used to compare 5-year risks of hepatic decompensation and non-portal hypertension-related major bleeding in initiators versus non-initiators of oral anticoagulants. The study included 1,160 patients (715 men [61.6%]; median [p25-p75] age of 73 years [67-79]). The 5-year risk of hepatic decompensation was 10.4% (33/383) in initiators and 16.6% (112/777) in non-initiators (risk ratio [RR]=0.62, 95% confidence interval [CI]=0.33-0.92), corresponding to a number needed to treat of 17 (95%CI=9-112). The risk reduction was primarily driven by a reduced risk of ascites (RR=0.58, 95%CI=0.26-0.90). The risk of major bleeding was 19.0% (63/383) in initiators and 19.8% (149/777) in non-initiators (RR=0.96, 95%CI=0.64-1.28). Risks were similar between treatment groups regarding fatal, intracranial, gastrointestinal, and other bleedings. In this nationwide observational study, patients with compensated cirrhosis and atrial fibrillation who initiated oral anticoagulants had lower risk of hepatic decompensation, and similar risk of major bleeding compared to non-initiators. The results suggest oral anticoagulants are safe in patients with compensated cirrhosis and may improve prognosis. Randomized trials are warranted to confirm these results.

Anticoagulation therapy in patients with atrial fibrillation (AF) has changed over time, particularly following the introduction of direct oral anticoagulants. However, it is unknown how the uptake of anticoagulation therapy and the related clinical outcomes in elderly patients with AF have changed over time. Patients with new-onset AF were included and divided into three age groups: older adults (65-74 years), elderly (75-84 years), and very elderly (≥85 years). Temporal trends in the initiation of oral anticoagulants (OACs), the stroke-free survival, major bleedings including intracerebral haemorrhage (ICH), and all-cause mortality were investigated from 1999 to 2022. In total, 243 938 patients were included, of whom 89 184 (36.6%) were older adults, 99 002 were elderly (40.6%), and 55 752 (22.8%) were very elderly. The proportion of very elderly patients with AF receiving OACs was 71% in 2022. The absolute improvement in the 5-year probability of stroke-free survival was 10.1% in the older adult patients, 12.8% in the elderly patients, and 3.5% in the very elderly patients. The 5-year absolute risk of ICH increased among the elderly and very elderly AF patients. Over the past two decades, the risk of stroke decreased significantly among all age groups, with no subsequent increase in the risk of bleeding among older adults in an era where OACs were almost fully implemented. In the very elderly patients aged ≥85 years, the risk of stroke only slightly improved over time, with an increase in the risk of ICH.

Healthy aging is defined as remarkable longevity (beyond 90 years of age) accompanied by preserved functional status and absence of major clinical conditions. Although the incidence of cardiac arrhythmias, including atrial fibrillation (AF), increases with age, epidemiological studies revealed a paradoxical reduction of AF prevalence in centenarians compared to octogenarians and nonagenarians. Emerging evidence indicates that the apparent cardioprotection in healthy aging may be related to specific molecular and cellular adaptations observed in long-lived individuals. These include reduced systemic inflammation (c-reactive protein, interleukin-6), attenuated oxidative stress (reactive oxygen species), improved mitochondrial function (PGC-1⍺), and preservation of atrial structural integrity with reduced fibrosis (TGFβ, ⍺-SMA). Together, these mechanisms may limit atrial remodeling and maintain more stable electrophysiological properties, thereby reducing susceptibility to AF. In this review, we first discuss the concept of healthy aging as a state of intrinsic cardioprotection, and its relevance to prevent age-related cardiovascular disease. We then examine how centenarian-associated protective mechanisms may mitigate atrial arrhythmogenic remodeling, with a particular focus on inflammation-driven pathways. In addition, we evaluate the contribution of experimental models of healthy aging in the understanding of cardiac electrophysiology and arrhythmia mechanisms. Finally, we summarize current therapeutic strategies for AF in elderly patients and highlight the complex necessity of considering underlying aging-related substrates. Overall, this review emphasizes that healthy aging phenotypes may harbor intrinsic anti-inflammatory and anti-fibrotic adaptations that protect against atrial arrhythmogenesis. Understanding these mechanisms may provide novel translational opportunities for the development of preventive and mechanism-based antiarrhythmic strategies in the aging population.

Congenital long QT syndrome (LQTS) is a heterogeneous disorder in which genotype and QTc duration modulate the risk of major arrhythmic events (MAEs), but contemporary paediatric outcome data remain limited. This study aimed to characterize clinical features, management strategies, and predictors of MAEs in a nationwide paediatric LQTS cohort. This retrospective multicentre study analysed children (<18 years) diagnosed with LQTS across 30 tertiary centres (2004-24) using 2022 European Society of Cardiology criteria. MAEs were defined as sudden cardiac death, aborted cardiac arrest, or appropriate implantable cardioverter-defibrillator (ICD) therapy. The cohort included 371 children (58% male; median diagnosis age 6.0 years; interquartile range .25-11 years). Pathogenic/likely pathogenic variants were identified in 86.5%, mainly in KCNQ1, KCNH2, or SCN5A, while 5.7% harboured high-risk genotypes (Jervell-Lange-Nielsen, calmodulinopathies, CACNA1C/Timothy). Beta-blockers were prescribed in 92.4%. Over a median 6-year follow-up, 14 children (3.8%) experienced MAEs, which occurred predominantly in those with high-risk genotypes, QTc ≥550 ms or very early presentation. MAEs were rare in LQT1-3 with QTc <500 ms. Foetal/neonatal bradycardia (5.1%) correlated with high-risk genotypes and adverse outcomes. ICDs were implanted in 33 children (8.9%); 10 (30%) received appropriate therapies, and 8 (24%) experienced complications. Left cardiac sympathetic denervation was performed in 33 (8.9%), mainly high-risk patients, and was associated with >80% arrhythmia-free survival without major complications. In this nationwide paediatric LQTS cohort, MAEs were uncommon and clustered in children with malignant genotypes, markedly prolonged QTc and very early presentation, particularly foetal or neonatal bradycardia. These data support the current genotype and QTc-guided management strategy, with beta-blockers as the cornerstone therapy and selective use of left cardiac sympathetic denervation and ICDs in high-risk profiles.

Synthetic cannabinoid receptor agonists (SCRAs) are a large group of structurally diverse designer drugs (analogues of controlled substances) associated with intense and sometimes fatal intoxication. Cardiac symptoms, including tachycardia and arrhythmia, are common consequences of SCRA consumption. However, little is known about the mechanisms through which SCRAs may perturb cardiac rhythm. Here, we used electrophysiological techniques to screen 36 SCRAs on two ion channels responsible for cardiomyocyte repolarization, hERG (also called KV11.1) and KV7.1/KCNE1. We report that the majority of tested SCRAs inhibited hERG, primarily by reducing channel conductance, and some also inhibited KV7.1/KCNE1. In silico data suggest that SCRAs may use both a known drug binding site in the central cavity of the hERG channel, shared by established hERG blockers like astemizole, and a recently identified side pocket site. Experimental and in silico data suggest SCRA structural features associated with prominent inhibitory effects on hERG, with chemical moieties allowing bond formation and/or the ability to fit into binding sites being important. Structure-activity relationships (SAR) for SCRA effects on hERG, KV7.1/KCNE1 and the cannabinoid receptor 1 (CB1) varied, demonstrating the need to assess SCRA effects on multiple potential targets. In conclusion, we found SCRAs to be inhibitors of cardiac voltage-gated potassium channels important for cardiomyocyte repolarization, highlighting the importance of more extensive investigation of SCRAs on cardiac function.

The Nav1.5 channel, a major isoform of voltage-gated sodium ion channel, is mainly found in ventricular cardiomyocytes, playing a key role in generating essential cardiac action potentials for normal heart rhythms. Mutations in Nav1.5 have been associated with severe heart conditions such as long QT syndrome, Brugada syndrome, cardiac conduction disorders, atrial fibrillation, and dilated cardiomyopathy. Recent research has linked Nav1.5 to cardiac fibrosis and proposed its role in non-cardiac illnesses, including specific neurological disorders and cancers, subjects that will be reviewed in this paper. On the other hand, sodium-glucose cotransporter 2 inhibitors (SGLT2i), initially designed to manage diabetes by facilitating glucose excretion through urine, have demonstrated unexpected and encouraging cardioprotective benefits in clinical trials. This review compares the important SGLT2 inhibitors empagliflozin, dapagliflozin, and canagliflozin in terms of their interactions with Nav1.5 and their therapeutic effects on the heart. We also investigate new medications and compounds being developed to regulate Nav1.5 function, providing a preview of potential future treatments. Past attempts to develop late INa inhibitors and difficulties in transitioning from the research phase to clinical trials have raised doubts about the optimal design of such trials. In addition, we cover the applications of molecular dynamics simulations in understanding the mechanism of action of these drugs within the Nav1.5 channel computationally. We hope that this review identifies new opportunities to generate more effective inhibitors using novel methods and advanced multiscale molecular modelling techniques.

