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Determining the source of thromboembolism in patients with acute ischemic stroke remains challenging because current diagnostic approaches rely largely on circumstantial and inferential associations rather than direct identification of the cause of stroke. Fluorine-18 GP1 ([18F]GP1) is a novel radiotracer that binds with high affinity and specificity to activated glycoprotein IIb/IIIa receptors on activated platelets. We aimed to determine whether hybrid [18F]GP1 positron emission tomography (PET) and computed tomography angiography could identify in vivo cardiovascular thromboembolism in patients with acute ischemic stroke and provide a mechanism-based assessment of stroke etiology. In a single-center prospective observational cohort study, 100 patients presenting with acute ischemic stroke underwent hybrid [18F]GP1 PET/computed tomography angiography within 21 days of symptom onset in addition to standard-of-care stroke investigations. Stroke etiology was classified using the causative classification system by an expert stroke physician blinded to [18F]GP1 PET findings. In parallel, [18F]GP1 PET/computed tomography angiography images were analyzed independently by readers who were blinded to all clinical data and causative classification system classification. We assessed whether [18F]GP1 PET/computed tomography angiography could identify the source of in vivo cardiovascular thromboembolism, influence stroke classification, and predict recurrent cerebrovascular events. Cardiovascular [18F]GP1 uptake indicative of thrombosis was identified in nearly two-thirds (n=63) of participants, changing stroke classification in over a quarter (n=26) of patients. In those with stroke of undetermined cause, the source of thrombus was identified in 18 of 41 (44%) participants, which included nonstenotic carotid atherothrombosis, native cardiac valve thrombosis, and paradoxical thromboembolism. During a median follow-up of 613 (interquartile interval, 251-788) days, recurrent stroke or transient ischemic attack occurred in 14 patients, 13 (93%) of whom had cardiovascular [18F]GP1 uptake at baseline. Cardiovascular [18F]GP1 uptake was associated with a 10.4-fold increased risk of recurrent events (95% CI, 1.35-79.40; P=0.024). Noninvasive thrombosis imaging is a novel technique that enables direct in vivo identification of thrombus formation and frequently reveals the source of thromboembolism in patients with acute ischemic stroke. This approach represents a shift from inference-based to mechanism-based stroke classification with potential implications for targeted prevention strategies and better patient outcomes. URL: https://www.clinicaltrials.gov; Unique Identifier: NCT05636748.

Endovascular treatment has emerged as a cornerstone intervention for acute ischaemic stroke caused by large-vessel occlusion. However, a subset of patients experience futile recanalisation, correlating with unfavourable long-term outcomes. We aimed to investigate the efficacy and safety of Y-6 sublingual tablets (cilostazol and dexborneol) in ischaemic stroke patients with endovascular treatment. This randomised, double-blind, double-dummy, placebo-controlled phase 2 trial in 33 centres in China prospectively enrolled patients aged 35-80 years, who had ischaemic stroke with large vessel occlusion in the anterior circulation within 24 h of onset, with an NIHSS score 7-25 at randomisation. Participants were randomly assigned (1:1:1:1:1) to the Y-6 high-dose group, Y-6 low-dose group, cilostazol high-dose group, cilostazol low-dose group, and placebo group for 28 days. The modified intention-to-treat analysis included the patients receiving at least one dose of the intervention. The primary efficacy outcome was the 90-day mRS 0-1 score, and the primary safety outcome was symptomatic intracranial haemorrhage at 28 days. The trial has been registered on ClinicalTrials.govNCT06138834. Between Dec 14, 2023, and Dec 25, 2024, of 300 enrolled Chinese patients, 294 patients were included in the intention-to-treat analysis with 213 (72.4%) male. A favourable functional outcome (mRS 0-1) at 90 days occurred in 25 patients (44.6%) in the Y-6 high-dose group (RR 1.25, 95% confidence interval [CI] 0.79-1.97; p = 0.34), 29 patients (46.0%) in the Y-6 low-dose group (RR 1.29, 95% CI 0.83-2.00; p = 0.25), 25 patients (41.7%) in the cilostazol high-dose group (RR 1.17, 95% CI 0.74-1.85; p = 0.51), 22 patients (37.3%) in the cilostazol low-dose group (RR 1.04, 95% CI 0.64-1.69; p = 0.86), and 20 patients (35.7%) in the placebo group. Symptomatic intracranial haemorrhage at 28 days occurred in 1 patient (1.8%) in the Y-6 high-dose group, 3 patients (4.8%) in the Y-6 low-dose group, 2 patients (3.3%) in the cilostazol high-dose group, 4 patients (6.8%) in the cilostazol low-dose group, and 2 patients (3.6%) in the placebo group. No significant differences in efficacy and safety outcomes were found compared with that in the placebo group. Serious adverse events within 90 days occurred in 14 patients (25.0%) in the Y-6 high-dose group, 18 patients (28.6%) in the Y-6 low-dose group, 18 patients (30.0%) in the cilostazol high-dose group, 24 patients (40.7%) in the cilostazol low-dose group, and 14 patients (25.0%) in the placebo group. Our findings indicate that, for patients with ischaemic stroke undergoing endovascular treatment for large vessel occlusion, Y-6 sublingual tablets (cilostazol and dexborneol) were safe with tolerance. Although the trial did not demonstrate statistically significant efficacy on the primary outcome, the signal toward improved functional outcomes without haemorrhage risk supports the biological plausibility of the intervention and justifies further investigation. Large-scale phase 3 clinical trials are warranted to further this research. The National Natural Science Foundation of China; Noncommunicable Chronic Diseases-National Science and Technology Major Project; Beijing Municipal Science & Technology Commission; Capital's Funds for Health Improvement and Research; National Key R&D Program of China.

Spinal cord infarction (SCI) is a rare stroke subtype with no established acute treatment guidelines. Thrombolytic therapy has been used empirically based on extrapolation from cerebral stroke protocols, but comparative effectiveness data are lacking. We compared outcomes between standard care and thrombolysis in acute spontaneous SCI. This retrospective cohort study used data from the TriNetX Global Collaborative Network. Adult patients with acute SCI (International Classification of Diseases, Tenth Revision, Clinical Modification code G95.11) were divided into the standard care group (antiplatelet therapy within 48 hours) or the thrombolysis group (alteplase or tenecteplase). Patients who underwent aortic repair procedures were excluded. Propensity score matching (1:1) balanced 68 covariates. The prespecified primary outcome was all-cause mortality; readmission and rehabilitation utilization at 180 days were secondary exploratory outcomes. E values were calculated for the significant association. Of the 965 patients in the standard care cohort and 103 in the thrombolysis cohort, 96 patients in each cohort remained after matching. Standard care was associated with significantly lower mortality (13.5% versus 29.2%; hazard ratio, 0.423 [95% CI, 0.219-0.817]; P=0.008); 180-day survival was 84.27% versus 68.69% (log-rank P=0.008), with an E value of 4.16. Readmission (14.6% versus 16.7%; P=0.669) and rehabilitation utilization (43.8% versus 49.0%; P=0.507) did not differ. The mortality association was consistent in direction across 3 sensitivity analyses. In spontaneous SCI, standard care was associated with significantly lower mortality than thrombolysis, without significant differences in readmission rates or rehabilitation utilization. These hypothesis-generating findings raise concerns about off-label thrombolytic use in SCI and support consideration of conservative management until higher-quality evidence emerges.

Despite significant progress in hospital quality initiatives and the organization of regional stroke systems of care, a significant gap persists between the number of patients eligible for acute ischemic stroke reperfusion therapies and those who receive them in a timely manner. This gap reflects persistent delays and variability across the prehospital and interhospital phases of care, from prehospital dispatch and field assessment to destination selection and interhospital transfer workflows. This expert narrative review synthesizes current evidence on acute stroke systems of care, with a particular focus on prehospital identification of stroke, destination decision-making for suspected large-vessel occlusion, and interhospital transfer for patients requiring endovascular thrombectomy. Key processes, including prehospital response and scene times, destination decision-making, and door-in-door-out metrics, are examined to illustrate how system-level bottlenecks affect access to and outcomes of reperfusion therapies. Emerging and novel technologies are also described, including mobile stroke units, blood-based biomarkers for prehospital stroke diagnosis, portable neuroimaging modalities, physiological and device-based detection systems, and cross-cutting tools such as telestroke, all aimed at shifting accurate diagnosis and treatment decisions earlier in the stroke care pathway.

Children with Down syndrome (DS) are at high risk for moyamoya syndrome (MMS) and ischemic stroke, yet early detection strategies remain poorly defined despite the condition being surgically treatable. We conducted a multicenter retrospective cohort study comparing children with Down syndrome-associated moyamoya syndrome (DS-MMS) and MMS without DS (MMS). The primary outcome was stroke as the primary presenting symptom. Secondary outcomes included diagnostic delays, angiographic features, prediagnostic systolic blood pressure percentiles, and 1-year neurological outcomes. Multivariable models adjusted for demographic and access-related covariates. In total, 271 patients were identified; 198 (73.1%) met inclusion criteria and comprised the analytic cohort. Among 198 patients (77 DS-MMS; 121 MMS), DS-MMS mean age was 9.5±5.2 years (50.6% female patients), and MMS mean age was 7.4±3.0 years (54.5% female patients). Stroke at presentation was more common in DS-MMS (71.4% versus 20.7%; absolute difference, 50.8%), corresponding to an adjusted odds ratio of 14.50 ([95% CI, 6.65-31.60]; P<0.001). Children with DS-MMS experienced longer delays from symptom onset to presentation and from presentation to diagnostic confirmation (both P<0.001). Posterior circulation involvement was more frequent in DS-MMS (adjusted odds ratio, 2.18 [95% CI, 1.09-4.37]; P=0.03), whereas angiographic severity was similar between groups. In the prediagnostic period, DS-MMS demonstrated a progressive rise in systolic blood pressure percentiles, exceeding the MMS cohort by 6 months (P<0.001). At 1 year, DS-MMS was associated with greater disability (adjusted odds ratio, 2.58 [95% CI, 1.45-4.57]; P<0.001) and spasticity (adjusted odds ratio, 6.33 [95% CI, 3.12-12.83]; P<0.001). DS-MMS represents a high-risk cerebrovascular phenotype characterized by delayed recognition and a markedly increased likelihood of stroke at presentation. Rising blood pressure percentiles preceding diagnosis may serve as an early physiological signal. These findings support targeted early detection strategies and a lower threshold for vascular imaging in symptomatic patients.

The effect of postthrombectomy blood pressure (BP) management on the development of acute kidney injury (AKI) in patients with acute ischemic stroke remains largely unexplored. This secondary analysis of the OPTIMAL-BP trial (Outcome in Patients Treated With Intra-Arterial Thrombectomy-Optimal Blood Pressure Control) included patients with acute ischemic stroke due to large-vessel occlusion who achieved successful endovascular thrombectomy and had a systolic BP ≥140 mm Hg. Patients were randomized to intensive (target systolic BP <140 mm Hg) or conventional (target systolic BP 140-180 mm Hg) BP management for 24 hours. The outcomes were AKI within 7 days and within 2 days, defined according to the Kidney Disease: Improving Global Outcomes criteria. In addition, we examined the associations between AKI and functional independence at 3 months, defined as a modified Rankin Scale score of 0 to 2. Multivariable logistic regression analyses were performed with adjustment for age, sex, time from stroke onset to enrollment, baseline National Institutes of Health Stroke Scale score, and baseline estimated glomerular filtration rate. Of 306 patients, 19 were excluded, and 287 patients were included in this analysis (mean age, 73.2 years; 117 [40.8%] women). AKI within 7 days occurred more frequently in the intensive management group than in the conventional group (20/147 [13.6%] versus 9/140 [6.4%]; adjusted odds ratio, 2.54 [95% CI, 1.10-6.35]). Most AKI events were stage 1 (20/29 [69.0%]). Early AKI within 2 days was also more common with intensive BP management. Patients with AKI had significantly lower rates of functional independence (4/29 [13.8%] versus 126/257 [49.0%]; adjusted odds ratio, 0.19 [95% CI, 0.05-0.55]) and higher stroke-related mortality at 3 months (11/29 [37.9%] versus 8/257 [3.1%]; adjusted odds ratio, 13.8 [95% CI, 4.14-49.64]). In a sensitivity analysis with equal creatinine ascertainment, the association with 48-hour AKI did not reach statistical significance (7/76 [9.2%] versus 2/66 [3.0%]; adjusted odds ratio, 4.20 [95% CI, 0.83-32.6]), although the absolute risk difference remained directionally consistent. Intensive BP lowering after successful endovascular thrombectomy was associated with a higher risk of AKI, even when kidney injury was predominantly mild. In addition, AKI was associated with worse neurological outcomes. These findings suggest that AKI is an important marker of systemic hemodynamic vulnerability after aggressive postendovascular thrombectomy BP lowering. URL: https://www.clinicaltrials.gov; Unique identifier: NCT04205305.

Health-related quality of life is a key secondary end point in stroke trials. Differential item functioning (DIF) occurs when individuals with the same underlying health-related quality of life interpret and respond differently to questionnaire items, potentially biasing treatment comparisons. This study evaluates DIF in the patient-reported 5-level EuroQOL questionnaire among patients with acute ischemic stroke across age, sex, and treatment groups. Data were from the AcT trial (Alteplase Compared to Tenecteplase), a registry-based randomized comparison of alteplase and tenecteplase conducted at 22 stroke centers across Canada (December 2019-January 2022). Patients with acute ischemic stroke presenting within 4.5 hours of symptom onset and eligible for thrombolysis completed the 5-level EuroQOL questionnaire at 90 days poststroke. DIF was assessed using multigroup graded response models with the Wald-based sweep procedure, which accounts for between-group differences in latent trait distributions. We quantified effect sizes using signed weighted area between curves (sWABC); |sWABC| <0.10=negligible. Of 1577 patients enrolled in the trial, 1264 survived to 90 days with complete 5-level EuroQOL questionnaire data (51.2% tenecteplase; 46.5% female; 30.1% aged ≥80). Omnibus testing revealed significant DIF only for age (χ2=86.9, P<0.001); neither sex (χ2=31.7, P=0.063) nor treatment (χ2=22.4, P=0.379) showed evidence of DIF. Four items flagged for age-related DIF: self-care, usual activities, pain/discomfort, and anxiety/depression. However, only self-care (sWABC=-0.46) and usual activities (sWABC=-0.34) showed moderate effects, while pain/discomfort (sWABC=-0.002) and anxiety/depression (sWABC=0.09) were negligible. Importantly, factor scores from models with and without DIF adjustment correlated (correlation coefficient=0.98). The 5-level EuroQOL questionnaire appears to function equivalently across sex and treatment groups in this stroke population. Age-related DIF, though statistically detectable in physical functioning items, had little practical consequence for individual scores, supporting the instrument's use for health-related quality of life comparisons in stroke trials. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03889249.

Tenecteplase has been previously evaluated in large- and medium-sized vessel occlusion subgroups, but its effectiveness in more distal occlusions, particularly those involving the distal middle cerebral artery branches or the anterior cerebral artery and posterior cerebral artery territories, and across varying ischemic core and perfusion profiles, remains uncertain. We performed a secondary analysis of TASTE (Tenecteplase Versus Alteplase for Stroke Thrombolysis Evaluation), a randomized clinical trial comparing tenecteplase and alteplase in patients presenting within 4.5 hours of symptom onset with perfusion imaging-confirmed stroke and evidence of target mismatch (penumbra/core ratio >1.8 and an absolute difference >15 mL). The primary outcome was the modified Rankin Scale (mRS) score of 0 to 1 at 90 days. We compared the effect of tenecteplase versus alteplase in subgroups based on occlusion site (proximal M2, distal M2, M3 and beyond, anterior cerebral artery, and posterior cerebral artery), ischemic core, core growth rate, and penumbra. The treatment effect of tenecteplase and alteplase was compared stratifying by the subgroup of interest, adjusting for age, baseline National Institutes of Health Stroke Scale score, and premorbid mRS score in modified Poisson regression models. Of the 680 patients enrolled, 492 were included in the primary analysis (median age, 73 [interquartile range, 63-82] years; male sex: 306/492 [62%]). Two hundred forty-two (49%) received tenecteplase, and 250 (51%) received alteplase. Tenecteplase was associated with a higher proportion of mRS score of 0 to 1 with distal (M3 and beyond) occlusions (tenecteplase: 62/81 [77%] versus alteplase: 59/93 [63%]; adjusted risk ratio, 1.23 [95% CI, 1.04-1.46]). Numerically higher rates of mRS score of 0 to 1 were observed with distal M2 (tenecteplase: 30/46 [65%] versus alteplase 28/48 [58%]; adjusted risk ratio, 1.14 [95% CI, 0.84-1.54]) and anterior cerebral artery occlusions (tenecteplase: 12/21 [57%] versus alteplase 5/13 [38%]; adjusted risk ratio, 1.46 [95% CI, 0.71-3.00]). No treatment differences were seen for proximal M2 or posterior cerebral artery occlusions (Pinteraction across all occlusion sites: 0.89). Across ischemic core, penumbra, and core growth rate subgroups, no difference in treatment effect was observed. Patients with distal middle cerebral artery occlusions who are treated with tenecteplase are more likely to achieve an mRS score of 0 to 1 at 90 days than those treated with alteplase. URL: https://www.anzctr.org.au; Unique identifier: ACTRN12613000243718.

Large language models (LLMs) may support patient education, but their clinical use remains challenging. We aimed to evaluate the preliminary feasibility of a structured clinical input-guided LLM workflow for generating discharge education drafts for patients with acute ischemic stroke. Patients with acute ischemic stroke discharged from 6 tertiary stroke centers in China between September 1, 2024, and March 31, 2025, were included. The workflow comprised electronic medical record-based data extraction, mapping to a predefined deidentified case report form, manual verification, standardized prompt-based LLM draft generation, and clinician-facing draft output. For each patient, Chinese-language discharge education drafts were generated using GPT-4o, Grok-3, and DeepSeek-R1. Physician-written discharge instructions prepared during routine clinical practice served as reference materials. Two blinded senior neurologists evaluated the materials across 5 predefined domains. Patient-centered evaluation was conducted in 50 patients. Interrater agreement between the 2 neurologists was assessed using intraclass correlation coefficients. Group comparisons were performed using Friedman tests followed by Bonferroni-corrected Wilcoxon signed-rank tests. A total of 67 patients with acute ischemic stroke were included. The mean age was 63.6±11.0 years, and 45 patients were men (67.2%). Interrater agreement was good to excellent, with intraclass correlation coefficients ranging from 0.862 to 0.943. Post hoc analyses showed that each LLM-generated draft group received higher expert ratings than physician-written discharge instructions in risk factor control, rehabilitation guidance, follow-up planning, and health education (all Bonferroni-adjusted P<0.001), whereas no pairwise difference in medication management remained significant after correction. Patient-centered ratings were generally favorable, and GPT-4o and Grok-3 received higher empathy ratings than physician-written discharge instructions (both Bonferroni-adjusted P<0.01). No clear hallucinations were identified during expert review, and LLM drafts had fewer unacceptable ratings. A structured clinical input-guided LLM workflow showed preliminary feasibility for generating clinician-supervised acute ischemic stroke discharge education drafts. Prospective implementation studies are warranted to evaluate workflow integration, usability, and effects on patient-reported and clinical outcomes.