Cigarette smoking and hyperlipidemia are major risk factors for cardiovascular disease. However, the mechanisms underlying their synergistic cardiotoxic effects remain insufficiently elucidated, particularly at the cellular electrophysiological level. To address this, we developed an electrophysiological biosensing platform to establish a real-time co-exposure model that simulates the combined stress of nicotine and palmitic acid-induced hyperlipidemia on the primary rat cardiomyocytes. This model enabled continuous, non-invasive monitoring and quantitative analysis of field potential under individual and combined conditions. Our results revealed a distinct concentration-dependent effect of nicotine on cardiomyocytes: low-dose nicotine induced transient and reversible electrophysiological suppression, while high concentrations triggered severe arrhythmias and cell death. Critically, the co-exposure model revealed that a hyperlipidemic state significantly sensitizes cardiomyocytes to nicotine, markedly exacerbating arrhythmogenesis and compromising cell viability compared to nicotine alone. Moreover, nicotine withdrawal experiments showed that the electrophysiological damage induced by moderate nicotine exposure was reversible, whereas the adverse effects of high-dose nicotine exposure were largely irreversible. This study establishes an in vitro model to investigate the multifactorial cardiotoxicity, and provides a predictive platform for risk stratification and therapeutic intervention in smoking- and/or diet-related cardiovascular diseases.

As the global population ages and individuals live longer with chronic diseases associated with venous thromboembolism, acute pulmonary embolism (PE) is expected to remain a major public health challenge. Like myocardial infarction and stroke, PE is linked to established cardiovascular risk factors, including advancing age, obesity, smoking, and chronic inflammatory conditions. Despite this, population-based primary and secondary prevention strategies for PE remain limited, highlighting the need for an updated epidemiological understanding. A comprehensive public health approach to PE should encompass not only the management of acute events and transient risk factors but also a detailed appreciation of epidemiology and risk patterns across populations and communities, to support clinician education, public awareness, long-term individual and community risk assessment, ultimately preventive efforts. In this review, we summarize current epidemiological evidence, highlighting trends on modifiable and non-modifiable risk factors for acute PE, with the goal of informing strategies for improved prevention and population health management.

Elevated lipoprotein(a) [Lp(a)] levels are an established risk factor for atherosclerotic cardiovascular disease, but the association between Lp(a) and venous thromboembolism (VTE) remains unclear. Sex and hormonal status may modify the relationship between Lp(a) and VTE. The present study included participants from the UK Biobank with available baseline Lp(a) data. Individuals with a history of VTE or cancer, as well as those using anticoagulants, were excluded. Multivariable-adjusted Cox models were used to assess the association between Lp(a) levels ≥125 nmol/L and incident VTE in premenopausal women, postmenopausal women, and men. Subgroup analyses stratified premenopausal women by oral contraceptive (OCP) use and postmenopausal women by menopausal hormone therapy (MHT) use. Among 55 302 premenopausal women, 129 045 postmenopausal women, and 189 013 men, the proportions with Lp(a) ≥ 125 nmol/L were 14.0%, 19.0%, and 15.0%, respectively. Over a median (interquartile range) follow-up of 13.6 (12.9-14.4) years, 8186 VTE events occurred (cumulative incidence 2.2%). Lp(a) ≥ 125 nmol/L was associated with incident VTE in premenopausal women [adjusted hazard ratio (aHR) 1.32; 95% confidence interval (CI) 1.04-1.66; P = .02] but not in postmenopausal women (aHR 1.03; 95% CI 0.94-1.13; P = .47; Pinteraction = .03) or men (aHR 1.00; 95% CI 0.92-1.08; P = .94). OCP use did not modify the Lp(a)-VTE association among premenopausal women (Pinteraction = .61). However, among postmenopausal MHT users, Lp(a) ≥ 125 nmol/L was associated with higher VTE risk (aHR 1.48; 95% CI 1.03-2.12; P = .03; Pinteraction = .04). Elevated Lp(a) was associated with VTE in premenopausal women and in postmenopausal MHT users, suggesting that hormonal context may influence Lp(a)-associated thrombotic risk.

The heart transplant allocation system is evolving in response to increasing demand for donor organs, technological advances, and changes in medical decision-making. In this evolving landscape, the historical focus of allocating donor hearts to the "sickest patients first" principle may warrant periodic reassessment and thoughtful safeguards to ensure responsible stewardship and fairness. It is important to note that ethical considerations are central to frontline transplantation cardiologists and cardiothoracic surgeons, who must balance their role in advocating for their individual patients while aligning with allocation policies designed to benefit all recipients equitably. The goals of this scientific statement are (1) to raise awareness of ethical principles in heart transplantation, (2) to review ethical implications of the past and current allocation systems, and (3) to encourage clinicians and stakeholders to address ethical issues that will provide the foundation for future allocation systems.

Dual antiplatelet therapy (DAPT) following percutaneous coronary intervention (PCI) is traditionally guided by rule-based scores providing static, single-time-point or fixed time-interval estimates with modest discrimination (C-index 0.63-0.73), limiting individualized DAPT duration decisions. We developed Transformer-DAPT, a transformer-based deep learning survival framework designed to estimate patient-specific ischemic and bleeding risks across clinically relevant time intervals during the first year after PCI. Using electronic health records from 29,032 patients at Mayo Clinic and externally validated in 19,173 patients from the OneFlorida+ Clinical Research Consortium, Transformer-DAPT achieved time-dependent concordance indices (Ctd) of 0.84-0.87 for ischemic events and 0.81-0.88 for bleeding events, outperforming DeepSurv and DeepHit by 2%-12%. In the external cohort, Ctd ranged from 0.74-0.84 and 0.75-0.83 for ischemic and bleeding events, respectively. Transformer-DAPT demonstrated improved discrimination and calibration performance, providing a framework for multi-interval risk prediction to support personalized DAPT management after PCI.

This study aims to define the association between severe coronary artery disease and widespread atherosclerosis in younger individuals. Individuals aged 1-50 years with sudden cardiac death (SCD) from 2019 to 2023, autopsy proven to be due to coronary artery disease, were identified using the state-wide EndUCD registry. The presence of extra-coronary atherosclerosis greater than modified American Heart Association Class III was assessed in five arterial beds (intra-cerebral vessels, aorta, and carotid, renal, and femoral arteries). A total of 3044 individuals experienced SCD; 356 were due to coronary artery disease and 64 (18.0%) had extra-coronary plaque. Plaque was identified in aorta (61/356 patients, 17.1%), carotid arteries (9/356, 2.5%), iliofemoral arteries (11/356, 3.1%), intracerebral arteries (4/153, 2.6%), and renal arteries (6/356 patients, 1.7%). The only feature associated with extra-coronary plaque was older age (median 47.8 vs. 44.4 years, P = 0.0002). Patients with extra-coronary plaque had higher rates of cardiomegaly (67.2% vs. 50.7%, P = 0.022), cardiac fibrosis indicative of previous myocardial infarction (45.3% vs. 31.2%, P = 0.030), and multi-vessel coronary disease (72.6% vs. 55.6%, P = 0.014). Fewer than one in five people aged 1-50 years experiencing SCD from a coronary cause exhibit extra-coronary plaque, suggesting that in young people, severe atherosclerosis is not necessarily a systemic disease. This limits the utility of screening for carotid or aortic plaque to predict coronary atherosclerosis on an individual level. Individuals with extra-coronary plaque were older with more established coronary disease.

In patients with Metabolic Dysfunction-associated Steatotic Liver Disease (MASLD), accurate and low-cost non-invasive risk stratification remains a major unmet need. We developed a clinical records-based neural network integrating patient history, routine laboratory tests, and ultrasound imaging features. Here we show that in an internal test set (n = 209), the model achieved receiver operating characteristic area under the curve (ROC-AUC) values of 0.85 vs 0.82 (F ≥2), 0.90 vs 0.86 (F ≥3), 0.96 vs 0.89 (F  = 4) compared with Fibrosis-4 (FIB-4). To address limitations of ROC-AUC, we applied RP-AUC0.5-0.7, a recall-precision metric focused on clinically relevant precision range, showing improved performance over FIB-4. External validation (n = 194) shows reduced liver biopsy failure rate from 86.6% to 50.0% for at-risk metabolic dysfunction-associated steatohepatitis (MASH) prediction. Our work presents a low-cost neural network improving FIB-4, introduces RP-AUC0.5-0.7 for biomarker comparison, and provides a generalizable framework for evaluating screening biomarkers in clinical care and drug trials.

Caffeine is one of the most commonly consumed drugs in the world. It is found in various naturally occurring substances and can be ingested in a synthetically derived pure form. The majority of human subject-based research is observational and has focused on beverages and foods that contain caffeine. The relationships between caffeine and cardiovascular risk factors and diseases are complex, exhibiting heterogeneity depending on the nature of the caffeine consumed and individual-level propensities. Acute versus chronic caffeine-associated cardiovascular effects are often different. Most studies suggest an inverse J-shaped relationship between consumption of naturally occurring caffeinated products and blood pressure. Data on relationships between caffeine and diabetes are not consistent, but habitual coffee consumption has been associated with a lower risk of incident type 2 diabetes. Whereas no clear relationship between caffeine and blood lipids is evident, unfiltered coffee raises low-density lipoprotein cholesterol. Caffeine, studied primarily in the context of coffee, has been shown either to have no relationship or to be associated with a lower risk of coronary artery disease and heart failure. Randomized controlled trial data among regular caffeinated coffee drinkers showed that caffeinated coffee decreases the risk of atrial fibrillation occurrence but increases the frequency of premature ventricular contractions. Data are fairly consistent that moderate caffeine consumption, again studied primarily in the setting of coffee consumption, was associated with a lower risk of stroke. Data on high doses of caffeine such as that found in energy drinks are limited and generally suggest cardiovascular harm.

Integrating metabolic biomarkers with anthropometric indicators has been shown to enhance the discriminative capacity for cardiovascular disease (CVD). However, the impact of the cholesterol-HDL-glucose index (CHG) and its derivatives on CVD risk remains unclear. This study aimed to investigate the associations of CHG and its derivatives with CVD and to compare their discriminative performance. This prospective study included 3,359 CVD-free participants from the China Health and Retirement Longitudinal Study (CHARLS). Repeated measurements obtained in 2011 and 2015 were used to derive cumulative exposure and longitudinal trajectory patterns of CHG and its derivatives. Associations of baseline values, cumulative exposure, and longitudinal trajectories of these indicators with incident CVD and stroke were examined using Cox proportional hazards regression models. During a median follow-up of 5 years, 466 participants (13.9%) developed CVD. Both CHG and its derivatives were significantly associated with CVD across baseline measurements, cumulative exposure, and longitudinal trajectories. Cumulative CHG derivatives showed significantly better discriminative power than isolated cumulative CHG (Delong's test P < 0.05), with the highest associations observed for cumulative CHG-waist circumference (HR = 1.29) and cumulative CHG-Chinese visceral adiposity index (HR = 1.28). Regarding trajectory patterns, participants with stably high CHG-CVAI exhibited the greatest risk compared with those maintaining stable low levels (HR = 1.79), followed by CHG-WC (HR = 1.65). Additionally, ascending and declining trajectories of both CHG-CVAI and CHG-WC were associated with increased CVD risk (ascending CHG-CVAI: HR = 1.79; declining CHG-CVAI: HR = 1.54; ascending CHG-WC: HR = 1.45; declining CHG-WC: HR = 1.54). CHG and its derivatives were strongly associated with incident CVD, with CHG-CVAI and CHG-WC exhibiting the most pronounced associations. Moreover, ascending and declining trajectories of CHG-CVAI and CHG-WC were linked to higher risk, highlighting the importance of tracking dynamic increases while also accounting for baseline metabolic status. These indicators may facilitate the identification of individuals at elevated risk for CVD.

Metabolic dysfunction-associated steatotic liver disease (MASLD) is associated with increased cardiovascular disease (CVD) risk. Lipoprotein(a) [Lp(a)] and insulin resistance (IR) are established cardiovascular risk factors, yet their joint associations with cardiovascular outcomes in MASLD remain poorly understood. We analyzed data from the UK Biobank and included 101,348 adults with MASLD for CVD mortality analyses and 94,089 individuals without baseline CVD for incident CVD analyses. IR was assessed using the triglyceride-glucose (TyG) index. Participants were categorized according to Lp(a) levels (< 125 vs. ≥ 125 nmol/L) and TyG index (low vs. high, defined by the 75th percentile) and further classified into four joint Lp(a)/IR groups, with low Lp(a)/low IR serving as the reference group. Cox proportional hazards models were used to evaluate associations of Lp(a), TyG, and their combined categories with incident CVD and CVD mortality. During a median follow-up of 15.7 years, elevated Lp(a) and higher TyG levels were each independently associated with increased risks of incident CVD and CVD mortality, regardless of each other's status. In the fully adjusted model, each SD increase in Lp(a) was associated with a 14% higher risk of CVD mortality (HR, 1.14; 95% CI 1.10-1.19; P < 0.001) and a 9% higher risk of incident CVD (HR, 1.09; 95% CI, 1.07-1.11; P < 0.001). Similarly, each SD increase in TyG was associated with a 27% higher risk of CVD mortality (HR, 1.27; 95% CI 1.21-1.34; P < 0.001) and a 9% higher risk of incident CVD (HR, 1.09; 95% CI 1.07-1.12; P < 0.001). Compared with participants in the reference group with Lp(a) < 125 nmol/L and low IR, those with concomitantly elevated Lp(a) and high IR exhibited the highest cardiovascular risk, with adjusted HRs of 2.04 (95% CI 1.63-2.55) for CVD mortality and 1.49 (95% CI 1.35-1.64) for incident CVD (both P < 0.001), with a significant dose-response trend across groups (P for trend < 0.001). These associations remained consistent across subgroups stratified by age, sex, obesity, diabetes, and hypertension. Elevated Lp(a) and IR were independently associated with adverse cardiovascular outcomes in MASLD, with the highest risk observed among individuals with concomitant elevations in both markers.

Longitudinal studies have shown an association between diet quality and depression. However, reverse causality, unmeasured confounding, and selection bias remained important limitations. We aim to examine the relationship between diet quality and depression in older adults while addressing these issues and explore modification role of genetic predisposition to depression and low-grade inflammation. We emulated a target trial of dietary interventions using data from the ASPREE cohort. An ultra-processed food (UPF) index and an anti-inflammatory diet measure were extracted from a food frequency questionnaire to quantify diet quality. Depressive symptoms were assessed annually with a Center for Epidemiologic Studies-Depression 10-item score of ≥8. A polygenic score was derived using the latest Psychiatric Genomics Consortium data for major depression. Systemic inflammation was assessed using circulating high-sensitivity C-reactive protein. Inverse probability treatment weighting was applied to balance measured confounders. The effects of diet quality on depressive symptoms were estimated using generalised estimating equations. A total of 7220 participants (52.7% female), aged 70+ years, were followed for a median of 5.7 years. High UPF consumption was associated with a higher risk of depressive symptoms (RR: 1.12, 95% CI: 1.03-1.21), while an anti-inflammatory diet was associated with lower depressive symptoms (RR: 0.93, 95% CI: 0.86-1.00). Genetic predisposition or low-grade inflammation did not modify the observed associations. Higher diet quality is associated with a lower risk of depressive symptoms, independent of genetic predisposition or low-grade inflammation, which may support dietary interventions as a modifiable lifestyle strategy for mental health promotion and prevention in older adults.

Stroke volume, the volume of blood ejected by the left ventricle during a contraction, is a key metric of cardiovascular health. Currently, stroke volume is measured in clinic with specialised equipment. While purpose-made wearables exist to measure stroke volume, no solution relies solely on commodity devices. We present a deep learning system for stroke volume estimation from in-ear audio of earbuds. We combine generative self-supervised/transfer learning, a transformer-based autoencoder, to predict average stroke volume in unseen subjects. With data from 23 healthy participants, we compare our estimations to clinically validated device estimations. We achieve a mean absolute error of 5.24 ml, a Pearson correlation of r=0.94 between average predicted stroke volume and average true stroke volume, and a Percentage Error in the limits of agreement of 11.05% (within clinical range for stroke volume measurement devices). These findings open the doors to longitudinal, scalable and affordable cardiovascular measurement out of clinic.

The Alzheimer's Prevention Initiative Autosomal Dominant Alzheimer's Disease (ADAD) Colombia Trial evaluated the biological, cognitive, and clinical effects of crenezumab, an anti-oligomeric and monomeric amyloid-beta (Aβ) monoclonal antibody, in 30-60-year-old PSEN1 E280A mutation carriers without cognitive impairment from the world's largest ADAD kindred, finding no significant treatment effects on Alzheimer's disease progression. This article describes baseline biomarker, cognitive, and clinical measurements and placebo-related longitudinal changes in the randomised prevention trial's mutation carrier and non-carrier groups. Crenezumab and placebo-treated mutation carriers and placebo-treated non-carriers were assessed using amyloid and fluorodeoxyglucose positron emission tomography (PET), magnetic resonance imaging, plasma, and optional tau PET and cerebrospinal fluid (CSF) biomarker, cognitive, and clinical measurements over 5-8 years. 94% of the 252 kindred members (85 crenezumab-treated mutation carriers, 84 placebo-treated carriers, and 83 placebo-treated non-carriers) completed the trial. 55% of the carriers had baseline PET evidence of substantial Aβ plaques. 32.9% and 6.8% of amyloid PET-positive and PET-negative carriers, respectively, 36.5%, 13.2%, and 0% of pTau217-positive, pTau217-intermediate, and pTau217-negative carriers, respectively, and no non-carriers became cognitively impaired over the next 5 years. Carriers were distinguished from non-carriers by several baseline and longitudinal Aβ, tau, neurodegenerative, and inflammatory biomarker measures, but not by CSF oligomeric Aβ measurements. Despite the absence of significant treatment effects, these findings and the trial itself continue to inform the course of preclinical ADAD, advance Alzheimer's disease prevention research, and provide a shared resource of data and samples for the field (ClinicalTrials.gov ID: NCT01998841; trial completed). National Institute on Aging, Banner Alzheimer's Institute, Genentech, Inc., and F. Hoffmann-La Roche Ltd.