Neurological deterioration is a frequent and clinically significant challenge in patients with acute stroke admitted to neurocritical care units, where timely neuroimaging is essential but access to advanced imaging may be limited by patient instability and logistical constraints. Low-field magnetic resonance imaging (LF-MRI) has recently emerged as a novel approach to extend MRI capability into critical care environments. This topic review synthesizes current evidence on the feasibility, safety, and evolving clinical applications of LF-MRI in neurocritical care stroke. Existing studies demonstrate its utility in diagnostic clarification, longitudinal monitoring of brain injury, and detection of selected secondary complications. Key applications include intracerebral hemorrhage detection and volumetric assessment, quantification of midline shift, ventricular monitoring, evaluation of infarct evolution and cerebral edema, and assessment of unexplained neurological deterioration. Beyond these applications, LF-MRI offers a unique opportunity to support repeated imaging during periods when neurological examination is unreliable or limited. LF-MRI should be viewed as a complementary imaging modality rather than a replacement for computed tomography or conventional high-field MRI. Future advances in sequence development, workflow integration, and rigorously validated artificial intelligence-assisted quantitative tools are expected to further define its role in risk stratification, time-sensitive decision-making, and longitudinal neurocritical care pathways. As access to portable imaging expands, LF-MRI has the potential to reshape neuroimaging strategies in critically ill patients with stroke.

Portable, low-field (LF) magnetic resonance imaging (MRI) is emerging as a clinically relevant adjunct in acute stroke care, enabling MRI in environments where conventional neuroimaging access is delayed, unavailable, or impractical. Advances in permanent magnet design, compact gradient and radiofrequency hardware, and the use of contemporary reconstruction methods have improved LF image quality and operational feasibility, supporting deployment at the point-of-care in emergency departments, intensive care units, and resource-limited settings. This review summarizes the evolving role of LF-MRI for acute stroke. LF sequence principles most relevant to stroke evaluation are summarized, focusing on how constraints in signal-to-noise ratio, achievable diffusion weighting, acquisition time, and diffusion direction sampling at LF influence lesion conspicuity and the reliability of quantification. The current clinical evidence base is then reviewed, including the role of LF-MRI in supporting stroke-type classification and tissue confirmation, in wake-up and unknown-onset stroke for tissue-based triage, and in posttherapeutic settings to enable serial assessment after thrombolysis or thrombectomy. Practical implementation considerations emphasize use case-driven deployment that preserves time-critical computed tomography and angiography pathways and clearly defines when LF-MRI should be used as an adjunct rather than a substitute for established initial imaging. Future directions include pragmatic workflow studies to determine where LF-MRI changes management, continued advances in hardware and pulse sequence development, and careful application of artificial intelligence for reconstruction and enhancement with task-specific validation in acute stroke.

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 and 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.

Population-based sex differences in large vessel occlusion (LVO) screening and thrombectomy use for acute ischemic stroke are not well understood. We compared the detection of LVO, thrombectomy use, and long-term clinical outcomes in female versus male patients with cerebral ischemia in Ontario, Canada. This retrospective cohort study used data from the Ontario Stroke Registry linked with health administrative data. We included adult patients hospitalized for cerebral ischemia within the first 24 hours of last seen normal time during 2 fiscal years (2019/2020 and 2022/2023). We used modified Poisson regression models to evaluate sex differences in intracranial neurovascular imaging, thrombolysis, or thrombectomy. Among patients with LVO, we used Cox proportional hazard and cause-specific hazard models to compare female versus male patients long-term mortality, readmission, or nursing home admission until 2025, stratified by thrombectomy treatment. Among 16 935 eligible patients (47% female patients; median age, 76 [interquartile range, 65-84] years), female patients were less likely than male patients to receive intracranial neurovascular imaging (83.6% female versus 87.8% male; P<0.01). Among those who underwent imaging, 19.3% of female patients had an LVO compared with 15.9% of male patients (P<0.01). Thrombectomy use was higher in female patients than male patients in the overall cohort (adjusted relative risk, 1.08 [1.01-1.16]), but, once restricted to those with LVO, thrombectomy use was similar (adjusted relative risk, 0.98 [0.93-1.03]). Adjusted hazard of the composite outcome was lower in female patients with LVO treated with thrombectomy compared with their male counterparts (adjusted hazard ratio, 0.88 [0.77-0.99]). Female patients with acute cerebral ischemia were less likely than male patients to receive intracranial neurovascular imaging but more likely to have an LVO, and long-term mortality was lower in female patients with LVO treated with thrombectomy. Stroke outcomes' research must account for neurovascular imaging and LVO status to accurately identify sex-based disparities in stroke care and outcomes.

The optimal management of isolated posterior cerebral artery occlusion (iPCAO) remains unclear. We investigated whether baseline perfusion imaging parameters are associated with clinical outcomes and whether they modify the association between endovascular therapy (EVT) and outcomes in iPCAO. This prespecified secondary analysis of the international, multicenter, observational PLATO (Posterior Cerebral Artery Occlusion) registry (35 centers, 10 countries, 2015-2025) included consecutive adults with unilateral iPCAO and baseline perfusion imaging (computed tomography or magnetic resonance imaging) with reconstructed parameters. The primary end point was an excellent 90-day outcome (modified Rankin Scale score, 0-1). Perfusion parameters included hypoperfusion volume, infarct core volume, and mismatch ratio. The primary analysis used multivariable mixed-effects regression models (center as random effect) to assess associations between perfusion parameters and outcomes, adjusting for age, sex, treatment year, prestroke modified Rankin Scale score, baseline National Institutes of Health Stroke Scale score, diabetes, stroke cause, posterior circulation Acute Stroke Prognosis Early Computed Tomography Score, occlusion site, intravenous thrombolysis, and onset-to-door time. To test whether the association between EVT and outcomes varies according to baseline perfusion parameters, we evaluated treatment-by-perfusion interactions by including interaction terms (treatment×perfusion parameter) in inverse probability of treatment weighting-adjusted models, with results expressed as ratios of odds ratios (ORs). Of 1811 patients with iPCAO, 443 met inclusion criteria (median age, 74 years; 41.8% female). Larger hypoperfusion volume was associated with lower odds of excellent outcome (adjusted OR, 0.72 [95% CI, 0.58-0.89] per 1-unit increase in natural logarithm-transformed volume). No interaction between perfusion parameters and EVT was observed for the primary outcome. However, increasing core volume was associated with a progressively less favorable modified Rankin Scale score shift (ratio of OR, 0.66 [95% CI, 0.48-0.90]; Pinteraction=0.009) and higher mortality (ratio of OR, 1.82 [95% CI, 1.10-3.03]; Pinteraction=0.021) with EVT compared with medical management. Increasing hypoperfusion volume was associated with a higher risk of symptomatic intracranial hemorrhage with EVT (ratio of OR, 10.15 [95% CI, 1.06-96.93]; Pinteraction=0.044). In iPCAO, perfusion imaging provides independent prognostic information but does not identify patients with potential benefit from EVT and may instead indicate those at higher procedural risk. URL: https://osf.io/62mwt; Unique identifier: NCT05291637.

Endovascular thrombectomy (EVT) for distal and medium vessel occlusion stroke remains uncertain. We aimed to develop a medium and distal mechanical thrombectomy score integrating clinical need and procedural risk to guide patient selection. This retrospective cohort analysis used an international distal and medium vessel occlusion stroke registry spanning the study period of 2017 to 2023. Patients with acute distal and medium vessel occlusion stroke who received medical management (MM) or EVT across 37 stroke centers were included, and those with baseline modified Rankin Scale score of ≥3 or those with missing covariable data were excluded. Multivariable logistic regression identified predictors of poor functional outcome (modified Rankin Scale score >2 at 90 days) in the MM cohort and predictors of EVT failure/complications in the EVT cohort. Predictors of poor outcome on MM were assigned positive weights (clinical need); predictors of EVT failure/harm were assigned negative weights (procedural risk). The medium and distal mechanical thrombectomy score summed these weighted points. Interaction analysis assessed the heterogeneity of EVT effect by score. A total of 1217 patients were identified, and 1007 were included (EVT: 822, MM: 185; median age 73 years; 41% female). Higher National Institutes of Health Stroke Scale score (+1 per point) and lack of intravenous thrombolysis (+7) predicted poor MM outcomes. In the EVT cohort, older age (-1 per 15 years above 25), absence of hypertension (-2), and absence of atrial fibrillation (-2) predicted failure/complications. The medium and distal mechanical thrombectomy score (range -8 to 49) significantly modified EVT effect versus MM (Pinteraction=0.048). In high-score patients (≥15; n=293), EVT yielded a better 90-day modified Rankin Scale score than MM (median, 3 versus 4; P=0.009). Conversely, in low-score patients (<15; n=710), EVT yielded a worse modified Rankin Scale score (median, 2 versus 1; P=0.014). The medium and distal mechanical thrombectomy score is a pragmatic tool that identifies patients with distal and medium vessel occlusion most likely to benefit from EVT while minimizing risk, supporting patient-centered decisions and future trial design.

Stroke remains a leading cause of death and long-term disability. Yet, much of its burden is preventable through earlier and more intensive management of vascular and cardiovascular-kidney-metabolic risk factors. Primary prevention is challenging as the first clinical event is often unpredictable and may manifest as stroke, myocardial infarction, heart failure, or peripheral arterial disease. Contemporary tools, therefore, estimate overall cardiovascular risk rather than stroke risk in isolation. The goal of this review is to emphasize that effective stroke prevention requires a shift toward global cardiovascular risk assessment and to highlight the potential clinical utility of newer risk prediction tools. The predicting risk of cardiovascular disease events equations, developed by the American Heart Association, update absolute risk estimation by modeling overall cardiovascular disease risk using sex-specific, race-free equations that incorporate kidney function, account for competing noncardiovascular death, and optionally include neighborhood deprivation. External validations suggest improved calibration compared with pooled cohort equations, supporting a more reliable estimation of absolute treatment benefit. For clinicians managing patients at risk for stroke, predicting risk of cardiovascular disease events is most useful when the clinical question is how aggressively to optimize risk factors before the first event, including decisions about blood pressure, lipid-lowering therapy, cardiovascular-kidney-metabolic management, and patient communication using 10-year, 30-year, and risk age outputs. Key limitations include its focus on overall rather than cause-specific cardiovascular risk, lack of stroke mechanism-specific estimates, absence of major nonatherosclerotic stroke drivers such as atrial fibrillation, and lack of imaging-stratified treatment-effect estimates. Predicting the risk of cardiovascular disease events' ultimate clinical impact and equity will depend on implementation within electronic health record workflows, autopopulated inputs, treatment pathways tied to estimated risk, and complementary cause-specific evaluation when clinically indicated.

Recent trials established the efficacy of thrombectomy for large-core stroke by utilizing the Alberta Stroke Program Early Computed Tomography Score (ASPECTS) as a pragmatic tool. However, whether this topographical scoring captures the therapeutic ceiling, or the upper threshold of infarct volume where the benefit of reperfusion diminishes, remains unclear. Leveraging a nationwide multicenter registry in Korea (2022-2024), we compared the prognostic value of quantitative volumetry and ASPECTS in thrombectomy-treated patients. We analyzed discordance between ASPECTS and volumetry derived from diffusion-weighted imaging, computed tomography perfusion, and noncontrast computed tomography. The primary outcome was poor functional outcome (90-day modified Rankin Scale score 5-6). To estimate treatment effects across specific volume spectra, we conducted target trial emulations that stratified causal estimates by volumetric thresholds, with the ordinal 90-day modified Rankin Scale score shift as the primary outcome. Among 552 patients, the mean age was 70.4±12.6 years, and 319 (57.8%) were men. Patients classified as large core by ASPECTS but not by diffusion-weighted imaging volumetry (ASPECTS-only large core) had poor outcome proportions comparable to the both small-core group (11.8% versus 11.7%), with no excess risk after adjustment. Conversely, volumetric confirmation of large core across diffusion-weighted imaging, computed tomography perfusion, and noncontrast computed tomography consistently predicted poor prognosis regardless of ASPECTS (adjusted odds ratio, 6.92 [95% CI, 2.58-19.34] for the diffusion-weighted imaging-only large-core group). In the target trial emulations, the overall benefit of thrombectomy was attenuated (common odds ratio, 0.56 [95% CI, 0.31-1.03]). Stratified analyses delineated a therapeutic ceiling, with benefit in the 50 to 110 mL range (common odds ratio, 0.38 [95% CI, 0.15-0.97]) disappearing in extensive infarctions >110 mL. Quantitative volumetry provided better prognostic discrimination and identified ≥110 mL as a therapeutic ceiling where the benefit of thrombectomy becomes negligible. These findings advocate integrating volumetric thresholds into patient selection to minimize futile reperfusion and prioritize safety, serving as a critical refinement to current topographical scoring.

Electromagnetic network-targeted field (ENTF) brain stimulation therapy is a promising approach to reduce poststroke disability. Two pilot, randomized, sham-controlled trials showed safety and signals of efficacy. The aim of this study was to perform a pooled analysis with greater statistical power to characterize with precision the effect of ENTF in promoting recovery and reducing disability. We pooled individual patient-level data from 2 double-blind, randomized, sham-controlled studies, BQ3 (BrainQ3 Trial; Unique identifier: NCT04039178) and EMAGINE 1 (Electromagnetic Field Ischemic Stroke-Novel Subacute Treatment Trial; NCT05044507). Key entry criteria in both trials were (1) 4 to 21 days post-ischemic stroke and (2) Fugl-Meyer assessment-upper extremity score of 10 to 45. For EMAGINE 1, an additional criterion was a study entry modified Rankin Scale (mRS) score of 3 to 4. The primary outcome for this pooled analysis was freedom-from-disability (mRS score, 0-1) at 8 to 12 weeks. Secondary outcomes were level of disability (ordinal mRS score distribution), disability change (delta mRS score) change from entry to 8 to 12 weeks, and 2 focused upper extremity motor end points. Altogether, 124 patients were included (active n=65; sham n=59). The mean age was 58.2±13.1 years, 31% were female, the study entry Fugl-Meyer assessment-upper extremity score was 25.3 (±10.6), and the therapy started 14.5 (±4.9) days poststroke. The study entry mRS score was 3.9 (±0.36), and 123/124 (99.2%) had a study entry mRS score of 3 to 4. Study entry features were well-balanced across treatment groups. At 8 to 12 weeks, freedom-from-disability was higher with active ENTF than sham stimulation (33.8% versus 11.9%; P=0.005). Ordinal shift across 3 disability strata (mRS score, 0-1, 2, and >2) also favored ENTF (P=0.009). Focused upper extremity motor end points nonsignificantly favored ENTF. Safety analyses showed no device- or procedure-related serious adverse events. In pooled data from 2 randomized, sham-controlled trials, treatment with ENTF compared with sham for patients with subacute ischemic stroke with moderate-severe study entry disability yielded increased achieved freedom-from-disability, greater disability improvement from study entry, and reduced final disability level. These findings, together with an attractive safety profile, support ENTF as a promising therapy for stroke recovery.

Ischemic stroke in patients with active cancer is heterogeneous and frequently classified as cryptogenic under the TOAST classification (Trial of ORG 10172 in Acute Stroke Treatment). The American Heart Association recently proposed an etiological classification for cancer-related ischemic stroke (CRIS). This study aimed to evaluate its clinical and prognostic implications. We analyzed data from the prospective SCAN study (Ischemic Stroke in Patients With Cancer and Neoplasia), which enrolled patients with acute ischemic stroke and active cancer in Japan. Among the registered patients, those with available D-dimer data were included in the analysis. Stroke subtypes initially classified according to the TOAST criteria were reclassified using the CRIS framework. Kaplan-Meier survival curves were constructed, and differences were assessed using the log-rank test. Of 135 enrolled patients, 132 (median age, 75; 37.9% female) were included. Under the TOAST classification, 9 patients had small vessel occlusion, 20 large artery atherosclerosis, 28 cardioembolism, 10 other determined cause, and 65 cryptogenic strokes. After reclassification, 2 patients originally categorized as other determined etiology due to disseminated intravascular coagulation, and 46 patients previously classified as cryptogenic stroke were reclassified as CRIS. Patients classified as CRIS demonstrated significantly worse 1-year survival than those classified as conventional etiologies or cryptogenic stroke (global log-rank, P<0.001). The 3-month survival rate was 37.5% in the CRIS group and 89.2% in the reclassified cryptogenic stroke group. The newly proposed CRIS classification reduced the proportion of cryptogenic strokes under the TOAST system and enabled prognostic stratification by identifying a subgroup with markedly worse outcomes.

Accurately identifying unfavorable outcomes is crucial for the clinical management of minor stroke. Conventional imaging prediction models, such as radiomics, rely on region-of-interest analyses that extract statistics parameter within the lesion. However, they often underestimate or omit the spatial properties of the lesion, which contain essential clinicopathological information in the context of the whole brain. By quantitatively extracting the spatial features of lesions at various topological levels, we developed and validated a novel spatial radiomics-based interpretable model using machine learning to better predict outcomes in minor stroke. A cohort of 4,164 patients with minor stroke from seven centers was enrolled. Using voxel-based and normative connection lesion analyses, we comprehensively quantified the spatial features of infarct lesions, including location, structural disconnection, and functional disconnection. These spatial features, spanning various topological levels, were integrated with radiomics to create a hybrid spatial radiomics. Six classifiers and a stacked multimodal machine learning model were developed to predict outcomes in minor stroke. The SHapley Additive exPlanations (SHAP) method was employed to interpret and visualize the output of the optimal model. The spatial radiomics model, combined with the eXtreme Gradient Boosting algorithm (AUC: 0.95/0.88/0.87; accuracy: 0.88/0.74/0.75 in the training cohort/validation cohort 1/ validation cohort 2), outperformed conventional radiomics models (net reclassification index/integrated discrimination improvement: 0.180/0.145; P < 0.01) in predicting outcomes of minor stroke. The mapping results and SHAP analysis consistently demonstrated that several specific spatial features - mainly lesion disconnection in the bilateral corticospinal tracts, left spinocerebellar tracts, and default mode regions - rather than location properties, were key factors associated with unfavorable outcomes in minor stroke. The spatial radiomics-based interpretable model significantly improved the accuracy of predicting unfavorable outcomes in minor stroke. Furthermore, integrating spatial radiomics enhanced conventional radiomics model and introduced a novel approach within the spatial-omics family.