Circulating proteins act as important hormonal signals of nutrient intake. We aimed to systematically characterise the time-resolved proteomic response to glucose ingestion in humans, and to assess its robustness following prolonged complete caloric restriction. We conducted oral glucose tolerance tests (OGTTs) in 11 healthy volunteers before and after 7 days of complete caloric restriction and measured the response of >2900 targets through high-resolution plasma protein profiling. We identified a signature of 44 proteins that changed significantly following glucose ingestion, which was reproducible after 7 days without food, and was strongly (20-fold) enriched for 'stomach-specific' proteins. We report that annexin A10 (ANXA10) shows the most significant post-glucose change observed, similar to the trajectories of secreted hormones. We present observational human evidence from multiple sources suggesting that ANXA10 is secreted upon sensing an increase in gastric pH, with the stomach as the major contributing tissue. Despite a profound metabolic shift after 7 days of complete caloric restriction, characterised by delayed insulin secretion and postprandial hyperglycaemia, only four proteins showed robust evidence for a differential trajectory during both OGTTs. This included plasma levels of tryptophanyl-tRNA synthetase 1 (WARS), for which we found a genetic association with glucose homeostasis and coronary artery disease. Our exploratory study identifies the proteomic response to glucose ingestion and demonstrates its reproducibility despite major shifts in glucose homeostasis. We characterise the gastrointestinal origin of these changes, and hypothesise a hitherto under-recognised role for sensing of changes in gastric pH on the plasma proteome.

Early-stage cardiovascular-kidney-metabolic (CKM) syndrome, encompassing stages 0-3, represents a critical window for identifying individuals at risk before the development of clinical cardiovascular disease (CVD). Metabolic dysregulation and frailty-related physiological vulnerability may jointly contribute to cardiovascular susceptibility in middle-aged and older adults. However, conventional single-domain markers may not adequately capture this combined risk burden. This study aimed to evaluate the association and predictive utility of the combined cholesterol, high-density lipoprotein, glucose index and frailty index (CHG-FI) for new-onset CVD, heart disease, and stroke among individuals with early-stage CKM syndrome. This cohort study used longitudinal data from the China Health and Retirement Longitudinal Study (CHARLS, 2011-2020), including 4,603 participants with CKM stages 0-3. New-onset CVD, defined as the occurrence of heart disease or stroke during follow-up, was the primary outcome; new-onset heart disease and stroke were analyzed separately as secondary outcomes. CHG-FI was calculated as the product of the cholesterol, high-density lipoprotein, glucose (CHG) index and frailty index (FI). Multivariable Cox proportional hazards models were used to assess the associations of CHG-FI with new-onset cardiovascular outcomes. Restricted cubic splines were applied to examine nonlinear dose-response relationships. Joint-exposure analyses were used to characterize CVD risk across combined CHG and FI categories, and multiplicative and additive interaction analyses were performed to assess whether CHG and FI interacted in relation to new-onset CVD. Predictive performance was compared with CHG, FI, triglyceride-glucose index (TyG), atherogenic index of plasma (AIP), and metabolic score for insulin resistance (METS-IR) using receiver operating characteristic curves, DeLong tests, net reclassification improvement (NRI), and integrated discrimination improvement (IDI). Formal incremental modeling was further performed by separately adding CHG-FI and comparator indices to the fully adjusted base model. During a median follow-up of 9 years, 1,189 participants (25.8%) developed new-onset CVD. In fully adjusted models, each one-unit increase in CHG-FI was associated with higher risks of new-onset heart disease (HR = 1.59; 95% CI 1.42-1.77), stroke (HR = 1.56; 95% CI 1.32-1.83), and composite CVD (HR = 1.56; 95% CI 1.41-1.72). Participants in the highest CHG-FI quartile had more than two-fold higher risks of all cardiovascular outcomes compared with those in the lowest quartile. Restricted cubic spline analyses showed nonlinear associations, with cardiovascular risk increasing more steeply across lower to moderate CHG-FI levels. In joint-exposure analyses, participants with both high CHG and high FI had the highest risk of new-onset CVD (HR = 2.05; 95% CI 1.71-2.47); however, no statistically significant multiplicative or additive interaction was observed. CHG-FI showed the highest AUCs for new-onset CVD (0.624) and heart disease (0.622) among the evaluated indices and statistically outperformed CHG, FI, TyG, AIP, and METS-IR for both outcomes; however, the absolute discriminative performance was modest. For new-onset CVD, CHG-FI showed statistically significant reclassification improvements compared with CHG, TyG, AIP, and METS-IR, with NRI values of 13.85%, 9.16%, 11.02%, and 20.90%, respectively, and yielded small but statistically significant IDI improvements ranging from 0.20 to 0.48% compared with all reference indices. In formal incremental models, adding CHG-FI to the fully adjusted base model provided statistically significant but limited improvement, with only small absolute gains over FI alone. Higher CHG-FI was independently associated with increased risks of new-onset CVD, heart disease, and stroke among middle-aged and older adults with early-stage CKM syndrome. Participants with both high CHG and high FI had the greatest risk of new-onset CVD, although this pattern did not reflect a statistically significant multiplicative or additive interaction. CHG-FI showed statistically significant but modest discriminative performance, and the incremental improvements beyond comparator indices and clinical covariates were limited in magnitude. These findings suggest that CHG-FI may serve as a complementary marker reflecting integrated glucose-lipid metabolic dysregulation and frailty-related vulnerability, but it should not be considered a standalone clinical prediction tool and requires further validation before clinical application.

Hepatic venous pressure gradient (HVPG) is the gold standard for assessment of prognosis in compensated advanced chronic liver disease (cACLD), yet its invasiveness limits broad clinical use. We developed and validated the Cirrhosis Risk Identifier (CIRI) model, a machine-learning tool using 11 demographic and routine laboratory parameters trained to prognosticate first decompensation; and benchmarked its performance against HVPG, liver stiffness measurement (LSM), FIB-4 and MELD. cACLD patients were identified in the U.S. Optum Clinformatics Data Mart (Optum CDM) for model development and internal validation and externally validated in a prospective European tertiary care cohort. The primary endpoint was first decompensation (ascites, encephalopathy, variceal bleeding) with HCC and death as competing events. CIRI was trained on 112,618 and internally validated on 18,852 cACLD patients in Optum CDM, with 210 HVPG-characterized cACLD patients (European cohort) included for external validation. In both Optum CDM and Europe, steatotic liver disease was the leading etiology (54%; 44%), with median follow-up of 18.5 months (IQR 7.2-40.4) and 27.5 months (21.2-34.8), respectively. In Optum CDM, CIRI showed higher 1- and 2-year time-dependent AUROCs (0.816, 0.815) than MELD and FIB-4 (both p<0.001). In Europe, AUROCs (0.836, 0.769) were comparable to HVPG (both p>0.900) and superior to LSM (both p<0.05). CIRI predicted decompensation independently (Optum CDM: adjusted subdistribution hazard ratio [aSHR]: 1.67, p<0.001; Europe: aSHR: 1.66, p=0.017) with a cutoff of ≥-8.25 identifying patients at comparable decompensation risk as HVPG ≥10mmHg (CSPH). The machine-learning-based CIRI model yielded robust prognostic performance and accurate risk stratification in cACLD patients. CIRI's discrimination of decompensation risk was comparable to that of HVPG, highlighting its potential future utility to non-invasively identify "at-risk" cACLD patients. NCT03267615 IMPACT AND IMPLICATIONS: Hepatic decompensation marks the key clinical transition from compensated to decompensated advanced chronic liver disease and is associated with substantially worse prognosis. However, current risk assessment remains limited by the invasiveness of the gold-standard hepatic venous pressure gradient (HVPG) measurement and the infrastructure required for established non-invasive tests such as liver stiffness measurement (LSM). In this study, we developed and validated "Cirrhosis Risk Identifier" (CIRI), a machine-learning model based solely on routine laboratory and demographic data, which predicted first hepatic decompensation with performance comparable to HVPG and superior to widely used non-invasive tests including LSM, MELD and FIB-4. These findings are important for clinicians and researchers aiming to identify patients with cACLD who are at increased short-term risk of hepatic decompensation. Pending further prospective validation, CIRI could support scalable and repeatable risk stratification and help guide surveillance intensity and targeted strategies intended to prevent hepatic decompensation for high-risk patients.

Brain-computer interfaces (BCIs) offer the potential to restore function and augment human capabilities. However, non-invasive electroencephalography (EEG)-based BCIs still face challenges in learning efficiency and control precision, particularly for naïve users performing complex tasks. Here, we present a sensory-guided joint learning framework that integrates human motor learning with adaptive machine learning to improve BCI training and performance. In 31 BCI-naïve participants, the framework enabled rapid skill acquisition, achieving average online discrete accuracies of 86.0% for one-dimensional (1D) and 77.5% for two-dimensional (2D) motor imagery tasks, along with continuous control accuracies of 77.5% (1D) and 66.9% (2D). Mechanistically, tactile guidance reduced user exploration and accelerated neural adaptation, while sample reweighting aligned decoder updates with human learning trajectories. By coupling reinforcement-driven neural plasticity with adaptive algorithmic optimization, this framework advances BCI training from passive calibration to active human-machine joint learning, enabling practical and scalable neural interfaces for communication and rehabilitation.

To evaluate the effects of supervised exercise on gestational diabetes mellitus (GDM) and other pregnancy outcomes and examine dose-response relationships. Systematic review with random-effects meta-analysis and meta-regression. Four databases were searched up to November 2025. Randomised controlled trials in pregnant women comparing supervised exercise with usual care were included if they reported GDM. GDM was prespecified as the primary outcome, while other outcomes were extracted where available, including gestational hypertension (GH), pre-eclampsia, excessive gestational weight gain (EGWG), macrosomia, caesarean delivery, preterm birth and low birth weight. Nineteen studies (n=6213; 48.6% in intervention groups) were included, with moderate certainty of evidence. Supervised exercise reduced the risk of GDM (risk ratio (RR) 0.74, 95% CI 0.57 to 0.96; I2=47%), GH (RR 0.55, 95% CI 0.40 to 0.77; I2=1%), EGWG (RR 0.75, 95% CI 0.61 to 0.92; I2=70%) and macrosomia (RR 0.61, 95% CI 0.46 to 0.81; I2=27%). Subgroup analyses for these outcomes suggested greater effects with earlier intervention (initiated in early pregnancy or duration >20 weeks), higher adherence (≥80%), combined aerobic and resistance training, and weekly exercise duration ≥150 min/week. Significant subgroup differences in GDM risk were observed for intervention initiation timing (p=0.009) and intervention duration (p=0.010). Dose-response analysis showed a peak effect at approximately 500-550 metabolic equivalent task-minutes per week for EGWG, with a plateau at higher doses. Supervised exercise during pregnancy reduces adverse pregnancy outcomes when initiated early, with high adherence, at moderate doses, and with combined aerobic and resistance training.

Patients with cancer usually report limitations of their functional capacity, which may range from subclinical impairment of cardiopulmonary exercise reserve to poor quality of life with physical, cognitive, or psychosocial consequences. Exercise training is a potent multi-targeted approach to control pre-existing and new risk factors. Preliminary evidence shows that it is associated with a lower risk of cancer therapy-related cardiotoxicity and increased self-reported well-being in patients with cancer. Current evidence demonstrates that supervised exercise therapy, including high-intensity interval training, is safe and well-tolerated and reduces risk in subjects with cancer in the pre-, active-, and post-treatment settings. The present consensus document will discuss the role of exercise training in cardio-oncology, focusing on patients with cardiovascular diseases induced by cancer treatment and on those who received cardiotoxic therapies.

High sodium and low potassium intake, well-established dietary risk factors for hypertension, may induce insulin resistance and increase the risk of type 2 diabetes. However, previous research based on self-reported intakes is inconclusive. We examined the association of sodium and potassium intake, assessed by multiple 24-h urine samples, with subsequent risk of developing type 2 diabetes. We included 3,173 adults without major chronic diseases from three prospective cohorts. Sodium and potassium excretions were assessed using two to four 24-h urine collections per participant. We used Cox proportional hazards models to estimate hazard ratios (HR) for type 2 diabetes, adjusting for major confounding factors, including total energy intake and BMI. Among 3,173 participants (mean age 62.2 ± 10.0 years, 69% women), diabetes developed in 161 over a median of 13.6 years. Risk of diabetes was 2.66 (95% CI 1.57-4.51) times higher in participants in the highest versus the lowest quartile of sodium excretion. Each 1,000 mg/day increase in sodium excretion was associated with a 32% (HR 1.32; 95% CI 1.16-1.52) higher risk of diabetes, whereas potassium excretion was not associated with diabetes risk (HR 0.87; 95% CI 0.69-1.11). Each unit increase in the sodium-to-potassium ratio was associated with a 26% higher risk of diabetes (95% CI 1.10-1.45). Higher sodium intake and a higher sodium-to-potassium ratio were associated with a higher risk of type 2 diabetes. Although these findings suggest that adopting a low-sodium diet may reduce diabetes risk, the associations may partly reflect residual confounding despite comprehensive covariate adjustment.

IgA nephropathy (IgAN) has diverse clinical presentations and responses to treatment. For systemic corticosteroids in particular, randomised controlled trials have reported conflicting effects, highlighting the need for individualised treatment strategies. In this retrospective cohort study, we derived and validated a causal machine learning (ML) framework to estimate individualised corticosteroid treatment effects in IgAN. Eight international cohorts, including the VALIGA, CureGN, and NURTuRE-CKD repositories, comprising 1022 patients, were analysed (derivation, n = 464; validation, n = 558). We integrated baseline clinical data, histopathological classification scores (MEST-C), and deep learning-based histomorphological biomarkers (pathomics) from digitised kidney biopsies. The framework estimated the effect of systemic corticosteroids on the composite endpoint of a ≥50% decline in estimated glomerular filtration rate or kidney failure within five years of biopsy. Across the overall study population, systemic corticosteroid therapy was not associated with a significant improvement in the composite outcome (p = 0·27). However, the causal ML framework revealed substantial treatment heterogeneity, identifying patients with high predicted benefit who achieved longer progression-free survival with corticosteroids (0·43 years, 95% CI 0·18-0·73, p < 0·01), while no benefit was observed in those with low predicted benefit (-0·005 years, 95% CI -0·3 to 0·22, p > 0·05). An individualised framework-guided treatment assignment was estimated to reduce systemic corticosteroid use by 60·7%. Pathomics facilitated the identification of interstitial inflammation and tubulitis as key features of corticosteroid response. This study demonstrates that a causal ML framework integrating clinical, histopathological, and pathomics predictors can individualise treatment assignments for systemic corticosteroids in IgAN. This approach provides a blueprint for precision therapy in IgAN, supporting AI-enhanced clinical decision-making in the era of emerging targeted treatments. German Research Foundation; European Research Council; German Federal Ministry of Education and Research; German Innovation Fund of the Federal Joint Committee; Clinician Scientist Program of the Faculty of Medicine RWTH Aachen University.

Hantaviruses have caused several recent human disease outbreaks. They carry a high mortality rate, and some species can spread from person to person although they are typically spread from rodents to humans. Neurological complications have been documented but are poorly understood. Broadly, 2 types of syndromes have been associated with hantaviruses. The pulmonary syndrome carries a high mortality rate and can result in pulmonary and cardiac failure. Neurological involvement is typically secondary to hypoxic and ischemic injury or metabolic dysfunction. Another manifestation of the infection that is associated with some species of the virus is termed hemorrhagic fever with renal syndrome. Some patients may develop a meningoencephalitis or pituitary apoplexy resulting in sudden visual loss and pituitary dysfunction. Rarely, seizures, myelitis, and peripheral neuropathy may occur. Although there are no specific antiviral drugs approved for treatment of hantavirus, there are several that showed efficacy in preclinical trials. Management is supportive care and treatment of symptoms. Neurological manifestations of hantavirus infection are uncommon but can be severe. Prospective studies and experimental models are needed to better characterize these manifestations, understand pathophysiology, identify therapeutic targets, and develop guidelines for management.

Pulmonary arterial hypertension (PAH) is a rare, progressive disease of the precapillary pulmonary arteries, characterized by fibroproliferative vascular remodeling, increased pulmonary vascular resistance, right ventricular failure, and premature death. Over the past four decades, substantial advances in understanding PAH pathobiology, epidemiology, diagnosis, and treatment have meaningfully improved patient outcomes. The pathobiology of PAH is multifaceted, involving endothelial dysfunction, smooth muscle cell hyperproliferation, inflammation, and dysregulation of key signaling pathways, including the prostacyclin, nitric oxide, endothelin 1, and bone morphogenetic/TGF-β (transforming growth factor β) axes. Dysregulation of the activin arm of the TGF-β pathway has emerged as a critical driver of vascular remodeling and is the target of sotatercept, the first antiremodeling therapy approved for PAH. Epidemiologically, PAH now more commonly affects older adults with cardiovascular and pulmonary comorbidities compared with historical cohorts. The global burden varies considerably, with methamphetamine-associated PAH rising in North America and schistosomiasis- and HIV-associated PAH prevalent in low- and middle-income countries, where underdiagnosis likely remains substantial. Diagnosis continues to be delayed, with advanced symptoms present at the time of diagnosis for most patients. Right heart catheterization remains essential for definitive diagnosis. Emerging tools, including artificial intelligence applied to electrocardiography, echocardiography, and electronic health records, hold promise for earlier case identification. Management and prognostication of PAH is based on regular risk stratification using validated multiparameter tools. The initial therapy choice is up-front combination therapy with 2 oral medications for most patients, with initial triple therapy that includes a parenteral prostacyclin used in high-risk patients. Add-on therapy with sotatercept is now an option for patients not achieving low risk, a strategy that led to improvements in hemodynamics, right heart function, and reduced the risk of adverse clinical outcomes in recent randomized trials. For patients who remain at higher risk despite maximal therapy, lung transplantation remains an important and life-saving option. Despite remarkable therapy progress, gaps persist in earlier detection, management of comorbid phenotypes, personalized therapy, and novel therapies targeting right ventricular failure. Ongoing clinical trials and translational research continue to advance the field toward the goal of normal survival and quality of life for patients with PAH.

Environmental risk factors-air pollution, noise, heat, chemical contamination, and light pollution-are increasingly recognized as key contributors to cardiovascular disease but remain underrepresented in clinical guidelines and public health strategies. This comprehensive review, developed under the auspices of the European Society of Cardiology (ESC), synthesizes current evidence on the cardiovascular consequences of environmental exposures. Building on prior ESC recommendations on air pollution, the consensus statement extends the focus to include climate change, urban heat islands, chemical pollutants, noise, and light pollution, highlighting their shared pathophysiological mechanisms: oxidative stress, inflammation, endothelial dysfunction, and circadian disruption. Epidemiological and experimental studies confirm that these exposures exacerbate the incidence of coronary artery disease, stroke, heart failure, arrhythmias, and hypertension-even at levels below existing regulatory thresholds. It is proposed the exposome framework as a conceptual tool to understand the cumulative lifetime impact of environmental hazards on cardiovascular health. Special attention is given to vulnerable populations, including children, the elderly, socioeconomically disadvantaged groups, and patients with pre-existing cardiovascular disease. The document outlines urgent research needs, such as the need for high-resolution exposure data, exploration of gene-environment interactions and molecular pathways, and the development of real-world and mechanistic studies assessing interventions. Mitigation strategies are discussed across individual, clinical, and policy levels, with a call for heart-healthy urban design, stricter emissions legislation, and equitable access to clean environments. Cardiologists are uniquely positioned to advocate for environmental cardiovascular health, bridging the gap between science, clinical care, and policy. This statement aims to accelerate that translation by raising awareness and promoting action across disciplines.