The clinical presentation of stroke-heart syndrome (SHS) underscores the interplay between the central nervous system and the cardiovascular system. While cardiac arrhythmia is the prevalent form of cardiac injury in SHS patients, the causal link between ischemic stroke and cardiac arrhythmia is still unclear. Mendelian randomization analyses and genome-wide association studies data were used to investigate the causal role of ischemic stroke on cardiac complications. Mediation and colocalization analyses were used to identify potential pathways and shared genetic variants. Single nucleotide polymorphisms (SNPs) associated with arrhythmias and ischemic stroke were used for Gene Ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) analyses. Gene expression omnibus (GEO) database from atrial fibrillation patients were used for validation. Mendelian randomization analyses showed a strong correlation between arrhythmias, including ventricular tachyarrhythmias and atrial fibrillation, with ischemic stroke. Diabetic microvascular (nephropathy, retinopathy) and macrovascular (cardiomyopathy, peripheral arterial disease) complications significantly mediated the effect of ischemic stroke on cardiac arrhythmias and atrial fibrillation, explaining 28.69 % and 20.48 % of the indirect effect, respectively. Colocalization analyses identified a shared causal variant in the Phosphodiesterase 3A (PDE3A) gene (rs11045239), providing genetic evidence for a shared pathogenic pathway between ischemic stroke and cardiac arrhythmias. Moreover, KEGG pathway enrichment analyses identified a role of the cyclic adenosine monophosphate (cAMP) signaling pathway in both ischemic stroke and arrhythmias. Validation using the GEO database confirmed a significant upregulation of the PDE3A gene expression in atrial fibrillation patients. This study demonstrated a causal link between ischemic stroke and cardiac arrhythmias, with diabetic complications as one mediating factor. The identification of a shared causal variant in the PDE3A gene and the role of the cAMP signaling pathway have the potential to improve prediction and management of SHS patients.

Patients with branch atheromatous disease (BAD)-related stroke are predisposed to early neurological deterioration (END) and disability. However, large-scale clinical trials focused on the prevention of the deterioration and recurrent stroke in this population are currently lacking. To evaluate the efficacy and safety of intensive antiplatelet therapy combining the tirofiban with aspirin for patients with BAD-related stroke. This randomized clinical trial was the multicenter, double-blind, randomized, placebo-controlled STRATEGY trial, conducted across 38 hospitals in China. Participants were patients with BAD-related acute ischemic stroke confirmed by magnetic resonance imaging within 48 hours of symptom onset were eligible for enrollment. Enrollment occurred from November 15, 2022, to November 19, 2024, with a 90-day follow-up period for all participants. Investigators, patients, and outcome assessors were blinded to treatment assignment. Eligible participants were randomized to receive either intravenous tirofiban or placebo (0.4 µg/kg/min for 30 minutes followed by 0.1 µg/kg/min for 24 hours). All patients received a 300-mg loading dose of aspirin on the day of randomization, followed by 100 mg daily until day 90. The primary efficacy end point was END within 7 days or new stroke within 90 days. The primary safety end point was moderate or severe bleeding. Of 1378 patients with acute ischemic stroke screened for eligibility, 408 were excluded for ineligible imaging findings, other exclusion criteria, lack of consent, or additional reasons, leaving 970 participants who underwent randomization (486 assigned to tirofiban plus aspirin, 484 to placebo plus aspirin). The median (IQR) age was 63.0 (56.0-70.0) years; 607 patients (62.6%) were male and 363 (37.4%) female. The incidence of the primary efficacy end point was 79 patients (17.1%) in the tirofiban group and 89 (19.6%) in the placebo group (hazard ratio, 0.88; 95% CI, 0.65-1.19; P = .39). The incidence of the primary safety end point was 1 of 486 patients (0.2%) in the tirofiban group and 0 patients in the placebo group (P > .99). This study found that in patients with BAD-related stroke, intravenous tirofiban combined with aspirin did not significantly reduce the risk of END or stroke compared with aspirin alone, nor was it associated with an increased risk of moderate or severe bleeding. ClinicalTrials.gov Identifier: NCT05310968.

Antiphospholipid antibodies (aPL) are associated with an increased risk of thrombosis. However, individual studies have reported conflicting findings regarding the prevalence of aPL in patients with ischemic stroke and their association with first or recurrent events. Systematic searches of PubMed and Embase through May 13, 2025 were conducted to identify case-control, cohort, or cross-sectional studies investigating 3 questions related to aPL seropositivity (defined as positivity for either immunoglobulin G/immunoglobulin M anticardiolipin antibody, immunoglobulin G/immunoglobulin M anti-β2 glycoprotein I antibody, or a lupus anticoagulant): (1) the prevalence of aPL seropositivity among individuals with ischemic stroke; (2) the association between aPL seropositivity and the risk of first ischemic stroke; and (3) the association between aPL seropositivity and the risk of recurrent ischemic stroke. Random-effects models with inverse weighting were used to calculate pooled prevalences and odds ratios (OR) with 95% CIs. Risk of bias was assessed using the ROBINS-I tool. A total of 52 studies were included (40 case-control, 12 cohort). The pooled prevalence of seropositivity for any aPL among patients with ischemic stroke (51 studies, 9438 patients) was 19.1% (95% CI, 15.4%-23.0%; I2=95.8%). aPL seropositivity was associated with higher odds of first ischemic stroke (43 studies, 19 097 patients; OR, 2.93 [95% CI, 2.31-3.73]; I2=68.7%). The strongest associations were for lupus anticoagulant (OR, 6.69 [95% CI, 2.94-15.2]; I2=92.6%) and immunoglobulin G anticardiolipin antibody (OR, 2.56 [95% CI, 1.96-3.35]; I2=92.5%). The odds of recurrent ischemic stroke among patients with versus without any aPL seropositivity were not significantly different (OR, 1.20 [95% CI, 0.87-1.67]; 9 studies, 2873 patients, I2=11.4%). Seropositivity for any aPL was present in nearly 1-in-5 patients with ischemic stroke and was associated with increased odds of ischemic stroke at presentation.

The "2026 Guidelines for Adult Stroke Rehabilitation and Recovery" replaces the 2016 "Guidelines for Adult Stroke Rehabilitation and Recovery." This updated guideline is intended to provide a comprehensive, up-to-date, evidence-based set of recommendations. The intended audience includes physicians, allied health professionals, and caregivers. A comprehensive search for literature published since the 2016 guideline, derived from research involving human participants, published in English, and indexed in MEDLINE, PubMed, Cochrane Library, and other selected databases relevant to this guideline, was conducted between June and October 2025. Other documents on related subject matter previously published by the American Heart Association were also reviewed. This guideline provides recommendations based on the most current evidence available for stroke rehabilitation and recovery. Key updates include new and revised recommendations across the stroke recovery continuum, including the assessment and treatment of medical comorbidities, fracture risk, fall prevention, technology-enabled rehabilitation, caregiver support, participation, and safe return to work and driving. Although this guideline reflects significant advances, it also highlights gaps in knowledge and underscores the urgent need for continued research to further refine and improve treatment strategies.

Post-stroke depression (PSD) represents a complex neuropsychiatric challenge characterized by persistent neuroinflammation and synaptic dysfunction, yet effective therapeutic interventions are constrained by the blood-brain barrier (BBB) and the lack of specific targets. Using a multidimensional screening strategy for Chaihu-Jia-Longgu-Muli Decoction (CLM), we identified ginsenoside Rd (Rd) as a key blood-absorbed bioactive constituent associated with Epidermal Growth Factor Receptor (EGFR) signaling. To overcome the bioavailability bottleneck, a biomimetic nanodelivery system is engineered by encapsulating Rd into microglia-derived exosomes (Exos@Rd). Based on the reported lesion-homing properties of microglia-derived exosomes, we developed a biomimetic Exos@Rd delivery system. Exosomal loading markedly enhanced the brain accumulation of Rd compared with free Rd. Mechanistically, it is demonstrated that aberrant EGFR activation functions as an upstream regulator of the JAK2/STAT3 cascade in microglia. Exos@Rd effectively suppressed this pathway and promoted anti-inflammatory microglial reprogramming, characterized by a shift from an M1-associated pro-inflammatory state toward an M2-associated anti-inflammatory profile. This microglia-centered anti-inflammatory regulation was accompanied by reduced oxidative stress and restoration of brain-derived neurotrophic factor (BDNF), postsynaptic density protein 95 (PSD95) and Synapsin I (SYN1) expression. In a PSD mouse model, Exos@Rd significantly restores cerebral perfusion and alleviates depressive-like behaviors. Collectively, this study elucidates a novel EGFR-driven neuroinflammatory mechanism and presents a bio-inspired strategy for precision CNS drug delivery, offering a promising therapeutic paradigm for PSD.

As stroke is the leading cause of long-term disability in the elderly, effective pharmacological therapies for neurorestoration remain an unmet clinical need. RXR (retinoid X receptor) signaling regulates inflammation and tissue repair, but the downstream repair processes linking RXR activation to stroke recovery in the aged central nervous system remain incompletely defined. We used aged mice to test the hypotheses that (1) pharmacological RXR stimulation with the brain-penetrant pan-RXR agonist bexarotene boosts poststroke recovery and (2) myeloid cell-specific RXR signaling facilitates white matter repair and underlies the therapeutic effects of bexarotene. Permanent focal cerebral ischemia was induced in 18- to 22-month-old C57BL/6J male and female mice by distal middle cerebral artery occlusion. Pharmacological RXR activation and genetic ablation were achieved by poststroke bexarotene administration and generation of myeloid cell-specific RXR conditional knockout mice, respectively. Functional (sensorimotor and cognitive performance) and structural measures of central nervous system recovery were assessed up to 35 days after stroke. Poststroke treatment with bexarotene (5-10 mg/kg) improved sensorimotor performance in the rotarod, foot fault, and adhesive removal tests and alleviated cognitive deficits in the Morris water maze and passive avoidance tests. Bexarotene improved white matter integrity at 35 days after distal middle cerebral artery occlusion, without impacting white matter at 3 days or preventing gray matter atrophy at chronic injury stages. Bexarotene also suppressed immune cell infiltration and proinflammatory cytokine production, enhanced inflammation-resolving efferocytosis, promoted long-term oligodendrogenesis and angiogenesis, and fostered a prorepair central nervous system microenvironment. Accordingly, stroke outcomes were markedly worsened in aged RXR conditional knockout mice compared with age-matched wild-type mice, and the functional and white matter benefits of bexarotene were blocked in RXR conditional knockout mice. Myeloid RXR signaling promotes long-term stroke recovery in aged mice of both sexes and engages anti-inflammatory and prorepair mechanisms. Bexarotene warrants further evaluation as a potential neurorestorative therapy for stroke.

Ischemic stroke (IS) is a major neurological disease that causes death and long-term disability worldwide. After ischemic injury, the brain undergoes complex pathological changes. As core components of the blood-brain barrier (BBB), endothelial cells and pericytes are crucial for maintaining barrier integrity, regulating cerebral blood flow, and mediating angiogenesis. Recent studies have demonstrated that, following IS, endothelial cells and pericytes can engage in mitochondrial transfer and exosome release through multiple pathways. This review constructs a signaling interaction network between endothelial cells and pericytes during IS, summarizing the cellular and molecular mechanisms underlying mitochondrial transfer networks and exosome-mediated communication. Furthermore, the physiological relevance of endothelial cell-pericyte interactions is discussed from the perspectives of vascular risk factors, non-coding RNAs, and cellular heterogeneity, as well as their potential therapeutic applications in the treatment of IS.

Alterations in circulating amino acid profiles have been observed in ischemic stroke patients; however, whether cerebral ischemia disrupts amino acid metabolism within brain tissue and whether this disruption contributes to cellular stress and cerebral injury remain unknown. This hypothesis-testing study investigates disrupted BCAA (branched-chain amino acid) catabolism as a key mechanism of ischemic brain damage and evaluates BCKDK (branched-chain α-keto acid dehydrogenase kinase) as a novel therapeutic target. Mouse primary cortical neurons subjected to oxygen-glucose deprivation and brain tissue from a mouse acute ischemic stroke model were used as experimental systems. Untargeted metabolomics and metabolic flux analysis were used to characterize BCAA metabolism in both models. In vivo pharmacological inhibition or in vitro knockdown of BCKDK was performed using BT2 (3,6-dichlorobenzo[b]thiophene-2-carboxylic acid) treatment or RNA interference. Primary outcome variables included infarct volume, BCKDH (branched-chain α-keto acid dehydrogenase) enzyme activity, neuronal viability, and markers of energy metabolism and glutamate excitotoxicity. Between-group differences were evaluated using 1-way ANOVA; data are presented as mean ± SD with 95% CIs and corresponding P values. Metabolomics analysis of oxygen-glucose deprivation-exposed primary neurons revealed impaired BCAA catabolism and significant BCAA accumulation compared with normoxic controls. In ischemic mouse brain tissue, BCKDH activity was significantly suppressed, and BCKDK expression was markedly upregulated relative to sham-operated animals. Both pharmacological and genetic suppression of BCKDK substantially reduced cerebral ischemic injury, as evidenced by decreased infarct volume and improved neuronal survival (95% CI and P values per comparison). Mechanistically, ischemia-induced BCKDK expression via HIF-1α (hypoxia-inducible factor 1α)-mediated transcriptional activation, which inhibited BCAA conversion to tricarboxylic acid cycle substrates, thereby potentiating energy deficiency and glutamate excitotoxicity. These data identify BCKDK as a novel hypoxia-responsive factor whose upregulation drives disrupted BCAA catabolism as a key mechanism of ischemic neuronal injury. BCKDK represents a promising therapeutic target for cerebral ischemia, directly supported by both in vitro and in vivo experimental evidence presented here.

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 Leducq-funded Stroke-Impact Transatlantic Network of Excellence 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.

Pericytes play essential roles in blood-brain barrier regulation and stroke pathogenesis. Given that pericytes are embedded in the ECM (extracellular matrix), it is speculated that ECM-receptor interactions are involved in these functions. Integrin-β1, the most common integrin subunit that can engage multiple ECM proteins, is highly expressed in pericytes. The function of pericytic integrin β1, however, remains unknown. To address this question, we generated brain pericyte-specific integrin-β1 knockout mice by crossing the Atp13a5 (ATPase type 13A5)-CreER with the Itgb1 floxed mice and characterized their phenotypes under homeostatic conditions and after intracerebral hemorrhage. Under homeostatic conditions, pericyte-specific integrin-β1 knockout mice were grossly normal and failed to show blood-brain barrier disruption or pericyte/astrocyte defects. In the collagenase-induced intracerebral hemorrhage model, however, the pericyte-specific integrin-β1 knockout mice exhibited larger hematoma volume, enhanced brain edema, aggravated blood-brain barrier damage caused by both paracellular and transcellular mechanisms, reduced pericyte number/coverage and aquaporin-4 coverage, increased neuronal death, elevated gliosis, and worsened neurological outcomes. Interestingly, hypertensive pericyte-specific integrin-β1 knockout mice demonstrated similar changes in the autologous blood model of intracerebral hemorrhage. These results suggest that brain pericyte-derived integrin-β1 is dispensable under homeostatic conditions but plays a protective role in intracerebral hemorrhage, likely through repairing blood-brain barrier damage and regulating gliosis.

Spontaneous recovery following an ischemic stroke is often limited, largely attributed to age-related decline in neuroplasticity. To overcome this, we demonstrated that ectopic expression of a cocktail of transcriptional factors (Oct4, Sox2, and Klf4, referred to as OSKTFs) reset developmental decline of epigenetic signatures in adult corticospinal neurons, without affecting their spinal projection patterns and function in controlling skilled locomotion. Corticospinal expression of OSKTFs had moderate effects on promoting collateral sprouting of the corticospinal tract axons and recovery of skilled motor function following a photothrombotic stroke. When combined with task-dependent rehabilitative training, OSKTFs treatment significantly enhanced its efficacy, suggesting that rejuvenating corticospinal neurons substantially amplifies the beneficial outcomes of rehabilitative training. Mechanistically, pharmacological perturbations and intersectional chemogenetic inhibition establish that both axon sprouting and functional recovery require mTOR activation and are mediated by newly sprouted corticospinal tract axons. Together, these findings identify a novel strategy to rejuvenate adult corticospinal neurons, which improves the otherwise modest benefits typically gained from rehabilitative training after traumatic brain injuries.

Ischemic stroke remains a leading cause of mortality and chronic disability worldwide, with limited therapeutic options. Tetramethylpyrazine (TMP) is a natural product with well-established clinical efficacy against ischemic stroke, yet its molecular target and mechanism of action remain elusive. By integrating a bifunctional photoaffinity TMP probe with stable isotope labeling by amino acids in cell culture and activity-based protein profiling (SILAC-ABPP), we identified thioredoxin 1 (Trx1) as a direct target of TMP. We demonstrate that TMP binds specifically to tyrosine 49 (Y49) on Trx1, antagonizes its nitrative modification, and functions as an allosteric activator. This binding enhances Trx1's reductase activity, strengthens its interaction with apoptosis signal-regulating kinase 1 (ASK1), and consequently suppresses the ASK1-p38/JNK signaling cascade. Genetic ablation of Trx1 or ASK1, or pharmacological induction of Trx1 nitration, completely abolishes TMP-mediated neuroprotection. Our findings not only decipher the mechanistic basis for TMP's clinical efficacy but also identify Y49 of Trx1 as a druggable allosteric site, unveiling a novel anti-nitrative therapeutic strategy for ischemic stroke and related disorders involving nitrative stress.