Ultra-processed foods (UPFs) have increasingly displaced traditional diets globally and have become a significant public health concern, particularly in relation to cardiovascular (CV) diseases. UPFs are defined as food products primarily composed of cheap industrial ingredients, additives, and neo-formed compounds, often with little to no nutritional value. These foods are highly processed and contain additives that can have harmful effects on health. While traditional dietary guidelines have long emphasized the importance of limiting animal-derived fats and promoting the intake of fruits, vegetables, and unsaturated fats, recent evidence suggests that the extent and nature of food processing are also key factors in the relationship between diet and health. Studies over the past decade have highlighted that the consumption of UPFs is associated with increased CV risk, often independent of the overall diet quality. Despite growing evidence linking UPF consumption to major CV risk factors (e.g. hypertension, dyslipidaemia, obesity) and adverse CV outcomes, the role of food processing in CV health remains underrecognized in cardiology. Current dietary counselling in clinical practice tends to overlook the potential adverse impact of UPFs, with patients not receiving comprehensive nutritional guidance. This European Society of Cardiology (ESC) clinical consensus statement, developed by a multidisciplinary group of European experts, is conceived to increase awareness among clinicians about the CV risks associated with UPFs. Starting from a comprehensive review of current evidence, it provides practical, actionable advice to help the general cardiologists incorporate UPF-related assessment and counselling into their routine care. The statement also proposes a stepwise framework focused on CV prevention, including tools designed to enhance patient communication and engagement. Moreover, it discusses these clinical advices within wider strategic and policy frameworks, therefore supporting a more integrated, food-centred approach to improve CV health.

Cardiovascular disease (CVD) has remained a predominant cause of mortality in China for several decades, experiencing notable epidemiological transitions. Numerous recent studies have provided valuable observational data on the evolution of CVD epidemiology across various dimensions. However, there is a paucity of comprehensive reviews that synthesize these findings and analyse their interrelationships. To address this gap, this review summarizes the key features from complex data presented in various literature reports and additional analyses of available databases. The impact of the primary drivers of these changed features and their intricate interconnections on total CVD and major subtypes, including ischaemic heart disease (IHD), ischaemic stroke (IS), and haemorrhagic stroke (HS), was quantitatively evaluated across different periods from 1990 to 2021. Four prominent transitional features of CVD mortality and the impact of underlying drivers elucidate not only new challenges for CVD prevention and control but also highlight the hidden effects of national efforts on CVD prevention. The analysis also indicated that despite a similar pattern in age-specific mortality for HS, IS, and IHD over the past decade, only the decline in HS mortality was largely attributed to the benefits of primary CVD prevention. In contrast, the declining age-specific IHD and IS mortality was due to reduced fatal events from improved medical care. The implications of these evolving features of CVD over time for further decision-making in CVD prevention strategies are discussed in depth.

Early identification of abnormalities in vascular and cardiac structure offers an opportunity for intervention to reduce future cardiovascular disease (CVD). This study examined factors contributing to increased CVD risk from adolescence to young adulthood. Raine Study participants (n = 716) classified as low- or high-CVD risk using cluster analysis at 17 years were re-studied at 27 years. Outcomes at 27 years were vascular stiffness assessed by pulse wave velocity (PWV) and left ventricular mass index (LVMI), left ventricular (LV), right ventricular (RV), and left atrial (LA) myocardial strain and respective ejection fractions (EF) assessed by cardiac magnetic resonance imaging. Outcomes were compared according to low- or high-risk classification at 17 years adjusting for sex and significant covariates at 27 years.At 27 years, individuals classified as high-risk at 17 years had significantly increased PWV (males: 6.6 ± 0.12 vs. 6.2 ± 0.04 m/sec; females: 6.2 ± 0.10 vs. 5.6 ± 0.04 m/sec) and LVMI (males: 75.2 ± 2.1 vs. 69.7 ± 0.5 g/m2; females: 55.4 ± 1.0 vs. 52.1 ± 0.4 g/m2) compared with low-risk individuals. Compared with low-risk individuals, LV global longitudinal strain in high-risk females (-16.7 ± 0.4 vs. -17.6 ± 0.17%, P = 0.041) and LV global circumferential strain in males (-19.1 ± 0.5 vs. -20.5 ± 0.2%, P = 0.013) and females (-21.3 ± 0.4 vs. -22.4 ± 0.2%, P = 0.022) were attenuated. These differences were significant in regression analysis after adjusting for sex and contemporary risk factors. An unhealthy CVD risk profile in adolescence leads to structural vascular and cardiac changes in young adults, predisposing them to future CVD. The results emphasize the importance of early public health measures to reduce the burden of cardiovascular and related lifestyle disorders.

Childhood physical fitness is a predictor of cardiovascular (CV) health but is underutilized in health surveillance. This study determined the predictive utility of child physical fitness levels on obesity, hypertension, dyslipidaemia, and the metabolic syndrome (MetS) in adulthood over traditional CV risk factors in childhood. This is a longitudinal cohort study of Childhood Determinants of Adult Health Study participants who had their fitness [cardiorespiratory fitness (CRF): 1.6 km run/walk, physical work capacity at 170 b.p.m.; muscular fitness: dominant handgrip strength and standing long jump] measured as children and their CV health assessed as children and adults (mean follow-up = 27 years). Participants had their body mass index (BMI), waist circumference, blood pressure, fasting blood sample (lipids, glucose), and smoking status assessed as children in 1985 and in early adulthood (2004-06, 26-36 years) and/or middle adulthood (2014-19, 36-49 years) where obesity, hypertension, dyslipidaemia, and MetS were defined. Logistic regression was used to model associations (n range = 578-5049). Additionally considering childhood CRF or muscular fitness improved the ability to discriminate and fit models to predict adult obesity, low HDL cholesterol (HDL-C), and MetS when added to demographics (age and sex) and the corresponding measure in childhood (BMI, HDL-C, and CV risk score), as reflected by increments in area under the curve (Δrange = 0.003-0.022), net reclassification index (range = 0.026-0.149), integrated discrimination index (range = 0.003-0.027), reductions in deviance and Brier scores, and statistically significant likelihood ratio tests. Cardiorespiratory fitness and muscular fitness are independent health indicators that could complement other risk factors in childhood to identify individuals at increased long-term CV risk.

This study aimed to investigate how nutritional exposures in early life, represented by birth weight (BW), and in later life, indicated by adult body mass index (BMI), interact to influence cardiometabolic disease (CMD) risk and to examine the underlying causal relationships. Included were 254 224 participants of White European ancestry from the UK Biobank. To evaluate the joint associations of BW and adult BMI with CMD risk, BW was categorized as low (LBW, < 2.5 kg) or high (HBW, ≥ 2.5 kg) and BMI as low (LBMI, < 30 kg/m²) or high (HBMI, ≥ 30 kg/m²). Multivariable Cox proportional hazard models and 2 × 2 factorial Mendelian randomization (MR) analyses were employed to assess these associations and the underlying causality. Compared with the participants with HBW-LBMI, the hazard ratio (HR) for atherosclerotic cardiovascular disease (ASCVD) was 1.19 (95% confidence interval: 1.12-1.26) in the LBW-LBMI group, 1.33 (1.28-1.38) in the HBW-HBMI group, and 1.62 (1.50-1.75) in the LBW-HBMI group. The LBW-HBMI group also exhibited higher risks for hypertension [HR: 2.42 (2.26-2.59)], diabetes [HR: 5.16 (4.73-5.63)], and hyperlipidaemia [HR: 1.95 (1.81-2.10)]. Additive interactions between LBW and HBMI were identified for metabolic diseases but not for ASCVD. The causality of these associations was confirmed by MR analysis. Combined exposure to LBW and HBMI was most strongly associated with an elevated risk of CMD, underscoring the critical role of the mismatch between early-life and adult nutritional status in shaping long-term cardiometabolic health.

A major goal of spinal cord injury research is to develop a path to endogenous regeneration. This approach has been heavily informed by animal models of natural regeneration. An unresolved question is whether these models rebuild the spinal cord exclusively by accessing developmental mechanisms of neuron differentiation. To address this question, we contrasted single-cell gene expression during regeneration with stage-matched controls in the conditionally regenerative frog Xenopus tropicalis. We generated an expanded atlas of neuronal diversity, annotating several previously unidentified neuron classes. From this atlas, we found that the neuron composition of the developing and regenerating spinal cord differ. So do the strategies employed, which favor waves of cell-type specific neurite projection and guidance then proliferative neurogenesis during regeneration. Low levels of early neurogenesis are then compensated by movement of post-mitotic neurons. Our work highlights the contributions of distinct developmental versus regenerative paths to heal post-injury.