Thrombin accumulation following ischemic stroke (IS) promotes lipid peroxidation and ferroptosis to exacerbate tissue injury; however, effective interventions targeting this pathological process remain limited. Although bile acids (BAs) have demonstrated potential benefits against IS, their alterations and specific roles in IS pathogenesis are still poorly understood. This study was designed to further validate the detrimental effects of thrombin in neuronal injury, investigate BA profile changes in an IS model, and elucidate the underlying mechanisms. Serum and cerebral bile acid profiles in a mouse middle cerebral artery occlusion (MCAO) model were analyzed. Infarct volume, neurological deficits, lipid peroxidation, and ferroptosis were assessed. RNA sequencing was employed to explore potential mechanisms, followed by verification using pharmacological inhibitors. Results showed that MCAO induced upregulation of thrombin and its receptor PAR1 in neurons, leading to lipid peroxidation, ferroptosis, and subsequent neuronal injury. Bile acid profiles in brain tissues were significantly altered, and ursodeoxycholic acid (UDCA) levels were negatively correlated with infarct size. Furthermore, UDCA supplementation alleviated thrombin-induced neuronal lipid peroxidation, restored mitochondrial function, suppressed ferroptosis, and improved neurological outcomes. Mechanistically, transcriptomic analysis revealed significant changes in arachidonic acid metabolism and aldehyde dehydrogenase 3A1 (ALDH3A1) expression. UDCA was found to upregulate ALDH3A1, thereby mitigating oxidative stress and lipid peroxidation-an effect that was reversed by ALDH3A1 inhibition. We further demonstrated that UDCA upregulated ALDH3A1 through the TGR5-PKA signaling pathway, which mediated Nrf2 nuclear translocation and its subsequent binding to the Aldh3a1 promoter. In summary, UDCA confered neuroprotection against thrombin-induced lipid peroxidation in IS through the TGR5/PKA/ALDH3A1 axis. These findings identified UDCA as a promising therapeutic candidate for IS and reveal a novel signaling mechanism underlying its neuroprotective effects.

Precision diagnosis and treatment of central nervous system (CNS) diseases are hindered by limited probe penetration, toxicity risks, and low imaging signal-to-noise ratio (SNR). The blood-brain barrier (BBB) further restricts drug delivery, especially in stroke therapy. This study proposes and validates a natural exosome (sExos) from cyanobacteria, featuring intrinsic near-infrared-I (NIR-I) autofluorescence, with strong imaging and neuroprotective functions. As a theranostic nanoplatform, sExos enable integrated diagnosis and treatment of stroke and other brain disorders. Enriched with the fluorescent phycobiliprotein ApcE, sExos support label-free, high-SNR brain imaging in the NIR-I window. In vivo, sExos cross the BBB and accumulate in ischemic lesions, enabling dynamic visualization. Mechanistically, sExos regulate lipid metabolism and inhibit NF-κB signaling, reducing oxidative stress and neuroinflammation, while promoting neural recovery. Toxicity and immunogenicity evaluations confirm excellent biocompatibility and safety. In summary, this naturally autofluorescent exosome offers a label-free, brain-penetrant, and therapeutically promising imaging-intervention strategy, opening avenues for noninvasive stroke therapy and precision CNS disease management.

Designing nanomedicines with full-active components to overcome the blood-brain barrier (BBB) and achieve multi-target immunomodulation and neuroprotection for effective ischemic stroke (IS) treatment still remains a great challenge. Herein, we developed bioactive per se hydroxyl-terminated phosphorus dendron (C17G1-OH) micelles to co-deliver fibronectin (FN), an anti-inflammatory and anti-oxidative protein drug and docosahexaenoic acid (DHA), an anti-inflammatory and neuroprotection drug. The constructed DHA@C17G1-OH/FN micelles with a mean size of 254.5 nm are cytocompatible, exhibit desired stability, and can be efficiently phagocytosed by brain endothelial cells and microglia. Importantly, the high density of peripheral hydroxyl groups and FN-mediated integrin recognition enable the multifunctional micelles to penetrate BBB and achieve targeted accumulation at the IS region, thus suppressing neuroinflammation by microglia M2 polarization and oxidative stress alleviation, while rescuing neuronal apoptosis by balancing mitochondrial homeostasis. In a rat IS model, the DHA@C17G1-OH/FN micelles significantly reduce the infarct area, restore neurological behavior, neutralize inflammation and attenuate neuronal damage by multi-target immunomodulation, neuroprotection and repairment of the damaged BBB through FN-promoted angiogenesis of endothelial cells. The developed full-active phosphorus dendron-based nanomedicine synergistically modulates microglia, neurons, and endothelial cells for synergistic immune modulation and neuroprotection, and may represent an advanced formulation for effective IS alleviation.

The treatment of ischemic stroke (IS) faces significant challenges due to the complex pathophysiology, which encompasses oxidative stress, neuroinflammation, and blood-brain barrier (BBB) dysfunction. Here, we report the development of a bioactive per se hydroxyl-terminated phosphorus dendrimer-based nanoplatform for protein/drug co-delivery to the ischemic brain. We show that through sequential physical complexation and loading, nanocomplexes (NCs) composed of phosphorus dendrimers, a protein drug of fibronectin (FN) with anti-inflammatory/antioxidant/angiogenic properties and a small molecular drug melatonin (MT) with antioxidant/mitochondrial protective activities can be formed. The created NCs have an average size of 146 nm, excellent stability, pH-sensitive MT release profile, desired cytocompatibility, and admirable BBB crossing ability via the dendrimer's high-density hydroxyl groups in vitro. The NCs can be conferred with active inflammatory targeting specificity through FN-mediated integrin αvβ3 binding to tackle three types of cells including microglia, neurons, and endothelial cells for potent anti-inflammatory/antioxidant/pro-angiogenic interventions of oxygen glucose deprivation/reperfusion-induced cells in vitro. In a rat IS model, the NCs incorporating full-active components are demonstrated to effectively accumulate in the ischemic brain, reduce infarct volume, restore mitochondrial function, mitigate neuronal apoptosis, promote vascular regeneration, and improve neurobehavioral outcomes. The developed full-active phosphorus dendrimer-based nanoplatform may represent an advanced nanomedicine formulation to tackle IS that enables combined modulation of neuroinflammation, neuroprotection, and vascular repair with a great clinical translation potential.

Ischemic stroke therapy remains challenging due to a detrimental post-reperfusion inflammatory cascade that exacerbates neuronal damage, a process critically mediated by neutrophils and microglia. Neutrophils infiltrate the brain to release pro-inflammatory factors and neutrophil extracellular traps (NETs), while microglia become activated and amplify neuroinflammation. However, both cell types possess phenotypic plasticity that allows for immunomodulation toward repair. To address this, we developed a biomimetic nanoparticle strategy designed to reprogram these immune cells. Specifically, we encapsulated rosiglitazone into mPEG-PLA nanoparticles and further coated them with platelet membranes, obtaining a targeted nanoplatform termed pmPELA@R. In a mouse model of middle cerebral artery occlusion (MCAO), the platelet membrane coating markedly enhanced neutrophil targeting and improved brain accumulation of pmPELA@R. The released rosiglitazone activated PPAR-γ to polarize neutrophils toward the N2 phenotype and suppressed NETosis. Concurrently, the lactate generated from PLA degradation promoted microglial M2 polarization via enhanced histone lactylation. This dual modulation synergistically shifted the inflammatory microenvironment toward a reparative state, leading to enhanced neural tissue recovery. Our findings present a novel nanotherapeutic approach for precise immunomodulation in ischemic stroke.

Electroacupuncture (EA) has been demonstrated as an effective therapeutic intervention for cerebral ischemia-reperfusion injury (CIRI); however, the fundamental processes underlying EA therapy remain largely elusive, which hinders the optimization and broader clinical application of EA. It has been reported that during CIRI, cellular metabolism undergoes a shift from oxidative phosphorylation to glycolysis, giving rise to an accumulation of lactate, but whether and how lactate is involved in CIRI and EA therapy is not fully understood. To explore the role of lactate in EA therapy against CIRI and the underlying mechanisms. Neurological outcome evaluations and TTC staining were performed to assess CIRI in mice. Western blotting and immunofluorescence were used to detect histone lactylation, and genes regulated by histone lactylation were identified by CUT&Tag, ATAC-seq and RNA-seq, followed by investigation of the role(s) of an iron transporter encoding gene Zip14 in EA therapy. Arterial lactate levels in stroke patients were assessed 30 min after recanalization using arterial blood gas analysis. Lactate markedly enhances histone H4 lysine 12 lactylation (H4K12la) in neurons, concomitantly upregulating PKM2 expression-a pivotal regulator of lactate production. EA protects neurons in the ischemic penumbra and improves neurological outcomes following CIRI by suppressing PKM2-mediated H4K12la. Furthermore, CIRI elevates H4K12la enrichment at Zip14, which facilitates chromatin accessibility, activates Zip14 transcription, and ultimately triggers ferroptosis. EA treatment attenuates ferroptosis and mitigates CIRI by decreasing ZIP14 expression. Clinically, EA significantly reduces arterial lactate levels after recanalization in patients with ischemic stroke. This study uncovered a previously unrecognized mechanism by which lactate is involved in EA therapy against CIRI, highlighting H4K12la-dependent ZIP14 expression as a potential therapeutic target for CIRI management and EA optimization.

Ischemic stroke severely threatens human health. Rapid restoration of cerebral blood flow (CBF) in ischemic microvessels is significant as it enhances neurovascular function, prevents neuronal death, and minimises cerebrovascular injury. Although butylphthalide (NBP) is commonly used to treat ischemic stroke, its exact molecular target remains unclear. Our research aims to explore NBP's molecular target and mechanism in ischemic stroke treatment, providing more evidence for its clinical application. We confirmed NBP's protective effect on the neurovascular network by performing MCAO/R surgery on rats and using immunofluorescence and optical coherence tomography angiography for monitoring. We then employed photoaffinity labeling click chemistry for activity-based protein profiling (PAL-CC-ABPP) to identify the NBP's target protein. Molecular docking and dynamics simulations were conducted to investigate NBP-protein interactions. Additionally, we examined the effect of VIM knockdown in vascular endothelium and neurons on cerebral microvessels. The Notch pathway was explored to understand the mechanism of NBP-induced post-stroke neovascularization and neurorestoration. Our research demonstrated that NBP can enhance CBF, increase microvessel density in the ischemic brains of rats, repair microvascular injuries and foster neurological recovery. Through PAL-CC-ABPP, vimentin (VIM) was identified as the target protein of NBP. And NBP could provide protective effects by targeting the amino acid residue Arg-304 in VIM's active site. Furthermore, our findings indicate that VIM knockdown within the vascular endothelium interferes with properly forming cerebral microvessels and neurons. In contrast, VIM knockdown in neurons primarily impacts electrical signals and brain development, rather than angiogenesis. This suggests that VIM in blood vessels is crucial in maintaining the neurovascular network. Additionally, NBP enhances post-stroke neovascularization and neurorestoration by targeting VIM, which affects the Notch pathway. Our study reveals NBP can effectively treat ischemic stroke by targeting VIM to revitalise microvasculature, facilitating neurorestoration.

Cerebral ischemic stroke (CIS) is characterized by high morbidity, disability, and mortality, representing a major global public health challenge and imposing a substantial social and economic burden worldwide. Cerebral ischemia/reperfusion (I/R) triggers complex pathological cascades, resulting in secondary brain injury, thereby limiting the therapeutic efficacy of single-target interventions. Therefore, the development of novel neuroprotective strategies with multitarget pharmacological properties remains an important research focus. Hydroxysafflower yellow A (HSYA), the major bioactive component of safflower (Carthamus tinctorius L.), has demonstrated protective effects in multiple experimental models of CIS. Accumulating preclinical evidence indicates that HSYA mitigates ischemic brain injury through multiple pathways, including maintaining mitochondrial homeostasis, suppressing excitotoxicity and calcium overload, attenuating oxidative stress, inhibiting inflammatory responses, and promoting angiogenesis. However, current mechanistic evidence is predominantly derived from cellular and animal studies. Limited clinical investigations have explored the effects of HSYA-containing preparations or HSYA injection in ischemic stroke; however, current evidence remains insufficient to establish definitive clinical efficacy. The clinical efficacy, optimal dosing strategies, and long-term benefits of HSYA remain to be fully established. In addition, limited brain distribution and unfavorable pharmacokinetic properties represent important challenges for its further clinical translation. This review summarizes the current understanding of the pharmacological effects of HSYA during different phases of CIS. Furthermore, from the perspective of the stroke-heart syndrome, the potential therapeutic value of HSYA in brain-heart comorbidity is discussed. Collectively, this review provides a new perspective on the therapeutic potential and translational challenges of HSYA in CIS management.

The pathophysiological mechanisms underlying the hypercoagulable state and thrombotic events associated with COVID-19 remain incompletely understood. To investigate prothrombotic alterations during SARS-CoV-2 infection, we performed an exploratory and integrated analysis of cerebral thrombi retrieved, during the first wave of the pandemic, by mechanical thrombectomy from stroke patients with (n=6) and without (n=6) COVID-19. We combined histological and ultrastructural assessment with quantitative proteomics and elemental profiling to identify differences in cellular organization and in protein and metal composition. Immunohistochemical quantification revealed a trend toward increased macrophage abundance, a more diffuse CD68⁺ staining pattern, and reduced platelet content in COVID-19 thrombi. In contrast, neutrophil extracellular traps (NETs) burden, neutrophil number, and erythrocyte content did not differ significantly between groups. Transmission electron microscopy showed a disorganized ultrastructural fibrillar network in thrombi from COVID-19 stroke patients, consistent with the irregular and less densely packed extracellular matrix observed by Masson's trichrome staining. Furthermore, quantitative proteomics by liquid chromatography-tandem mass spectrometry (LC-MS/MS) identified 48 differentially expressed proteins among 720 shared proteins, with marked upregulation of hemoglobin subunits (α, β, γ, and δ), haptoglobin, biliverdin reductase and redox-regulating proteins, alongside downregulation of platelet-related proteins in COVID-19 thrombi. Total reflection X-ray fluorescence (TXRF) confirmed increased iron levels in COVID-19-associated thrombi. Notably, glycophorin A immunostaining did not indicate increased erythrocyte abundance, and erythrocyte structural proteins were not differentially expressed in proteomic analysis, suggesting that hemoglobin and iron were largely present in a cell-free form within the retrieved thrombi of COVID-19 stroke patients. In addition, acute-phase reactants, classical complement components, and immunoglobulins were detected exclusively in COVID-19 samples, consistent with a distinctive immune-inflammatory and oxidative signature. Overall, these findings support a novel pathophysiological mechanism underlying COVID-19-associated hypercoagulability and thrombosis, involving elevated circulating cell-free hemoglobin and increased iron content. Furthermore, this study highlights the potential contribution of hemoglobin/iron-related processes to the COVID-19 prothrombotic state and may provide molecular targets for future therapeutic strategies.

Angiogenesis contributes to vascular repair and functional recovery after ischemic stroke, yet how nitric oxide-mediated S-nitrosylation shapes this response remains unclear. We investigated the role of S-nitrosylation in postischemic angiogenesis and the underlying molecular mechanism. S-nitrosylation proteomics was performed in ischemic brain tissue from 8-week-old male mice subjected to transient middle cerebral artery occlusion and in brain microvascular endothelial cells exposed to oxygen-glucose deprivation/reoxygenation. Candidate modification sites were validated by cysteine mutagenesis and biotin-switch assays. Wild-type and C339A-mutant FKBP5 (FK506-binding protein 5) were compared in endothelial angiogenesis assays. Four-week-old male mice received endothelial-targeted adeno-associated virus 9 encoding wild-type or C339A-mutant FKBP5 and underwent transient middle cerebral artery occlusion 4 weeks later. Vascular and neurological outcomes were assessed through day 28. Protein-interaction and signaling analyses defined the downstream mechanism. S-nitrosylated FKBP5, but not total FKBP5, was increased in ischemic brain tissue and oxygen-glucose deprivation/reoxygenation-treated endothelial cells; inducible nitric oxide synthase was an upstream mediator. Mass spectrometry and mutagenesis identified cysteine 339 as the predominant modification site. C339A prevented FKBP5 S-nitrosylation and rescued endothelial proliferation, migration, sprouting, and tube formation after oxygen-glucose deprivation/reoxygenation. In mice, endothelial-targeted expression of FKBP5-C339A promoted peri-infarct angiogenesis and perfusion, reduced tissue injury, and improved chronic sensorimotor recovery. Mechanistically, S-nitrosylation strengthened FKBP5 binding to PHLPP (PH domain leucine-rich repeat protein phosphatase) and reduced AKT (serine/threonine kinase) phosphorylation. C339A weakened this interaction and restored AKT activation, whereas PHLPP inhibition with NSC117079 enhanced AKT signaling and angiogenic responses in vitro. We identify endothelial FKBP5 as a previously unrecognized regulator of poststroke vascular regeneration and establish S-nitrosylation at cysteine 339 as a molecular switch that restrains angiogenesis and functional recovery through PHLPP-dependent inhibition of AKT signaling. Targeting this modification may offer a strategy to enhance vascular repair after ischemic stroke.

Growing evidence implicates gut dysbiosis in heart failure (HF) pathogenesis. This systematic review and meta-analysis synthesises prognostic associations of microbial metabolites in HF. Electronic databases were searched through February 2026 for studies investigating associations between gut microbial metabolites and HF outcomes. Study characteristics, baseline covariates and outcomes were extracted in duplicate. The prespecified primary outcome was all-cause mortality; the secondary outcome was major adverse cardiac events (MACE). Random-effects models were applied to pool hazard ratios. Subgroup analyses stratified cohorts by HF phenotype and aetiology; meta-regression explored potential effect modifiers. This study was preregistered on PROSPERO (CRD42025631114). Twenty studies comprising 17,715 patients were included in meta-analysis; six studies were synthesised narratively. Median follow-up was 31.7 months. Elevated trimethylamine-N-oxide (TMAO) was associated with all-cause mortality in the overall population (HR 1.72, 95%CI 1.42-2.08, p=0.0002, I2 37.3%) and across HF phenotypes (HRHFrEF 2.17, 95%CI 1.68-2.81, I2 0%; HRHFpEF 1.55, 95%CI 0.92-2.61, I2 0%). Higher TMAO was also associated with MACE (HR 1.60, 95%CI 1.44-1.78, p<0.0001, I2 0%), consistent across HF phenotypes (HRHFrEF 1.43, 95%CI 1.15-1.78, I2 0%; HRHFpEF 1.76, 95%CI 1.21-2.55, I2 31.6%). Elevated phenylacetylglutamine (PAGln) was associated with mortality (HR 1.60, 95%CI 1.33-1.94, p<0.0001, I2 0%) and MACE (HR 1.65, 95%CI 1.37-1.99, p<0.0001, I2 2.1%) in the overall population. Meta-regression demonstrated no significant effect modification by baseline age, NT-proBNP, renal function or BMI. Elevated TMAO and PAGln are consistently associated with adverse outcomes across diverse HF cohorts, highlighting their potential relevance as indicators of residual risk in HF.

AbstractIron deficiency is common in patients with chronic kidney disease (CKD). Contemporary guidelines recommend the use of iron therapy only in the presence of anemia. However, patients with CKD are at increased risk of heart failure, and the coexistence of both conditions is associated with impaired quality of life, reduced physical function, and increased mortality compared with either condition alone. In this Tomorrow's Trial article, we review current evidence for intravenous iron in CKD and heart failure and propose the design of a randomized trial of intravenous iron, independent of hemoglobin, to assess its effects on mortality, heart failure, and physical function.

Risk prediction is fundamental to pulmonary hypertension (PH) guideline-based care, yet pediatric-specific risk prediction models remain limited, relying primarily on single predictors, expert opinion, or application of adult models to children. The authors developed and externally validated a data-driven 1-year risk prediction model for pediatric PH. Pediatric patients with PH (n=345; World Symposium on Pulmonary Hypertension groups 1 and 3) enrolled in the Pediatric Pulmonary Hypertension Network Registry (2014-2020; 50.4% male; median age, 4.9 years [interquartile range, 1.9-10.3]) were split into training (80%) and test cohorts (20%). The Dutch National Registry for Pulmonary Hypertension in Childhood (n=155 [1993-2020]) and the Spanish Registry of Pediatric Pulmonary Hypertension (n=327 [2009-2023]) were used for external validation. From 176 variables, BorutaSHAP feature selection with random forest identified 16 predictors for a 1-year outcome of time to death, transplant, Potts shunt, or atrial septostomy, modeled using extreme gradient boosting. Performance was assessed with the area under the receiver operating characteristic curve, confusion matrices, calibration, and Kaplan-Meier event-free survival. The final model achieved an area under the receiver operating characteristic curve of 0.90 (0.79-0.97) and 99% (96%-99%) negative predictive value in testing, dividing participants into 3 groups with strong outcome discrimination. External validation showed an area under the receiver operating characteristic curve of 0.76 (Dutch National Registry for Pulmonary Hypertension in Childhood, 0.70-0.81) and 0.77 (Spanish Registry of Pediatric Pulmonary Hypertension, 0.73-0.82) with negative predictive values of 93% (93%-97%) and 96% (93%-97%), respectively. Kaplan-Meier analysis significantly differentiated outcomes by risk group. This multicenter, validated model provides good 1-year risk prediction in pediatric PH across World Symposium on Pulmonary Hypertension groups 1 and 3, providing a robust tool for clinical risk stratification to guide therapy and addressing a gap in pediatric PH care.

Among the most commonly cited reasons for failure to initiate comprehensive medical therapy in patients with heart failure are concerns relating to hypotension, kidney dysfunction and hyperkalemia. Here we performed a pooled individual participant-level analysis and developed a prediction model to estimate the short-term (2-12 weeks) treatment effects of combination medical therapy on systolic blood pressure (SBP), diastolic BP, estimated glomerular filtration rate (eGFR) and serum potassium. A total of 38,753 participants (16,877 with heart failure with reduced ejection fraction (HFrEF) and 21,876 with heart failure with mildly reduced or preserved ejection fraction (HFmrEF/HFpEF)) across nine randomized trials were included in the analysis, which tested angiotensin receptor blocker-neprilysin inhibitor (ARNI), steroidal mineralocorticoid receptor antagonist (sMRA), nonsteroidal MRA (nsMRA) and sodium glucose cotransporter-2 inhibitors (SGLT2i). For HFrEF, the estimated mean (95% prediction intervals (PIs)) treatment effect on SBP with combination ARNI + SGLT2i + sMRA therapy was -9.2 (-10.6 to -7.8) mmHg. For HFmrEF/HFpEF, the estimated mean (95% PI) treatment effects on SBP with SGLT2i + sMRA therapy and with SGLT2i + nsMRA therapy were -5.9 (-7.3, -4.6) and -4.8 (-5.7, -4.0) mmHg, respectively. For HFrEF, the estimated treatment effects of ARNI + SGLT2i + sMRA on eGFR and serum potassium were -6.8 (-7.9, -5.4) ml min-1 m-2 and +0.30 (0.25, 0.35) mmol l-1, respectively. For HFmrEF/HFpEF, the treatment effects for combination SGLT2i + sMRA and SGLT2i + nsMRA on eGFR were -7.7 (-8.9, -6.4) and -6.1 (-6.7, -5.5) ml min-1 m-2, respectively and for serum potassium were +0.34 (0.29, 0.38) and +0.21 (0.18, 0.25) mmol l-1, respectively. These analyses provide individualized estimates of the expected treatment effect for any combination of medical therapies in HFrEF and HFmrEF/HFpEF on BP, kidney function and serum potassium.

Refractory advanced biventricular heart failure (RAHF) has a poor prognosis, and many patients are ineligible for left ventricular assist device (LVAD) support. The "historical" total artificial heart (TAH) is associated with high rates of stroke, bleeding, and haemolysis. The bioprosthetic TAH (bio-TAH), a pulsatile, autoregulated, and haemocompatible device, was assessed here as a bridge to transplantation. EFICAS (NCT04475393) was a prospective, multicentre trial conducted at 10 French centres. Adults with RAHF who were ineligible for LVAD support and listed or eligible for heart transplantation were enrolled. The primary composite endpoint was survival at 180 days free from disabling stroke, device malfunction requiring reoperation or urgent transplantation, or elective heart transplantation. Secondary endpoints included serious adverse events, NYHA class, the 6-min walk test, and quality of life measured using the EQ-5D-5L. Fifty-five patients underwent implantation (December 2022 and May 2025; median age, 56 years [IQR, 48-63]; 49% INTERMACS profiles 1-2; 36% on VA-ECMO). The primary endpoint was achieved in 40 patients (72.7%; 95% confidence interval, 57.1-85.1), exceeding the prespecified "historical TAH" threshold of 38% (p<0.0001). At 180 days, 96% were free of disabling stroke, 76% were discharged, and 92% were NYHA class I-II. Median 6-minute walk distance improved by 305 m (p=0.0002) and EQ-5D by 40 points (p<0.0001). No haemolysis occurred, and major bleeding was limited to the first 30 days. The bio-TAH achieved its primary endpoint with a favourable safety profile, supporting its use as an effective bridge-to-transplant strategy in patients with RAHF ineligible for LVAD support.

Circadian patterns influence cardiovascular physiology, yet have not been characterized in intracardiac pressures of ambulatory chronic heart failure patients. We aimed to assess diurnal variation via a novel remote intracardiac left atrial pressure sensor. Daily ambulatory left atrial pressure (LAP) measurements were obtained with an implantable intracardiac sensor. Patients performed morning and evening measurements during longitudinal follow-up. We compared diurnal variability in morning and evening LAP, examined its potential association with diuretic regimen, presence of atrial fibrillation and acute decompensated heart failure (ADHF) events.Across >15,500 measurement days with an average follow up time of 25.5±18.6 months in 73 heart failure patients, median left atrial pressure was higher in the evening than in the morning (12.4 [6.8, 18.3] vs.10.7 [5.5, 17.3] mmHg; p < 0.01). Neither higher diuretic dose, twice-daily dosing, nor atrial fibrillation modified this diurnal variation (p =0.98, p=0.50).Patients who suffered ADHF events demonstrated higher left atrial pressures (14.3 [9.5, 19.9] vs 10.4 [5.4, 17.3] mmHg, p < 0.01). Higher LAP was also independently associated with increased risk of ADHF events (OR 1.40, 95% CI 1.10-1.78; p < 0.01). Diurnal variation was present irrespective of acute decompensated heart failure status (p = 0.79). Using direct ambulatory intracardiac LAP monitoring, we observed consistent diurnal variation with higher evening pressures, largely unchanged by diuretic dose or dosing schedule, atrial fibrillation, or association with ADHF events.

Advances in cancer care have improved survival, increasing the importance of comorbidities at diagnosis for longer-term outcomes. Pre-existing cardiovascular disease (CVD) can complicate management and prognosis, yet its long-term trends and future burden at cancer diagnosis are unclear. This study aimed to quantify temporal trends in pre-existing CVD among patients with newly diagnosed cancer and project prevalence through 2050. Linked primary care, cancer registry, and hospitalization records were used to identify 773 590 adults (≥18 years) diagnosed with the five most common cancers between 2001 and 2020 in England. Serial cross-sectional analyses estimated annual crude and age-standardized prevalence of pre-existing CVD and comorbidities. Temporal trends were assessed using logistic regression adjusted for demographics and cancer type. The contributions of changes in risk factor domains were evaluated using sequential modelling, and CVD prevalence was projected to 2050 using demographic-adjusted spline models. The age-standardized prevalence of pre-existing CVD rose from 31.4% [95% confidence interval (CI) 31.2-31.6] in 2001-2005 to 39.2% (95% CI 39.0-39.4) in 2016-2020, with the steepest increases in lung and haematological cancers. Valvular disease, heart failure, atrial fibrillation, and diabetes showed the largest subtype rises. Sequential modelling showed the greatest attenuation of the temporal trend after adjustment for cardiometabolic conditions and chronic comorbidities. Projection analyses suggest that, if current temporal patterns continue, approximately half of patients may present with pre-existing CVD at cancer diagnosis by 2050. Pre-existing CVD at cancer diagnosis has increased substantially over 2 decades and is projected to affect nearly half of patients by 2050. These trends underscore the need for the expansion of cardio-oncology services.

Blood pressure (BP) control is a Class I recommendation for the management of heart failure with preserved ejection fraction (HFpEF); however, evidence supporting systolic BP (SBP) targets remains limited. We investigated associations between BP control and subsequent outcomes in patients with HF with mildly reduced EF (HFmrEF)/HFpEF. We pooled TOPCAT (Americas), PARAGON-HF, DELIVER, and FINEARTS-HF, which tested spironolactone, sacubitril/valsartan, dapagliflozin, and finerenone, respectively, versus placebo or active control in patients with HF and an LVEF >40% (DELIVER), ≥40% (FINEARTS-HF), or ≥45% (TOPCAT-Americas, PARAGON-HF). Daily BPs were estimated by interpolation from standardized office measurements obtained at randomization and prespecified visits. Time in target range (TIR) was the percentage of the first year after randomization during which SBP was 110-<130 mmHg. Continuous associations between TIR and subsequent risk of HF hospitalization or cardiovascular death, its individual components, and all-cause death was assessed using landmark Cox proportional hazards models with linear splines, adjusted for baseline cardiovascular risk factors. Among 17,788 patients (mean age 72±9 years; 47% women; mean baseline SBP 129±15 mmHg), the median TIR was 38% (≈139 days). Randomization to active therapies increased TIR by 2% (95% CI: -2 to 6) with spironolactone, 7% (5 to 9) with sacubitril/valsartan, 2% (0 to 4) with dapagliflozin, and 3% (1 to 5) with finerenone. Higher TIR was associated with lower subsequent risk of the composite outcome (P=0.021), primarily driven by lower HF hospitalization risk (P=0.007); associations with cardiovascular death and all-cause death were not significant. Sensitivity analyses using stricter (120-<130 mmHg) or more liberal ranges (100-<130 and 120-<140 mmHg) yielded qualitatively similar findings. In patients with HFmrEF/HFpEF, BP control during the first year was associated with a lower subsequent risk of HF hospitalization. ClinicalTrials.gov ID NCT00094302 (TOPCAT), NCT01920711 (PARAGON-HF), NCT03619213 (DELIVER), NCT04435626 (FINEARTS-HF).

Heart failure therapy (HFT) is routinely continued in breast cancer survivors after recovery from anti-HER2 cancer therapy-related cardiac dysfunction (CTRCD), despite limited evidence. HER-SAFE is the first randomised trial to assess HFT withdrawal in this population. In this open-label, multicentre, randomised controlled trial, breast cancer survivors with recovered anti-HER2 CTRCD (asymptomatic, left ventricular ejection fraction [LVEF] ≥50%, normalised biomarkers) were randomised to HFT withdrawal or continuation. Antecedent CTRCD was mild (relative global longitudinal strain [GLS] decline >15%, LVEF ≥50%), moderate (LVEF fall >10% to <50%), or severe (LVEF <40%). The primary endpoint was a moderate or severe CTRCD event over 12 months analysed by intention to treat; secondary endpoints included serial cardiac function, biomarkers, and quality of life. Between July 2023 and June 2025, 90 patients were randomised (all female; median age 50 years [IQR 43-59]; median 17.3 months [IQR 7.7-33.2] since CTRCD recovery; HFT predominantly renin-angiotensin system inhibitors [98%] and beta-blockers [88%]) - 46 randomised to HFT withdrawal (1 lost to follow-up) and 44 to continuation. The primary endpoint occurred in 1 of 45 with withdrawal (moderate asymptomatic CTRCD) versus 0 of 44 with continuation (between-group difference 2.2pp; 90% CI upper limit 9.4pp). No cardiovascular deaths, heart failure hospitalisations or symptomatic CTRCD occurred. Cardiac magnetic resonance-derived LVEF remained stable in both arms at 12 months (between-group difference -0.8% [-2.0 to +0.4], p=0.21). Among breast cancer survivors with recovered anti-HER2 CTRCD, HFT withdrawal was not associated with symptomatic events or significant between-group difference in LVEF at 12-months.

Heart failure with reduced ejection fraction causes high mortality and recurrent hospitalizations in India. We evaluated the effectiveness of the collaborative care model in improving days alive and out of the hospital and overall survival. We conducted a parallel-group, cluster-randomized controlled trial involving 1507 adults with heart failure with reduced ejection fraction across 22 centers in India (CTRI/2021/11/037797). Centers were randomized 1:1 to the intervention or usual care. Participants were followed up for 2 years. The intervention included risk stratification, lifestyle and pharmacological optimization, and a nurse-coordinated, mobile health-supported disease management program with self-care education, active follow-up, and continuous outpatient monitoring throughout the study period. The primary outcome was days alive and out of the hospital, and all-cause mortality was assessed as a secondary outcome. Days alive and out of the hospital was analyzed with a one-inflated β model. All-cause mortality was analyzed with Cox proportional hazards models adjusted for the clustered study design. Among 1507 participants (752 usual care; 755 intervention), the mean age was 61.9 years, and 77.6% were men. All participants except one completed 24 months of follow-up. Most participants (70%) had low educational attainment; 57.3% lived in rural areas; and ischemic heart disease was the predominant cause (77.4%). Baseline characteristics were comparable between the intervention and usual care groups. In the one-inflated β model, the probability of surviving up to 730 days without hospitalization was 79.4% (95% CI, 77.7%-81.2%) in the usual care group and 84.0% (95% CI, 82.2%-85.8%) in the intervention group. Participants in the intervention group had 78% higher odds of achieving a percent days alive and out of the hospital of exactly 1 (730/730 days) compared with those in the usual care group (odds ratio, 1.78 [95% CI, 1.42-2.23]). There were 201 deaths (26.73%) in the usual care group compared with 163 deaths (21.59%) in the intervention group (risk ratio, 0.80 [95% CI, 0.67-0.97]). In the multivariable Cox proportional hazards model, the intervention group had a 22% lower mortality risk than the usual care group (hazard ratio, 0.78 [95% CI, 0.63-0.95]; P=0.028). A nurse-coordinated, mobile health-supported collaborative care model for heart failure with reduced ejection fraction in India increased the number of days alive and out of hospital, raised the absolute probability of remaining out of hospital by 4.5 percentage points, and reduced all-cause mortality by 22%. URL: www.ctri.nic.in; Unique identifier: CTRI/2021/11/037797.

Stimulation of the relaxin family peptide receptor 1 experimentally reduces systemic vascular resistance and afterload, improves organ perfusion, and fosters reverse cardiac remodeling. We hypothesized that AZD5462, an oral once-daily relaxin family peptide receptor 1 agonist, may benefit individuals with chronic heart failure (HF). In this international, multicenter, double-blind, placebo-controlled, dose-ranging trial, adults with chronic HF and left ventricular ejection fraction ≤35% (cohort A) or 41% to 55% (cohort B) were randomized 1:1:1:1 to 3 (20, 80, or 360 mg) once-daily oral doses of AZD5462 or placebo. Primary end points were changes in end-systolic volume index (cohort A) and systemic vascular resistance index (cohort B) after 24 weeks. A total of 235 (cohort A) and 140 (cohort B) participants were randomized across 57 sites in 10 countries. The mean age was 65 and 70 years, and 88% and 69% were male; baseline concomitant guideline-directed medical therapy for HF was excellent. Treatment with AZD5462 was well tolerated compared with placebo. In cohort A, at week 25, treatment with AZD5462 20 mg showed a placebo-adjusted end-systolic volume index change from baseline of -5.4 mL/m2 (95% CI, -10.9 to 0.1; P=0.054). In cohort B, AZD5462 treatment resulted in significant placebo-adjusted reductions in systemic vascular resistance index at week 25 across all dose groups (all P <0.05). Among individuals with well-treated chronic HF, the addition of oral AZD5462 was well tolerated and demonstrated encouraging effects on cardiovascular hemodynamic measures across a wide range of left ventricular ejection fraction. Larger and longer duration trials are warranted to assess the impact of AZD5462 on clinical outcomes in HF. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06299826.

Digitoxin reduced the composite of death or worsening heart failure in DIGIT-HF, but whether these benefits translate into economic value remains unknown. We assessed its cost-effectiveness as add-on therapy for heart failure with reduced ejection fraction (HFrEF) across all 27 European Union Member States (EU-27) and the United States (US). We developed a DIGIT-HF-informed, multi-jurisdictional three-state Markov cost-utility model projecting 10-year and lifetime outcomes. Clinical risks and intention-to-treat effects were held constant; hospitalization costs, EQ-5D-5L utilities, digitoxin costs, discounting, and willingness-to-pay (WTP) thresholds varied by jurisdiction. Uncertainty was assessed using 10 000 probabilistic simulations. Across the EU-27, digitoxin was cost-effective at 10 years, with incremental costs of -€338 to +€25 per patient, incremental quality-adjusted life-years (QALYs) of 0.188-0.231, and a maximum incremental cost-effectiveness ratio (ICER) of €120/QALY. Over lifetime, corresponding ranges were -€79 to +€72, 0.373-0.453 QALYs, and a maximum ICER of €174/QALY. At €50 000/QALY, cost-effectiveness probability was 92%. Digitoxin was cost-saving in 24 of 27 Member States at 10 years and 10 of 27 over lifetime. In the USA, it was cost-saving (lifetime savings US$405 per patient; 0.43 QALYs; 93.4% probability of cost-effectiveness). Digitoxin generated clinically meaningful health benefits at negligible incremental cost and remained cost-effective across every evaluated EU-27 healthcare system and the USA. Economic value emerged earliest within the first decade and in higher-cost hospital systems, while lifetime analysis captured larger cumulative gains in quality-adjusted survival.