Cytoskeleton is an important component of cell structure and function. In the cardiovascular system, it is involved in the remodeling process of a variety of cardiovascular diseases, including cardiac fibrosis, valvular disease, atrial fibrillation, thoracic aortic aneurysm and vascular stiffness related changes. Recent studies have shown that there is a significant synergy between cytoskeletal regulation and epigenetic processes. Notably, epigenetic alterations have been identified as one of the core features of ageing, a major risk factor for cardiovascular disease. Together, these factors regulate the fate determination, function maintenance and pathological transformation of cardiovascular cells. This review focuses on how age-related epigenetic changes, such as DNA methylation, histone modifications, and chromatin remodeling, directly affect cytoskeletal dynamics and nuclear mechanics, and ultimately lead to cardiovascular remodeling. This review systematically summarizes the key molecular pathways that drive pathological remodeling of cardiomyocytes during contraction, phenotypic switching of vascular smooth muscle cells, and activation of fibroblasts. In addition, we discuss potential therapeutic targets, biomarkers, and intervention strategies in this rapidly evolving field to address current challenges and identify future directions for research in order to lay the theoretical foundation for precision medicine in cardiovascular disease.

The global incidence and prevalence of kidney diseases continue to rise, posing a serious public health challenge. SIRT6 is an NAD⁺-dependent histone deacetylase with broad essential regulatory roles across various pathophysiological processes, including DNA repair, chromatin accessibility, telomere stability, and glycolipid metabolism. As an epigenetic regulator specifically expressed in kidney tissues, SIRT6 serves as a central mediator of kidney homeostasis. Notably, accumulating evidence has implicated aberrant SIRT6 expression in the onset and development of various kidney diseases, such as acute kidney injury, diabetic kidney disease, hypertensive nephropathy, renal fibrosis, and renal cell carcinoma. In the present review, we provide an overview of the sirtuin family, systematically characterize the enzymatic activities and critical biological functions of SIRT6, and discuss its molecular mechanisms across various kidney diseases, focusing on its cell type-specific functions. We further summarize the latest research advances in SIRT6-targeted modulators for improving kidney diseases and analyze the challenges associated with their clinical application. Overall, we highlight SIRT6 as a highly promising novel target in the treatment and prevention of kidney diseases, with strong potential for clinical translation.

FDA-approved oncolytic herpes simplex virus-1 (oHSV) therapy has emerged as a promising viro-immunotherapy for solid tumors. However, tumor- and tumor microenvironment (TME)-associated adaptations following viral treatment, such as feedback immune suppression, neoangiogenesis, and enhanced tumor aggressiveness, often hinder complete tumor eradication. A deeper understanding of the molecular mechanisms underlying resistance to oHSV is crucial to enhancing its clinical impact. We recently discovered that oHSV induces Insulin-like growth factor 2 (IGF2) secretion, shaping an immunosuppressive TME. Similarly, radiotherapy (RTx) activates the IGF1/IGF1R and YAP1 signaling pathways, further promoting therapeutic resistance. In this study, we investigated how oHSV-induced Insulin-like growth factor 1 receptor (IGF1R) signaling drives feedback pro-survival and proliferative pathways in tumor cells and evaluated the therapeutic potential of combining IGF1R blockade with oHSV and RTx. We first demonstrated that oHSV activates IGF1R signaling in vitro and in vivo, promoting tumor proliferation. While IGF1R-targeted monotherapies have shown limited cytotoxicity, its combination with oHSV led to a modest but significant increase in cytotoxicity across tested breast cancer (BC) and primary glioblastoma (GBM) cells in vitro and in vivo xenograft models. Furthermore, we observed that co-treatment with oHSV and RTx robustly activated both IGF1R and YAP1 in resistant cells, revealing the IGF1R/YAP1 axis as a key mediator of resistance to dual oHSV and RTx therapy. Notably, the triple combination of oHSV, RTx, and IGF1R blockade yielded synergistic anti-tumor effects, abolished YAP1 expression and nuclear localization, and significantly enhanced survival in orthotopic BC and GBM models. Collectively, these findings identify the IGF1R/YAP1 axis as a critical driver of resistance to oHSV and RTx and provide a strong rationale for the clinical evaluation of this triple-combination strategy to enhance therapeutic efficacy in patients with BC and GBM.

Peripheral nerves regulate skin homeostasis by secreting neurotransmitters, but their role during skin aging remains incompletely understood. Here, we report that cutaneous denervation accelerates skin aging, as evidenced by collagen reduction. Neurofilament heavy chain (Nefh) is decreased in aged skin and is predominantly expressed in vesicular glutamate transporter 2-positive (Vglut2+) skin-innervating glutamatergic neurons. Notably, dermal fibroblasts, the primary producers of collagen, frequently contact Nefh+ nerve fibers. Moreover, Nefh deletion in Vglut2+ glutamatergic neurons drives skin fibroblast senescence and collagen loss, whereas additional glutamate improves skin aging phenotypes. Mechanistically, cyclin-dependent kinase 5 (Cdk5) interacts with both Nefh and Vglut2 and maintains glutamate release and collagen homeostasis. Additionally, in skin fibroblasts, solute carrier family 1 member 3 (Slc1a3) governs the collagen-promoting and anti-senescence functions of glutamate. Together, these findings reveal Nefh-mediated glutamatergic neuromodulation of skin aging and provide therapeutic targets for aging-related skin disorders.

Neurogenesis, a critical process implicated in diverse brain disorders, is greatly diminished in the adult human brain, complicating direct investigations into its mechanistic role in disease. In the olfactory epithelium (OE), olfactory sensory neurons (OSNs) maintain homeostasis via continual neurogenesis throughout life, providing a niche to investigate neurogenesis in vivo. However, the molecular mechanisms underlying this process and its similarities to brain neurogenesis remain largely unknown. Here, we performed single-nucleus RNA-seq on specimens of human OE from 6 living adult donors, yielding high-quality transcriptomes representing 145,720 cells. Integrating with two independent OE single-cell transcriptomics datasets, different developmental stages of OSNs were identified, including neural precursor cells (globose basal cells, GBCs), as well as immature and mature OSNs. We inferred trajectories and assessed the transcriptional and regulatory dynamics of OSN development. Genes and transcription factors (TFs) involved in regulating neuronal differentiation and neurogenesis were highly expressed in GBCs and early immature OSNs, but were downregulated in mature neurons. OSNs and cortical excitatory neurons exhibited convergence during early developmental stages, including dynamically expressed genes, TFs, biological processes, and polygenic enrichment for psychiatric disorders. In addition, expression trajectory alignment between OSNs and cortical excitatory neurons (CENs) revealed that OSNs could partially track the expression dynamics of autism spectrum disorder (ASD) risk genes in CENs. Overall, cells in the neuronal lineage of the OE represent a potential proxy to study gene programs involved in neurogenesis in the human brain, providing an accessible model for investigating neurodevelopmental dysfunction in psychiatric disorders.

Glucagon-like peptide-1 receptor agonists (GLP-1RAs) have revolutionized the management of type 2 diabetes and obesity. Due to class-wide reduction in major adverse cardiovascular events in cardiovascular outcome trials and pleiotropic actions in multiple tissues, the use of GLP-1RAs has expanded beyond metabolic diseases. Recent studies have reported GLP-1RA efficacy for the treatment of atherosclerosis, heart failure and peripheral artery disease, alongside evolving potential in chronic kidney disease. The recent discovery that GLP-1RAs can improve vascular regenerative progenitor cell flux during type 2 diabetes has uncovered a novel mechanism implicating 3 classical hallmarks of vascular aging: (1) stem cell exhaustion, (2) altered intercellular communication, and (3) chronic systemic inflammation. In this review we discuss recent evidence demonstrating that imbalances in hematopoiesis during cardiometabolic diseases intersect with the senescence-associated secretory phenotype to elevate chronic inflammation and accelerate vascular aging. With a focus on stem cells as the master regulators of regenerative processes, we integrate the activities of GLP-1RAs that shift the balance from damage accumulation to repair competence in blood vessels prematurely aged by cardiometabolic syndrome.

Tumor evolution is driven by various mutational processes, ranging from single-nucleotide variants (SNVs) to large structural variants (SVs) to dynamic shifts in DNA methylation. Current short-read sequencing methods struggle to accurately capture the full spectrum of these genomic and epigenomic alterations due to inherent technical limitations. To overcome that, here we introduce an approach to identify and analyze the genomic and epigenetic events in different stages of tumoral evolution from long-read sequencing of single-cell derived sublines. We then use it to profile 23 sublines of a mouse cutaneous melanoma cell line, characterized with distinct growth phenotypes and treatment responses. We develop a computational framework for harmonization and joint analysis of different variant types in the evolutionary context. Uniquely, our framework enables detection of recurrent amplifications of putative driver genes, generated by independent SVs across different lineages, suggesting parallel evolution. In addition, our approach revealed gradual and lineage-specific methylation changes associated with aggressive clonal phenotypes. We also show our set of phylogeny-constrained variant calls along with openly released sequencing data can be a valuable resource for the development and benchmarking of computational methods.