N-terminal pro-B-type natriuretic peptide (NT-proBNP) is recommended to guide echocardiography referral in community-based patients with suspected heart failure (HF), but diagnostic performance is influenced by individual characteristics including age, ethnicity, kidney function, cardiac rhythm, and body mass index (BMI). An individualised probabilistic approach may have superior diagnostic performance to guideline-recommended universal thresholds. This study aimed to develop and validate the PRECISE-HF model to provide probabilistic rule-out and rule-in thresholds based on NT-proBNP and relevant clinical characteristics. Cohort study performed from January 1, 2018 to March 31, 2025, using primary care data from the Clinical Practice Research Datalink (CPRD), broadly representative of the UK population. Patients were included if they had an NT-proBNP measured due to clinical suspicion of HF with no known history of HF. HF diagnosis was recorded as a primary care diagnosis or HF hospitalisation within 12 months of NT-proBNP measurement. Using XGBoost machine learning, the probability of HF was modelled incorporating NT-proBNP alongside age, sex, ethnicity, estimated glomerular filtration rate, BMI, systolic blood pressure, anaemia, loop diuretic prescription and history of atrial fibrillation, diabetes, myocardial infarction and chronic obstructive pulmonary disease. Rule-out and rule-in thresholds were identified based on ≥90% sensitivity and specificity, respectively, and compared to current European Society of Cardiology (ESC) recommendations. External validation was performed in the REVOLUTION-HF Swedish cohort. Overall, 535 583 patients were included, randomly split into derivation (n=374 909) and internal validation (n=160 674) cohorts. A HF diagnosis was recorded in 10% of the validation cohort. The PRECISE-HF model demonstrated excellent discrimination (area under the receiver operating characteristic curve [AUROC] 0.896) and calibration (Brier score 0.061). The rule-out threshold had a sensitivity of 90.1% and a negative predictive value of 98.5%, ruling out 64.8% of patients. The rule-in threshold ruled in 16.1% with a specificity of 90.0% and a positive predictive value of 44.1%. Compared to the ESC thresholds, PRECISE-HF13 ruled out 144 additional patients per 1000 at the expense of three missed diagnoses, with 73 fewer false positives per 1000 at rule-in. In external validation, the model retained good discrimination (AUROC 0.757) and calibration (Brier score 0.163). The PRECISE-HF model, integrating multiple clinical characteristics with NT-proBNP, demonstrated superior diagnostic performance compared with universal rule-out and age-adjusted rule-in thresholds in community-based patients with suspected HF. This individualised approach may enable earlier confirmatory testing and initiation of disease-modifying treatment in those most likely to have HF.

Longitudinal metabolomic studies can refine understanding of heart failure (HF) progression and enable precision prevention. This study aims to identify serum metabolites associated with HF risk via longitudinal metabolomic analysis, delineate their dynamic trajectories, and explore metabolite profiles in populations with different metabolic disorders. This study analyzed longitudinal serum metabolomic data from 4774 serum samples from 1728 HF-free participants in the Chinese Multi-Provincial Cohort Study Metabolomics Project at 4 time points over a 20-year follow-up. Intensity models and Cox proportional-hazards models identified metabolites associated with HF risk. Latent variable mixed-effects models evaluated metabolite trajectories. Of the 784 detected metabolites, 23 were associated with HF risk at a false discovery rate-adjusted P<0.05, including 9 not previously reported in relation to HF. The HF risk-associated metabolites exhibited 4 distinct trajectory clusters and corresponding biological trends. Most metabolites that showed positive associations with HF risk remained relatively stable throughout the 20-year follow-up period, whereas metabolites that were negatively associated with HF risk generally exhibited a declining trend. The levels of these 23 metabolites in the group who developed HF began to diverge from the levels in the non-HF group >5 years before clinical HF diagnosis, with most changes initiating 15 to 20 years before clinical manifestation. Populations with different metabolic disorders exhibited distinct metabolite profiles related to HF. The HF-associated metabolites were primarily involved in energy metabolism and the vasodilatory response among individuals with hypertension, lipotoxic effects and oxidative stress among those with obesity, and inflammatory processes and glucotoxic mechanisms among individuals with dysglycemia. This longitudinal metabolomic study identifies HF-associated metabolite profiles, characterizes their changes during the 20 years preceding clinical diagnosis, and reveals heterogeneity across individuals with different metabolic disorders, thereby informing future biomarker and intervention research.

The aim of this narrative review is to focus on the epidemiology and new advances in the management of cardiovascular diseases (CVDs) in the elderly and very elderly, with particular emphasis on those CVDs that are most relevant and have the greatest impact on morbidity and mortality, such as heart failure (HF), ischaemic heart disease, atrial fibrillation and stroke, valvular heart diseases, and cardiomyopathies. The review highlights the specificities of CVD in this population and the special considerations that need to be made in the management of these patients to maximize benefit and avoid futility. Another major objective is to find a contemporary definition of the elderly, including functional capacity and the concept of vascular, biological, and prospective age. A final aim is to review and discuss the definition and measurement of frailty and its impact on CVD management. The key points are that old and very old people are a peculiar growing population across the globe, in which CVDs have a different impact and epidemiology compared with young people. Among CVDs, HF is clearly the most relevant and impactful on the quantity and quality of life. Each time we approach an elderly patient, a frailty multidisciplinary evaluation should be conducted, especially to avoid futile and aggressive invasive approaches with a risk-benefit balance in favour of harm.

The use of anti-programmed cell death-1 (PD-1) antibody increases heart failure (HF) risk in patients with cancer with preexisting cardiovascular conditions. However, the underlying mechanism remains incompletely understood. To evaluate the effects of anti-PD-1 antibody on transverse aortic constriction (TAC)-induced cardiac remodeling and HF, anti-PD-1 antibody-treated mice; T cell-, myeloid-, and CD8+ T cell-specific Pdcd1 knockout; C-X-C motif chemokine receptor 3 (Cxcr3) knockout; and granzyme B (Gzmb) knockout mice combined with flow cytometry, Western blotting, immunofluorescence staining, pharmacological approaches, and bulk RNA-sequencing analyses were used. Administration of anti-PD-1 antibody, T cell-, or CD8+ T cell-specific Pdcd1 deletion, but not myeloid-specific Pdcd1 knockout, aggravated TAC-induced cardiomyopathy and HF in mice. Mechanistically, PD-1 blockade or deletion increased myocardial infiltration of CXCR3+ CD8+ T cells, leading to granzyme B/perforin-mediated impairment of cardiomyocyte mitochondrial complex I to exacerbate TAC-induced cardiac injury and HF. TAC-enhanced chemotaxis, between cardiac fibroblast-derived CXCL9/CXCL10 and CXCR3+ CD8+ T cells, was a driving force for recruiting CXCR3+ CD8+ T cells under the conditions of PD-1 blockade or deletion. The worsened TAC-induced cardiomyopathy caused by anti-PD-1 antibody or T cell-specific Pdcd1 deletion was rescued by genetic deletion or pharmacological blockade of granzyme B and CXCR3. Anti-PD-1 antibody enhances myocardial infiltration of CXCR3+ CD8+ T cells under TAC condition through CXCL9/CXCL10-mediated chemotaxis. The increased granzyme B and perforin likely derived from CD8+ T cells impair function of mitochondrial respiratory chain complexes to cause cardiomyocyte apoptosis, thereby exacerbating TAC-induced cardiomyopathy and HF. CXCL9/CXCL10-CXCR3+ CD8+ T cell axis may represent a promising target for combating anti-PD-1 antibody-associated cardiotoxicity.

Pharmacological tools to selectively modulate extracellular vesicle (EV) secretion are scarce. Here, we identify the ALK5 (TGF-β receptor I) inhibitor SD-208 as a potent suppressor of small EV (sEV) secretion that acts independently of its canonical anti-fibrotic activity. SD-208 not only reversed myofibroblast activation but also markedly inhibited sEV secretion. Strikingly, this inhibitory effect persisted in non-activated cardiac fibroblasts and non-fibrotic HEK293 cells, demonstrating that SD-208 regulates EV secretion through mechanisms uncoupled from TGF-β/Smad signalling. Mechanistic analyses revealed that SD-208 disrupts vesicle trafficking rather than EV biogenesis. Reduced secretion of CD63+ EVs was accompanied by intracellular accumulation of CD63+ structures and their selective diversion into LAMP1+ lysosomes. Proteomic profiling of SD-208-treated and control HEK293 cells and cardiac fibroblasts revealed dysregulation of vesicle trafficking pathways, enrichment of ubiquitin ligase complexes, and enhanced endosome-to-lysosome transport. Together, these findings demonstrate that SD-208 diverts CD63+ multivesicular bodies (MVBs) from a secretory fate toward lysosomal degradation. This work identifies SD-208 as a small-molecule tool to interrogate the secretory-versus-degradative fate of MVBs and uncovers a new regulatory link between lysosomal pathways and EV trafficking. Beyond its established role as an anti-fibrotic agent, SD-208 provides mechanistic and therapeutic opportunities for the control of EV secretion in diseases such as fibrosis, cardiac remodelling, hypertrophic cardiomyopathy, and cancer.

Metabolic syndrome describes a set of risk factors that can eventually lead to the occurrence of cardiovascular and cerebrovascular disease. Metabolic syndrome has emerged as a significant global health issue, associated with various metabolic diseases, including obesity, diabetes, hypertension, dyslipidemia, chronic kidney disease, metabolic dysfunction-associated steatotic liver disease, and other metabolic disorders. Here, we summarize the intricate mechanisms including insulin resistance, chronic low-grade inflammation, oxidative stress, and epigenetic modifications, and how they contribute to the disease progression of metabolic syndrome. The gut-adipose tissue axis in the progression of metabolic syndrome is emphasized here, mainly involving adipocyte-derived extracellular vesicles and adipokines, as well as specific gut microbiota and their secreted factors, such as lipopolysaccharide, short-chain fatty acids, endocannabinoids, bile acids, aryl hydrocarbon receptor ligands, and tryptophan derivatives. Furthermore, the contemporary management for metabolic syndrome mainly includes some established pharmacological treatments such as GLP-1 receptor agonists, SGLT2 inhibitors, and RAAS inhibitors, as well as promising emerging therapies targeting the gut-adipose tissue axis such as lifestyle modifications, prebiotics, probiotics, synbiotic supplements, FMT, bariatric surgery, CB1R antagonists, and novel pharmacological agents. These strategies may pave the way for the development of effective treatments for metabolic diseases in future research.

• The novel mitochondria/lysosomes membranes-coated nanoparticles were synthesized. • The active ingredient combination SNCF was screened out from QFD. • This work provided a scientific basis for SNCF from QFD in the treatment of HF. • An integrated model of cardiac mitochondrial and lysosomal proteomics was developed. • SNCF can modulate cardiac mitochondria-lysosome dysfunction and contacts against HF.

Diabetic vascular complications are a major determinant of poor prognosis in diabetic patients, with their development closely linked to persistent low-grade inflammation. Macrophages, as key regulatory cells in the immune system, undergo significant metabolic reprogramming in the diabetic hyperglycemic microenvironment. This reprogramming involves a coordinated remodeling of key metabolic pathways, including carbohydrate metabolism, lipid metabolism, and amino acid metabolism. This review systematically discusses the classical theories of macrophage polarization and provides an in-depth analysis of how key molecules drive the M1/M2 imbalance. Additionally, it explores the intricate regulatory interactions between the three major metabolic pathways. The metabolic reprogramming-polarization axis is further examined in the context of four typical diabetic vascular complications-diabetic atherosclerosis, diabetic kidney disease, diabetic retinopathy, and diabetic cardiomyopathy-highlighting their specific pathological roles. This work aims to elucidate the theoretical value of this regulatory axis as a central mechanism in diabetic vascular complications and explores its clinical translational potential as a precise therapeutic target. It provides a systematic theoretical foundation and proposes new directions for future research.

Decidual protein induced by progesterone 1 (DEPP1), also known as DEPP or C10ORF10, was originally identified as a progesterone-induced protein in endometrial stromal cells. Over the past two decades, research has progressively elucidated its involvement in various biological processes such as energy metabolism, redox regulation, and cellular autophagy. Additionally, DEPP1 has been implicated in the pathogenesis of several diseases, including diabetes, atherosclerosis, ischemic cardiomyopathy, breast cancer, and colon cancer. In this review, we systematically summarise the research progress on DEPP1, with particular emphasis on its molecular mechanisms in the crosstalk between oxidative stress and autophagy. Its cellular localization and functional uniqueness are discussed within the context of the classical redox-autophagy regulatory network. Furthermore, key issues in DEPP1 research and its potential translational applications are discussed to provide insights and perspectives for future studies centred on DEPP1.

Lactate and β-hydroxybutyrate (βHB), once regarded mainly as metabolic byproducts or alternative fuels, are now increasingly recognized as redox-active metabolites that regulate energy partitioning, mitochondrial function, and adaptive stress responses. Here, we propose a unifying framework in which lactate and βHB form a redox-coupled inter-organ circuit linking the liver, kidney, heart, and skeletal muscle. Through coordinated LDH- and BDH1-dependent reactions and monocarboxylate transport, the lactate-βHB axis integrates carbohydrate and lipid metabolism, supports dynamic fuel switching, and links distinct cytosolic and mitochondrial NAD+/NADH redox states during fasting, exercise, hypoxia, and metabolic stress. Disruption of this circuit contributes to mitochondrial dysfunction, impaired metabolic flexibility, and maladaptive redox signaling in disorders including metabolic dysfunction-associated steatotic liver disease, type 2 diabetes, chronic kidney disease, heart failure, and sarcopenia. Beyond their bioenergetic roles, lactate and βHB also act as signaling metabolites that influence transcriptional, epigenetic, post-translational, and stress-response pathways, including protein lysine lactylation and β-hydroxybutyrylation, thereby linking metabolic state to cellular adaptation, tissue resilience, and long-term remodeling. Importantly, interventions including exercise, ketogenic or low-carbohydrate diets, SGLT2 inhibition, ketone-based strategies, and NAD+-enhancing approaches may help restore lactate-βHB coupling and improve redox homeostasis. This framework positions the lactate-βHB axis as a systems-level mechanism of inter-organ redox communication and provides a redox-biological basis for therapeutic targeting in metabolic and degenerative disease.

Excessive alcohol consumption leads to neurodegeneration, driven primarily by oxidative stress and mitochondrial dysfunction, yet no specific treatment exists. Nicotinamide riboside chloride (NRC), a nicotinamide adenine dinucleotide precursor, has demonstrated therapeutic potential in mitigating mitochondrial dysfunction in heart failure, but its role in alcohol-induced neurodegeneration remains unexplored. This study investigated NRC's neuroprotective effects using behavioral tests, serum ethanol and inflammatory marker analysis, hematoxylin-eosin staining, and molecular assays of in vitro models. Proteomics and GEO database analysis further elucidated the mechanisms of alcohol-induced brain injury. Results showed that NRC significantly improved alcohol-related cognitive impairment and neuroinflammation. Both our experimental data and external datasets identified mitochondrial dysfunction as a key driver of alcohol-induced neuronal damage, characterized by impaired mitophagy and disrupted mitochondrial unfolded protein response (UPRmt). NRC supplementation restored mitochondrial homeostasis by enhancing UPRmt and Fundc1-dependent mitophagy. Mechanistically, UPRmt inhibition abolished NRC's protective effects by suppressing Fundc1 expression and mitophagy, whereas mitophagy inhibition did not affect UPRmt, suggesting a hierarchical regulation where UPRmt governs Fundc1-mediated mitophagy. In conclusion, alcohol disrupts mitochondrial quality control, but NRC counteracts neuronal toxicity by activating UPRmt and restoring Fundc1-driven mitophagy, offering a promising therapeutic strategy for alcohol-related neuronal damage.

The 3' untranslated regions (3'UTRs) have been known to regulate mRNA location, stability, and translation. 3'UTR length regulation is involved in the pathogenesis of cardiac dysfunction; however, more about the roles of 3'UTRs in cardiac remodeling remains elusive. In this study, we found slit guidance ligand 1 (SLIT1) 3'UTR with 3074 nt in length, which was 10-fold higher than SLIT1 coding sequence (CDS), was significantly decreased in the myocardium of patients with heart failure (HF) (n = 40) in comparison with healthy organ donors (n=17). We revealed that SLIT1 3'UTR and the 1526 nt fragment of SLIT1 3'UTR (FS1UTR) mainly and specifically combined miR-34a-5p, and improved cardiac remodeling through the miR-34a-5p/SIRT1 axis independently of Slit1 expression. Furthermore, a 260 nt restructured RNA derived from FS1UTR, S1UTRSP5, which contains 5 binding sites of miR-34a-5p seed sequence, alleviated cardiac remodeling in vitro and in vivo. We demonstrated that S1UTRSP5 blocked the function of miR-34a-5p and activated the SIRT1-PGC-1α-Nrf2 axis in cardiomyocytes, and promoted the SIRT1/Smad3 signal in cardiac fibroblasts and the SIRT1-eNOS-VEGFA axis in endothelial cells, collectively contributing to the amelioration of cardiac remodeling. These results provide new insights into the development of S1UTRSP5 as a novel inhibitor of miR-34a-5p for cardiac remodeling and HF. The human SLIT1 3'UTR or FS1UTR combines miR-34a-5p to increase SIRT1 level in CMs, CFs and ECs. Notably, S1UTRSP5, a 260-nt stable RNA derived from SLIT1 3'UTR, efficiently sponged miR-34a-5p to activate SIRT1-PGC-1α-Nrf2 pathway in CMs, and to promote SIRT1/Smad3 signal in CFs and the SIRT1-eNOS-VEGFA pathway in ECs, collectively contributing to amelioration of cardiac remodeling.