The function of topologically associating domain (TAD) boundaries as transcriptional insulators remains a fundamental controversy in genome biology. Here, we demonstrate that bona fide Functional Insulators (FINs) should be defined dynamically by their capability to block architectural rewiring. Leveraging DeepLoop to enable robust cross-platform Hi-C analysis, we performed a meta-analysis of nine high-resolution 3D genomic datasets following acute CTCF or cohesin depletion, mapping FINs genome-wide. We show that CTCF loss triggers the reproducible formation of new enhancer-promoter loops at only a few hundred specific loci. These loops are cohesin-dependent, enriched at G-rich cis-regulatory elements, and directly drive recurrent, early-response gene activation. Multiplexed CTCF-displacement assays functionally confirmed the causal role of FINs in these localized rewiring events. Crucially, FINs reside within active euchromatin, infrequently coincide with traditional TAD boundaries, and are sensitive to WAPL depletion. Our results reveal that the genome's functional insulation is mediated by these discrete, dynamically active sites rather than static TAD boundaries.

The extent to which the cerebrovasculature is affected in various brain disorders is still not well understood. To address this, we established a transcriptomic repository of major vascular cell types and microglia to compare the global transcriptomic response in mouse models of three human brain disorders linked to neuroinflammation and associated vascular reactivity: Alzheimer's disease (AD), traumatic brain injury (TBI), and cerebral autosomal dominant arteriopathy with subcortical infarcts and leukoencephalopathy (CADASIL). Single-cell analysis of >250,000 cells at different disease stages led to identification of two previously unknown vascular cell subtypes, expanded the endothelial zonation spectrum and allowed for a detailed analysis of the cellular and molecular responses. Surprisingly, most vascular cell types lacked major transcriptomic changes across the three conditions, while microglia exhibited significant, disease-specific transcriptional changes. Notably, microglial responses converged between late-stage TBI and AD, offering insights into the predisposition for neurodegeneration following TBI.

Risdiplam and branaplam represent two classes of small-molecule splicing modulators that promote U1 snRNP recognition of weak non-canonical GA/GU-containing 5' splice sites (ss). We demonstrate that branaplam enhances recognition of these 5' ss by reconstituted U1 snRNP in vitro, and that this effect depends on the ZnF domain of U1C and Helix H of U1 snRNA, but not U1A or U1-70K. We also demonstrate that branaplam enhances the weak 5' ss recognition through a dual act of strengthening the U1 snRNP-5' ss interaction and U1 snRNP-U1C interaction. In cells, depletion of U1C reduces or abolishes compound-induced exon inclusion for most cassette exons. Interestingly, a subset of cassette exons become responsive to compound only upon U1C knockdown, supporting a model in which U1C stabilizes specific conformations at the 5' ss-U1 snRNA interface in a context-dependent manner that can either facilitate or hinder compound binding. Surprisingly, risdiplam shows no effect on weak 5' ss recognition in vitro, suggesting additional cellular factors are required for its activity.

Speech brain-computer interfaces (BCIs) can restore communication in individuals with neuromotor disorders who are unable to speak. However, current speech BCIs limit patient usability and successful deployment by requiring large volumes of patient-specific data collected over long periods of time. A promising solution to facilitate usability and accelerate their successful deployment is to combine data from multiple patients. This has proven difficult, however, due to differences in user neuroanatomy, varied placement of electrode arrays, and sparse sampling of targeted anatomy. Here, by aligning patient-specific neural data to a shared latent space, we show that speech BCIs can be trained on data combined across patients. Using canonical correlation analysis and high-density micro-electrocorticography (μECoG), we uncovered shared neural latent dynamics with preserved micro-scale speech information. This approach enabled cross-patient decoding models to achieve improved performance relative to patient-specific models facilitated by the high resolution and broad coverage of μECoG. Our findings support future speech BCIs that are more accurate and rapidly deployable, ultimately improving the quality of life for people with impaired communication from neuromotor disorders.

Heterozygous variants in SYNGAP1 and STXBP1 cause distinct neurodevelopmental disorders due to haploinsufficiency of essential synaptic proteins. As gene targeted approaches to correct these disorders often target non-conserved genomic regions, thus limiting their clinical translation, we generated humanized mouse models wherein the entire Syngap1 or Stxbp1 loci were replaced with their human counterparts. Stxbp1 humanized mice exhibited impaired viability, while Stxbp1 hybrid mice (Stxbp1Hu/+) were viable and suitable for evaluating target engagement of human-specific therapeutics. Syngap1 humanized mice were viable and successfully crossed with Syngap1 heterozygous mice to produce a Syngap1 humanized-haploinsufficient model (Syngap1Hu/-). Syngap1Hu/- mice displayed haploinsufficient levels of human SYNGAP1, disease-relevant behaviors, and EEG abnormalities including epileptiform activity and generalized slowing. Importantly, parallel analysis in a cohort of patients with SYNGAP1-disorder revealed similar electrophysiological signatures. Finally, we showed that human gene-targeted antisense oligonucleotides modulate human SYNGAP1 expression in Syngap1Hu/- neurons. Together, we describe new models to support pre-clinical therapeutic development for SYNGAP1 and STXBP1 disorders and identify translational biomarkers of SYNGAP1-disorder in mice and humans to benchmark therapeutic testing.

Vascular remodeling is a central characteristic of pulmonary hypertension (PH), yet the precise mechanisms underlying this process remain poorly understood. The coimmunoprecipitation assay was used to explore prolyl hydroxylase that modifies BACH1 (BTB and CNC homology 1). Cultured pulmonary artery smooth muscle cells, rodent models with PH, specimens from patients with idiopathic pulmonary arterial hypertension, and single-nucleus RNA sequencing were used to study the role of BACH1 in the regulation of PH and the underlying mechanisms. In this study, we found that the transcription factor BACH1 was upregulated in lung tissues and pulmonary artery smooth muscle cells from patients with idiopathic pulmonary arterial hypertension and animals with experimental PH. Under normoxia, the prolyl hydroxylation of BACH1, mediated by PHD (prolyl hydroxylase) 2, facilitated BACH1 degradation by VHL (von Hippel-Lindau) protein. Hypoxic exposure decreased this prolyl hydroxylation with subsequent increased BACH1 protein stability. The deficiency or overexpression of BACH1 in smooth muscle cells in mice alleviated or exacerbated pulmonary vascular remodeling and hypoxia-induced PH. Hypoxia triggered the accumulation of BACH1 and its recruitment to the promoter region of TGFBR2 (transforming growth factor β receptor type II) in smooth muscle cells. This recruitment activated TGFBR2 transcription, thereby promoting vascular remodeling by upregulating SMAD (suppressor of mothers against decapentaplegic) signaling and extracellular matrix deposition. Decreased TGFBR2 expression or inhibited kinase activity significantly attenuated the BACH1-induced extracellular matrix genes. Furthermore, the BACH1-enhanced PH development was blunted by a TGFBR2 kinase inhibitor. Our study illustrates that BACH1 is prolyl-hydroxylated in an oxygen/PHD-dependent manner, affecting its stability through VHL. BACH1 is crucial for hypoxia-induced PH by activating TGFBR2/SMAD in smooth muscle cells. Thus, BACH1 inhibition may be a potential therapeutic strategy for PH.

Pulmonary hypertension (PH) is a serious complication of heart failure with preserved ejection fraction (HFpEF), for which no targeted therapies are currently available. Endothelial dysfunction plays a crucial role in PH associated with HFpEF (PH-HFpEF), yet its molecular drivers remain poorly defined. Transcriptome profiling uncovered endothelial characteristics of PH-HFpEF. Endothelial-specific GPRASP1 (GPCR [G protein-coupled receptor]-associated sorting protein 1 deletion in mice was conducted to investigate its participation in PH-HFpEF pathology. Multimodal metabolomics, isotope tracing, proteomics, and mechanistic biochemical assays were used to map downstream pathways and identify druggable mediators. GPRASP1 was significantly lowered in pulmonary endothelial cells of PH-HFpEF models. Endothelial Gprasp1 knockout mice exhibited major PH-HFpEF features, including pulmonary vascular remodeling, elevated pulmonary pressure, diastolic dysfunction, and abnormal glucose/lipid metabolism. GPRASP1 loss impaired tricarboxylic acid cycle activity by stabilizing ASNS (asparagine synthetase), preferentially shifting aspartate toward asparagine synthesis over oxaloacetate production. This metabolic reprogramming led to adenosine triphosphate depletion, reactive oxygen species accumulation, endothelial nitric oxide synthase uncoupling, and nitric oxide deficiency. We discovered that, beyond its classic role in GPCR sorting, GPRASP1 functioned as a noncanonical adaptor protein that scaffolded the E3 ubiquitin ligase PRKN (Parkin) and ASNS, promoting PRKN-dependent K48-linked ubiquitination and proteasomal degradation of ASNS via its C-terminal domain. In parallel, under mitochondrial stress, GPRASP1 strengthened PRKN interactions with MFN1/2, enhanced their K63-linked ubiquitination, and facilitated PRKN-mediated mitophagy. Restoration of GPRASP1 expression or pharmacological inhibition of ASNS activity with olopatadine normalized aspartate utilization, improved mitochondrial bioenergetics, rescued endothelial function, and attenuated cardiopulmonary pathology in PH-HFpEF models. Our findings unlocked a noncanonical role of GPRASP1 in preserving pulmonary endothelial homeostasis and delineated a novel GPRASP1-PRKN-ASNS axis that connected proteostasis with endothelial metabolic integrity, highlighting aspartate metabolism as a targetable vulnerability in cardiopulmonary disease.