Heart failure (HF) following myocardial infarction (MI) remains a major threat to health worldwide. While transcriptomics has revealed numerous genes whose expression is altered in HF, distinguishing therapeutic targets remains challenging. In this study, we aimed to identify novel therapeutic targets for HF and explore potential pharmacological interventions. We integrated human HF datasets with weighted gene coexpression network analysis (WGCNA) and machine learning (LASSO/SVM-RFE) to screen for candidate genes and applied Mendelian randomization (MR) to assess causality. SLCO5A1 emerged as a prioritized candidate, as it showed a genetically supported protective association with HF and was consistently downregulated in the ischemic failing myocardium. In mice, cardiomyocyte-targeted SLCO5A1 overexpression attenuated post-MI systolic dysfunction and pathological remodeling. Using drug-gene signature mining followed by biophysical and cellular validation, we identified 3-iodothyronamine (T1AM) as a small molecule that directly binds to SLCO5A1 and increases SLCO5A1 protein levels. Pharmacological administration of T1AM increased post-MI survival, improved cardiac function and reduced fibrosis; these benefits were markedly weakened by cardiomyocyte-specific SLCO5A1 knockdown, supporting a functional requirement for SLCO5A1. Mechanistically, SLCO5A1 reduced cardiomyocyte transforming growth factor beta 1 (TGF‑β1) secretion, thereby limiting fibroblast Smad3 activation and myofibroblast marker expression in conditioned-medium assays. In conclusion, our findings demonstrate that SLCO5A1 is a cardioprotective regulator of cardiomyocyte-fibroblast communication in post-MI HF and support a pharmacological increase in SLCO5A1 levels as a potential therapeutic strategy. SLCO5A1 serves as a novel therapeutic target for heart failure. Enhancing SLCO5A1 expression protects against MI-induced HF by inhibiting TGF-β1/Smad3-mediated cardiomyocyte-fibroblast crosstalk.

Cardiac fibrosis is a pathological remodeling process that contributes to the development and progression of heart failure. Although glucose-dependent insulinotropic polypeptide (GIP) may exert antifibrotic effects, how GIP receptor activation regulates cardiac fibrogenesis and modulates cardiac function in heart failure remains unclear. This study investigated whether GIP receptor agonism suppresses cardiac fibroblast activity and improves heart failure and explored the underlying mechanisms by using cellular and animal models. Human cardiac fibroblasts were treated with [D-Ala2]GIP (DA-GIP; 10, 100, or 300 nM) for 24 h or left untreated (control). Fibroblast migration, collagen production, and intracellular signaling were examined using wound healing, immunoblotting, enzyme-linked immunosorbent, and fluorometric assays. Cardiac structure, function, and fibrosis were assessed through echocardiography and Masson's trichrome staining in rats with isoproterenol-induced heart failure with and without DA-GIP (24 nM/kg, twice daily for 2 weeks) administration. Compared with control cells, DA-GIP (300 nM)-treated cardiac fibroblasts exhibited a significantly lower migratory activity and reduced expression levels of pro-collagen IA1, pro-collagen III, and transforming growth factor-β1 proteins. Additionally, DA-GIP increased nitric oxide (NO) production and promoted endothelial NO synthase (eNOS) and protein kinase B (Akt) activation in cardiac fibroblasts. Notably, Akt inhibition blocked DA-GIP-induced eNOS activation, and treatment with Nω-nitro-L-arginine methyl ester (a NO synthase inhibitor, 100 μM) attenuated the antifibrotic effect of DA-GIP. In heart failure rats, DA-GIP reduced myocardial fibrosis, chamber dilatation, and systolic dysfunction. DA-GIP suppresses cardiac fibroblast activity through Akt-dependent eNOS activation and subsequent NO production, thereby improving cardiac remodeling and function in experimental heart failure.

Cardiac fibrosis is a key pathological driver of heart failure and cardiovascular mortality, with environmental pollutants being increasingly implicated. Tetrabromobisphenol A (TBBPA), a dominant brominated flame retardant (BFR), is environmentally pervasive and poses potential cardiotoxic risks. However, direct evidence for TBBPA-induced cardiac fibrosis in mammals is lacking. Additionally, its ability to adsorb onto nanoplastics, such as polystyrene (PS-NPs), raises concerns about combined toxicity, especially cardiotoxicity. To addressed this, we systematically evaluated the cardiotoxicity of TBBPA and PS-NPs in vivo and in vitro. In mice, environmentally relevant TBBPA exposure impaired cardiac function and induced inflammation and fibrosis, leading to cardiac remodeling, whereas co-exposure with PS-NPs only induced fibrosis. In H9C2 cells, TBBPA and PS-NPs individually promoted the expression of inflammatory, fibrotic, and hypertrophic markers, with co-exposure resulting in a synergistic exacerbation and a remodeling phenotype. Furthermore, transcriptomic and mechanistic data showed that ESR inhibitors blocked the H19/Wnt pathway activation induced by TBBPA or PS-NPs. Through gain- and loss-of-function experiments, we further confirmed that H19 mediates pollutant-induced Wnt/β-catenin activation and fibrotic responses, positioning H19 as a critical downstream mediator of the ESR/H19/Wnt axis. Overall, for the first time, this study elucidates the cardiotoxic profiles of TBBPA and PS-NPs and identifies the ESR/H19/Wnt axis as a key pro-fibrotic mechanism, highlighting a cardiovascular risk and a potential therapeutic target.

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. HFpEF was induced in mice by combining a long-term high-fat diet with the nitric oxide synthase inhibitor l-NAME (Nω-nitro-l-arginine methyl ester). Microglial depletion was achieved with PLX3397. GW4869 was administered via intraperitoneal injection. BV2 microglial cells were treated with sEVs derived from palmitate-treated HL-1 cardiomyocytes. Cardiomyocyte-specific miR-200c-3p sponge, mimic, and inhibitor were used for functional studies. The downstream target, DUSP1 (dual-specificity phosphatase 1), was validated through experimental approaches. The HFpEF mice exhibited activation of microglia and hypothalamic inflammation. Microglial depletion suppressed sympathetic activity and improved cardiac dysfunction. 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 GW4869 reversed these changes in HFpEF mice. Similar pathological changes were observed in BV2 microglial cells treated with sEVs from palmitic acid-treated HL-1 cardiomyocytes. miR-200c-3p was markedly upregulated in sEVs derived from both HFpEF myocardial tissues and palmitic acid-treated HL-1 cells, as well as within microglia themselves. Cardiomyocyte-specific miR-200c-3p sponge inhibited microglial activation, hypothalamic inflammation, and sympathetic activation in HFpEF mice. Conversely, the miR-200c-3p mimic exacerbated proinflammatory responses in BV2 cells, while the miR-200c-3p inhibitor prevented the transition to a proinflammatory phenotype. DUSP1 was validated as a 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.

To elucidate the genetic architecture of blood pressure (BP) and heart rate (HR) during early life and assess their potential relevance to adult health outcomes. The largest genome-wide association study (GWAS) meta-analyses to date of childhood systolic BP, diastolic BP, pulse pressure, and mean arterial pressure (n = 28 425) and HR (n = 22 565) were conducted in children of European ancestry aged 4-17 years. Follow-up analyses included comparisons with adult GWAS results, polygenic risk score (PRS) analyses in independent cohorts of diverse ancestries, and a phenome-wide association study in the UK Biobank. Eight genome-wide significant loci were identified for childhood BP (KIAA2013, CACNB2, PLCE1, PAX2, COL4A2, RP11-236L14.1, CFDP1, TPX2) and three loci for childhood HR (CCDC141, ACHE, MYH6); all novel in children but previously reported in adults. Childhood PRSs explained up to 1.6% of BP variance and 5.2% of HR variance among children of European ancestry. Genetic correlations between childhood and adulthood BP traits were moderate (rg = 0.4-0.7), suggesting age-specific genetic effects on BP. In the UK Biobank, higher childhood BP PRS levels were significantly associated with a broad range of adult health outcomes, particularly cardiometabolic outcomes such as hypertension, angina, myocardial infarction, and cardiovascular disease-related mortality. These findings advance the understanding of the genetic architecture of childhood BP and HR and provide compelling genetic evidence linking childhood BP to a broad spectrum of adult health outcomes-particularly cardiometabolic conditions-which may inform targeted prevention strategies from a young age.

Diabetes mellitus is a common but incompletely characterised manifestation of mitochondrial diseases (MD). Data on risk factors, clinical course, and treatment recommendations are lacking. In this multinational cohort study, we analysed longitudinal data of patients with a genetically confirmed MD from the GENOMIT registry included at German, Austrian, and Italian sites between 07/2009-01/2025. Our objectives were to (1) expand the genetic spectrum of mitochondrial diabetes mellitus (mDM), (2) identify risk factors, (3) delineate the clinical course, and (4) characterise real-world use of antidiabetic therapies. Of 2399 patients, 1225 (51%) were female, and 281 (12%; 172 female) had mDM. Diabetes occurred across 31 genotypes and exhibited marked genotype dependence, with the highest prevalence in m.3243A>G carriers (177/360 [49%]). Only the m.3243A>G variant was associated with a significantly increased risk of mDM (HR = 10.3; 95% CI 5.2-20.4, p < 0.0001), whereas single mtDNA deletions, multiple mtDNA deletions, and primary LHON variants, as well as sex, BMI, ethnicity, smoking, hypertension and dyslipidaemia did not show a significant association. Median diabetes onset in patients with the m.3243A>G variant was at 47.7 years (SD 45.2-52.0). Among patients with mDM, 140/281 (50%) used insulin, and 111/281 (40%) received non-insulin antidiabetic drugs, most commonly metformin, which was discontinued in 8/50 users. Literature review revealed neurological events temporally linked to metformin application in m.3243A>G carriers, though long-term use without adverse events was likewise reported. mDM is frequent in patients with MD, and the individual risk is strongly genotype dependent. While caution is warranted, our data do not justify universal avoidance of metformin; prospective, genotype-informed studies are needed to guide management. German Ministry of Research, Technology and Space; Italian Ministry of Health; European Union.

Pregnancy represents a critical period during which the maternal cardiovascular system adapts to profound haemodynamic and metabolic demands. When these adaptive mechanisms are impaired, adverse pregnancy outcomes (APOs)-including hypertensive disorders of pregnancy, gestational diabetes, pre-term birth, small-for-gestational-age birth, and pregnancy loss-occur. Extensive epidemiological evidence demonstrates that APOs are not isolated obstetric events but early clinical markers of cardiometabolic dysfunction that identify women at increased risk of coronary artery disease, heart failure, stroke, chronic kidney disease, and premature cardiovascular mortality. Shared mechanisms include endothelial dysfunction, inflammation, and insulin resistance, establishing a continuum between obstetric complications and later cardiovascular disease. Early post-partum studies reveal persistent hypertension, adverse cardiac remodelling, and metabolic abnormalities that mediate much of the long-term excess cardiovascular risk. These findings redefine the 'fourth trimester' as a preventive window in which timely blood pressure surveillance, metabolic screening, and lifestyle optimization can yield durable cardiovascular benefit. Integrated cardio-obstetric care models, digital follow-up, and systematic transition to primary care are crucial for maintaining long-term prevention. Addressing persistent gaps in limited provider awareness, fragmented follow-up, and disparities across socially disadvantaged populations remains critical. Recognizing pregnancy complications as indicators of underlying cardiovascular vulnerability offers an opportunity to shift prevention upstream and promote lifelong cardiovascular health for women.

The benefits of improved systolic blood pressure (SBP) control on stroke, coronary heart disease, and heart failure are well-established, yet its effect on overall cerebral small vessel disease (SVD) burden remains uncharacterized. We examined the association between intensive SBP control and change in SVD burden. We conducted a post-hoc analysis of the Systolic Blood Pressure Intervention Trial (SPRINT), a multicenter randomized clinical trial. Of 1267 hypertensive individuals aged ≥50 years without diabetes or prior stroke screened for the brain MRI substudy, 663 and 442 participants completed brain MRI that met quality control criteria and had complete data on SVD indicators at baseline and at a median of 3.9 (interquartile range, 3.6-4.1) years after randomization, respectively. From November 2010 to March 2013, participants were randomly assigned to an intensive SBP target of <120 mmHg (n = 348) or a standard target of <140 mmHg (n = 315). Post-hoc outcome was change in a global SVD factor, longitudinally validated using confirmatory factor analysis and designed to capture overall SVD-related vascular brain injury by integrating three complementary imaging endophenotypes: periventricular white matter hyperintensities, white matter free water, and basal ganglia perivascular spaces. This trial is registered with ClinicalTrials.gov (NCT01206062). Mean [SD] baseline age was 68.1 (8.6) years; 263 [40%] participants were women. Compared with standard SBP treatment, intensive treatment was associated with significantly less SVD progression (standardized mean difference [Cohen's d] = -0.40 [95% CI, -0.62 to -0.17]). We also observed gradually more favorable SVD burden changes with greater attained SBP reductions, demonstrating a clear dose-response relationship: 21.2% (95% CI, 7.4%-35%), 26.3% (13.1%-39.5%), and 39.4% (24.2%-54.5%) less progression relative to baseline SVD burden for SBP reductions of 0-10 mmHg, 10-20 mmHg, and ≥20 mmHg, respectively. Among hypertensive adults, targeting an SBP of <120 mmHg, compared with <140 mmHg, was associated with less progression of SVD burden. Even modest SBP reductions of ≤10 mmHg conferred measurable brain benefits, with larger reductions providing incrementally greater protection against SVD progression. National Institutes of Health, National Heart, Lung, and Blood Institute, National Institute of Diabetes and Digestive and Kidney Diseases, National Institute on Aging, and National Institute of Neurological Disorders and Stroke.

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.

While therapeutic advances have improved survival for patients with Group 1 pulmonary arterial hypertension (PAH), patients with Group 1.5 "PAH with features of venous/capillary involvement" (formerly pulmonary veno-occlusive disease or pulmonary capillary hemangiomatosis, now collectively termed PVOD/PCH) remain underrecognized, develop serious complications from usual PAH therapy titrations, and suffer high mortality awaiting necessary lung transplant. Identifying PVOD/PCH early before therapy initiation could aid management and expedite transplant referral. We aimed to develop a likelihood score distinguishing PVOD/PCH from other forms of PAH using clinical variables. Due to low PVOD/PCH prevalence and no dedicated registries, we leveraged published case-control/case-series studies to assess the ability of several clinical variables to discriminate PVOD/PCH from PAH. From pooled literature-derived data, we performed sensitivity/specificity and simulation-based receiver operating characteristic (ROC) analyses to estimate variable performance. Top-performing variables formed a PVOD/PCH likelihood score, which had its accuracy tested for distinguishing histopathology-confirmed PVOD/PCH cases (n = 37) from PAH controls (n = 60) in 3 cohorts of transplant-eligible patients from the United States, Spain, and the Netherlands. DLCO, 6-minute walk desaturation, PaO2, sex, smoking history, computed tomography (CT) septal line thickening, and CT lymphadenopathy had the highest sensitivity and specificity performance and were incorporated into the PVOD score. Across test cohorts, the score achieved a ROC area under the curve of 0.97 (95% CI, 0.93-1.00) for discriminating PVOD/PCH and it retained accuracy when data were missing. This score could facilitate early PVOD/PCH identification in incident PAH, potentially helping expedite transplant referral and informing therapy initiation/titration decisions.

The association between metabolic syndrome (MetS) and excessive scarring risk remains unclear. To examine the association of MetS and its components with excessive scarring. Using data from 466,625 UK Biobank participants, we conducted multivariable Cox regression to assess this relationship. Stratified analyses were performed by gender, age, and ethnicity. During a median follow-up of 13.65 years, 714 new cases of excessive scarring were identified. After adjusting for confounders, patients with MetS had an increased risk of excessive scarring (HR: 1.28, 95% CI: 1.08-1.52). Specifically, increased waist circumference (HR: 1.42, 95% CI: 1.15-1.76), hypertension (HR: 1.30, 95% CI: 1.08-1.55), high triglycerides (HR: 1.25, 95% CI: 1.06-1.46), and low high-density lipoprotein cholesterol (HR: 1.27, 95% CI: 1.08-1.49) were all linked to higher risk. Additionally, risk rose with the number of MetS components present. Sensitivity analyses using alternative MetS definitions yielded consistent results. Stratified analyses showed stronger associations in males, individuals under 60 years, and White participants. No verification in other ascertained populations. This study indicates that MetS is associated with an elevated risk of excessive scarring, underscoring the potential benefit of MetS management in scarring prevention.

Chronic kidney disease (CKD) is closely intertwined with obesity, diabetes, hypertension, dyslipidemia, and cardiovascular disease. In 2023, the American Heart Association formally recognized these interconnections as a unified entity, the cardiovascular-kidney-metabolic (CKM) syndrome. The CKM syndrome brings renewed attention to the importance of CKD in cardiovascular disease and reinforces the need for effective, evidence-based, interdisciplinary approaches to diagnose and prevent its intersecting components. The Kidney Disease: Improving Global Outcomes (KDIGO) organization has long led efforts to synthesize knowledge and translate evidence to practice in this area through the lens of the kidney. This review highlights KDIGO clinical practice guidelines and controversies conference publications that directly address the CKM syndrome. These include guidelines addressing CKD, blood pressure, diabetes, and lipids; an upcoming guideline addressing heart failure in CKD; and controversies conference reports addressing obesity and CKD prevention. Overarching themes include the importance of early detection and intervention; comprehensive, personalized management of kidney and cardiovascular risk; and multidisciplinary care. Through integrated, evidence-based, disease-specific guidelines and reports, KDIGO has established a robust framework for the management of people at risk for or with CKM syndrome as well as priorities for ongoing research.

To examine the associations between cumulative BMI burden from childhood to adulthood and the risk of adult metabolic multimorbidity. This prospective cohort study used data from the Hanzhong Adolescent Hypertension Study (1987-2023). A total of 2,446 participants with at least two BMI measurements in both childhood (6-18 years) and adulthood (19-52 years) were included. Cumulative BMI exposure was quantified using total and incremental area under the curve (AUC). Outcomes included metabolic multimorbidity, defined as the presence of two or more or three or more metabolic diseases, specifically hypertension, diabetes, dyslipidemia, elevated liver enzymes/bilirubin, and kidney damage. Higher total and incremental BMI AUC during childhood, adulthood, and over the life course were consistently associated with an increased risk of adult metabolic multimorbidity (two or more diseases). For total AUC, odds ratios (ORs) ranged from 1.51 to 2.59 (all P < 0.05); for incremental AUC, ORs ranged from 1.94 to 4.33 (all P < 0.05). Compared with total AUC, incremental AUC showed a stronger association with metabolic multimorbidity in childhood (OR 4.33 [95% CI 2.93, 6.40] vs. 1.51 [1.17, 1.95], respectively). Conversely, total AUC exhibited a stronger association in adulthood than in childhood (OR 2.51 [2.08, 3.04] vs. 1.94 [1.62, 2.31]). Furthermore, the associations for adulthood and life course BMI AUC were significantly stronger in males than in females (P for interaction <0.05). These findings highlight the importance of life stage-specific strategies: curbing rapid BMI gain in childhood and maintaining long-term weight control throughout adulthood.

Autism spectrum disorder (ASD) is a neurodevelopmental condition affecting 2% of the global population. Beyond core symptoms such as social communication deficits and repetitive behaviors, individuals with ASD are at increased risk of cardiometabolic comorbidities, including obesity, diabetes, and cardiovascular disease. Here, we investigate the shared genetic architecture between ASD and cardiometabolic traits using large genome-wide association studies datasets and advanced statistical approaches: the bivariate causal mixture (MiXeR) model and pleiotropy-informed conditional false discovery rate (pleioFDR). Our results show significant polygenic overlap between ASD and several cardiometabolic phenotypes, despite almost negligible genetic correlation between the traits. Specifically, we observed positive genetic correlations within the shared component for ASD and metabolic traits, such as body mass index (rg=0.03), type 2 diabetes (rg=0.23), and total cholesterol (rg=0.78). In contrast, negative correlations emerged between ASD and cardiovascular traits, including diastolic and systolic blood pressure (rg = -0,22, for both), pulse pressure (rg = -0.25), and coronary artery disease (rg = -0.90). Finally, we identified 100 shared loci between ASD and cardiometabolic traits, mapping to 124 genes and suggesting shared biological mechanisms underlying these phenotypes and pointing to potential therapeutic targets. Shared loci between ASD and metabolic traits predominantly showed concordant effects, whereas those overlapping with cardiovascular traits-particularly blood pressure-related traits-tended to exhibit discordant effects. Together, these findings deepen our understanding of the biological connections between ASD and cardiometabolic comorbidities and may help inform more personalized strategies for managing ASD and its associated long-term health risks.

Clinically significant portal hypertension (CSPH) is the main driver of hepatic decompensation, and its early identification allows timely initiation of preventive therapies. Hepatic Venous Pressure Gradient (HVPG) is the current gold standard for assessing portal hypertension (PH), but it may underestimate PH in conditions with a presinusoidal component. Endoscopic ultrasound-guided portal pressure gradient (EUS-PPG) enables direct measurement of portal pressure and may overcome these limitations. We evaluated the prognostic performance of EUS-PPG compared with HVPG for predicting hepatic decompensation in patients with suspected CSPH. This preliminary exploratory analysis of the ongoing prospective EVADIPP study included 90 patients who underwent paired HVPG and EUS-PPG measurements and were followed for decompensation. Mean EUS-PPG and HVPG values were 13.8 ± 5.8 mmHg and 8.9 ± 4.8 mmHg, respectively, with poor overall agreement (ICC 0.08, 95% CI -0.08 to 0.24). Agreement remained poor in porto-sinusoidal vascular disorder (PSVD), slight in metabolic dysfunction-associated steatotic liver disease, and substantial in alcohol- and viral-related liver disease. During follow-up, 28 patients (31%) developed decompensation; no events occurred among patients with EUS-PPG<10 mmHg, whereas 60.7% had HVPG <10 mmHg. In multivariable analysis, EUS-PPG (HR 1.19, 95% CI 1.10-1.30; p<0.001) and albumin were independently associated with decompensation. EUS-PPG demonstrated better discrimination than HVPG (C-index 0.78 vs 0.56), and time-dependent ROC analysis identified an optimal threshold of 12 mmHg. EUS-PPG is independently associated with hepatic decompensation and showed better prognostic discrimination than HVPG in this exploratory cohort.

Kidney transplantation (KT) remains the optimal treatment for kidney failure, improving survival and quality of life. However, long-term graft outcomes have plateaued, largely due to transplant CKD and cardiovascular disease; agents such as mineralocorticoid receptor antagonists (MRAs) may help mitigate these risks. Mineralocorticoid receptor (MR) overactivation contributes to oxidative stress, inflammation, and fibrosis in both the heart and kidneys, suggesting a potential role for mineralocorticoid receptor antagonists (MRAs) in improving long-term patient and graft outcomes. Although evidence in KT is limited, MR blockade may offer clinical benefits by targeting aldosterone-mediated pathways. Proteinuria promotes sodium reabsorption in the aldosterone-sensitive distal nephron via epithelial sodium channels (ENaC), contributing to hypertension and volume overload. MRAs have been shown to reduce albuminuria and blood pressure in patients with diabetic nephropathy, even on background renin-angiotensin-aldosterone system (RAAS) blockade. The use of MRAs post-KT should be individualized, considering patient comorbidities and concomitant immunosuppressive therapy. While MRAs may provide cardiovascular and antiproteinuric benefits, the risk of hyperkalemia-though reduced with non-steroidal MRAs-must be carefully managed. PLAIN LANGUAGE SUMMARY: When the kidneys no longer work properly, receiving healthy kidney is the best way of treatment, called transplantation. After kidney transplantation (KT), the patient should receive several medicines to keep the new kidney healthy and protect it from rejection and failure. These medicines may help with immunity against the transplanted kidney or protect the kidney in general. One way the medicines may work is to decrease the effect of the hormone aldosterone, which helps control water and salt balance in the kidney by hanging on to sodium while releasing potassium from the body. By blocking aldosterone receptors, the body reduces protein leaking in the urine, controls blood pressure, minimizes kidney scarring, and protects against the hazardous effects of diabetes on the kidneys. Most evidence for these benefits comes from people who have not received a transplant, and transplant-specific studies are still small. In transplant recipients, these medicines may interact with anti-rejection therapy and can raise potassium. Care therefore requires careful patient selection, review of other medicines, and close monitoring of potassium, kidney function, and anti-rejection drug levels.

Healthcare professionals (HCPs) play a central role in preventive care, yet their own cardiovascular health management remains poorly characterised. We evaluated cardiovascular risk profiles, awareness, treatment use, target achievement and subclinical atherosclerosis among HCPs attending the European Society of Cardiology (ESC) Congress. HCPs participating in the ESC Congress Cardiovascular Health Check 2025 (n=1366) underwent standardised assessment of cardiovascular risk factors, medication use, treatment targets, and carotid ultrasonography in a subgroup. HCPs without established atherosclerotic cardiovascular disease (ASCVD) were compared with age- and sex-matched individuals from the general population (REACT initiative; n=2732). Among HCPs, excess body weight was the most prevalent modifiable risk factor (46.8%), followed by hypertension (23.2%), and hyperlipidaemia (22.7%). Established ASCVD was present in 11.1% and subclinical atherosclerosis was detected in 21.8% of HCPs without established ASCVD. Compared with matched controls, unrecognised hyperlipidaemia (7.5% vs. 8.4%; P=0.293), hypertension (11.9% vs. 13.9%; P=0.079), and diabetes (0.4% vs. 0.4%; P=0.864) were similarly frequent; awareness was higher only for hyperlipidaemia (62.2% vs. 54.9%; P=0.049). In primary prevention, HCPs were less likely to use recommended antihypertensive (27.6% vs. 46.5%; P<0.001) and glucose-lowering therapy (60.0% vs. 85.0%; P=0.001), but more often achieved LDL-C (57.5% vs. 32.0%; P<0.001) and systolic blood pressure targets (47.5% vs. 24.6%; P=0.003). In secondary prevention, 41.4% of HCPs used lipid-lowering therapy, only 9.2% used antiplatelet therapy, and only 22.2% of those using lipid-lowering therapy achieved the LDL-C target. HCPs showed important gaps in cardiovascular prevention, particularly regarding the use of guideline-recommended therapy, highlighting the need for systematic implementation strategies among HCPs.Clinical Trial Registration: NCT07613229.

Patients with prostate cancer have a high burden of cardiovascular risk factors, often suboptimally controlled, and adverse cardiovascular outcomes. To determine whether the routine referral of patients with prostate cancer to a cardiovascular specialist to implement a systematic risk factor strategy is more likely to reduce adverse cardiovascular outcomes and improve risk factor control than usual care. This randomized clinical trial included patients with prostate cancer from 55 sites in 8 countries between 2015 and 2025. Eligible patients were diagnosed with prostate cancer during the past 12 months; had received treatment with androgen deprivation therapy (ADT) for the first time within the past 6 months; or planned to start ADT in the next month. Patients taking a statin with a systolic blood pressure of 130 mm Hg or lower were ineligible. Data were analyzed from May 25 to August 7, 2026. Patients were allocated in a 1:1 ratio to receive usual care alone or usual care plus routine referral to an internist or cardiologist. The specialists provided a systematic intervention, including a target of systolic blood pressure of 130 mm Hg or lower and a statin medication, irrespective of the patient's cholesterol levels (even if not usual or guideline-driven practice); encourage smoking cessation; and provide guidance on diet and exercise. Hierarchical composite of cardiovascular death, myocardial infarction, stroke, heart failure, suboptimal cholesterol (total cholesterol, >155 mg/dL [to convert to mmol/L, multiply by 0.0259]) and suboptimal blood pressure (systolic blood pressure, >130 mm Hg) as evaluated by the win ratio. The analysis included 2487 patients with prostate cancer (mean [SD] age, 68 [8] years). During median (IQR) follow-up of 5.8 (2.7-8.2) years, the win ratio in favor of the intervention was 1.60 (95% CI, 1.42-1.81), mostly attributable to lower cholesterol in the intervention group (mean difference, 12 mg/dL; 95% CI, 9-15 mg/dL) as a consequence of greater protocol-mandated statin use. Mean (SD) close-out systolic blood pressure values were 131.1 (16.9) mm Hg in the intervention group and 132.9 (18.3) mm Hg in the control group. There was no difference in time to cardiovascular death, myocardial infarction, stroke, or heart failure between groups (subdistribution hazard ratio, 1.08; 95% CI, 0.79-1.49). In this randomized clinical trial, routine referral of patients with prostate cancer to a cardiovascular specialist lead to improved outcomes, specifically through better cholesterol control. However, it is uncertain whether this reduced clinical cardiovascular events. ClinicalTrials.gov Identifier: NCT03127631.

Simultaneous pancreas-kidney transplantation (SPKTx) and kidney transplantation alone (KTx) are common treatment modalities for individuals with type 1 diabetes with end-stage kidney disease. This study compared metabolic and macrovascular disease outcomes between SPKTx and KTx in recipients with type 1 diabetes. We conducted a systematic search of the Embase, MEDLINE and Scopus databases (last searched 23 February 2025). We included retrospective and case-control studies, owing to a lack of randomised controlled trials in English, with adult patients. We excluded studies reporting on a return to dialysis post transplant, islet-kidney transplantation or separate pancreas-kidney transplants. Bias and study quality were assessed via the Newcastle-Ottawa scale for cohort studies. Demographic and outcome data were synthesised as both categorical and continuous data, with pooled means and summary statistics computed where applicable. Meta-analysis was performed on post-transplant outcomes in studies evaluating total cholesterol (TC), triglyceride (TG) level, HDL, LDL, blood pressure, HbA1c and renal function. Macrovascular outcomes included the frequency of new or adverse events associated with coronary artery disease (CAD), cerebrovascular disease (CeVD) and peripheral vascular disease (PVD). A total of 15 studies (n=564 SPKTx, 419 KTx) were included. Meta-analysis demonstrated lower post-transplant TC (mean difference -0.41 mmol/l [95% CI -0.60, -0.22], p<0.01, I2=37%), TG level (mean difference -0.76 mmol/l [95% CI -1.02, -0.49], p<0.01, I2=86%), LDL (mean difference -0.28 mmol/l [95% CI -0.42, -0.14], p<0.01, I2=15%), HbA1c (mean difference -28.79 mmol/mol [95% CI -35.75, -21.82], p<0.01, I2=98%; mean difference -2.61% [95% CI -3.05, -2.16], p<0.01) and creatinine levels (mean difference -21.54 μmol/l [95% CI -39.23, -3.85], p=0.02, I2=90%) following SPKTx compared with KTx. Mean antihypertensive agent use per participant decreased post SPKTx (1.0 vs 2.5 pre transplant; p<0.01), but was not significantly different from post-KTx groups. HbA1c increased following KTx (69 mmol/mol [8.5%]) compared with pre KTx (53 mmol/mol [7.0%], p<0.01). Progression of CAD, CeVD and PVD occurred across both groups post transplant. PVD showed more than a twofold increase in amputations and revascularisations post transplant. No difference was observed in the post-transplant frequency of CAD, CeVD or PVD between SPKTx and KTx. Evidence from this study was limited by a lack of subgroup data for analysis, a lack of randomised studies and a paucity of reported lifestyle factors influencing outcomes. SPKTx demonstrates a superior metabolic profile post transplant to that in KTx in recipients with type 1 diabetes. However, this does not translate into differences in the risk of CAD or PVD post transplant, with PVD accounting for the greatest burden of macrovascular disease. This protocol has been registered a priori on PROSPERO (CRD42024622408).

Hypertension is the leading risk factor for cardiovascular disease (CVD) worldwide. Implementation-based blood pressure (BP) control programs improve BP control and reduce CVD risk, but whether their benefits persist after withdrawal of trial-supported intervention components remains uncertain, especially when intensive BP control is targeted. In CRHCP (China Rural Hypertension Control Project), a nonphysician community healthcare provider (NPCHP)-led program with the intensive target of <130/80 mm Hg reduced CVD risk during the 4-year active intervention period. We extended follow-up for an additional 3 years to assess BP control and CVD outcomes over the 7-year overall period and during the 3-year posttrial period. CRHCP was a cluster-randomized controlled trial conducted in rural China. Eligible participants were ≥40 years of age with BP ≥140/90 mm Hg or ≥130/80 mm Hg if at high CVD risk or receiving antihypertensive treatment. We randomly assigned 326 villages 1:1 to NPCHP-led intensive BP control or usual care. During the 4-year intervention, trained NPCHPs initiated and titrated antihypertensive medications using a standardized protocol under primary care physician supervision and provided coaching on home BP monitoring, lifestyle modification, and medication adherence. The program also provided discounted or free antihypertensive medications, additional training, and performance incentives. Participants in the usual care group received local standard BP management throughout. During the 3-year posttrial period from years 4 to 7, intervention participants continued care with their original NPCHPs, with physician and hypertension specialist consultation available; discounted or free medications, additional training, and performance incentives were discontinued. The primary outcome was a composite of myocardial infarction, stroke, hospitalization for heart failure, and CVD death. Treatment effects were evaluated separately over the 7-year overall and 3-year posttrial periods with prespecified subgroup analyses. Between May 8 and November 28, 2018, 33 995 participants were enrolled; 31 334 entered the posttrial follow-up. At the end of the 7-year overall period, BP was 138.8/80.7 mm Hg in the intervention group versus 152.3/86.1 mm Hg in the usual care group (between-group difference, -13.5/-5.4 mm Hg; P<0.0001 for both systolic and diastolic BPs); percentage of the participants with BP <130/80 mm Hg was 33.9% versus 10.5% (P<0.0001). During the 7-year overall period, the rate of composite CVD events was 2.4% versus 3.0% per person-year in the intervention and usual care groups, respectively (hazard ratio, 0.76 [95% CI, 0.72-0.81]; P<0.0001). During the 3-year posttrial period, the corresponding rates were 3.4% versus 4.2% per person-year (hazard ratio, 0.79 [95% CI, 0.73-0.85]; P<0.0001). Posttrial effects in CVD risk reduction were generally consistent across subgroups defined by baseline age, sex, education, and antihypertensive medication use. Over the 7-year overall period, the intervention group had higher risks of hypotension (risk ratio, 1.58 [95% CI, 1.39-1.79]) and mild hypokalemia (risk ratio, 1.38 [95% CI, 1.23-1.56]; P<0.001 for both). Multicomponent BP management strategy with a BP target <130/80 mm Hg led by NPCHPs achieved sustained BP control and reduced CVD risk during both the 7-year overall and 3-year posttrial periods. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03527719.

To examine the effect of the Dietary Approaches to Stop Hypertension for Diabetes (DASH4D) diet (a DASH-style diet tailored for diabetes) on biomarkers of glycemia. In this controlled feeding trial, adults with type 2 diabetes were fed four diets in a random order: DASH4D diet and comparison diet (representative of a typical American diet), each with higher and lower sodium. Each feeding period lasted 5 weeks. Using a modified intention-to-treat approach, we estimated the effect of the DASH4D (versus comparison) diet on fructosamine, fasting glucose, and HbA1c with linear mixed-effects models. Among 101 participants (mean age 67 years, 65% female, 87% Black adults), compared with the comparison diet, the DASH4D diet significantly reduced end-of-period fructosamine (adjusted difference: -5.6 μmol/L, P = 0.002), fasting glucose (adjusted difference: -4.5 mg/dL; P = 0.02), and HbA1c (adjusted difference: -0.09 percentage points; P = 0.04). Our results support recommending the DASH4D diet for glycemic management in type 2 diabetes.

Improving Global Outcomes (KDIGO) has published the Clinical Practice Guidelines (CPG) on managing diabetes in CKD in 2022 and the CPG for managing blood pressure in CKD in 2020. KDIGO organized a guideline implementation summit targeting the Asia-Pacific region in Kuala Lumpur in 2024 with the aim to understand existing barriers and challenges in implementation of the two CPGs and to propose possible solutions, tailored to the country or region's income level to bridge existing gaps in guideline implementation. The implementation summit discussion covered 4 key themes: i) lifestyle intervention; ii) adoption of comprehensive team-based integrated care model; iii) achievement of various treatment targets albuminuria screening and monitoring of kidney disease; and iv) implementation of guideline-directed medical therapies. The Summit was attended by co-chairs of the KDIGO CPGs on diabetes and blood pressure management in CKD, with nephrologists, endocrinologists, primary care physicians, dietitians, a health economist, and patient partners from 13 Asia-Pacific countries or regions. This conference report summarizes the key challenges in the CPG implementation for diabetes, hypertension in people with CKD in Asia-Pacific region, and provides a strategic framework of actions to overcome these barriers.

Acute respiratory distress syndrome (ARDS) is a common and clinically significant complication in patients with acute brain injury (ABI), affecting up to one-third of critically ill individuals and contributing to increased mortality, prolonged mechanical ventilation, and worse neurological outcomes. The coexistence of ARDS and ABI creates a fundamental therapeutic dilemma: strategies that protect the lung may adversely affect cerebral physiology, whilst neuroprotective targets may compromise respiratory management. This narrative review examined the pathophysiological interactions between the injured lung and brain, highlighting the competing effects of key ventilatory variables. Lung-protective ventilation, including low tidal volume and higher positive end-expiratory pressure (PEEP), reduces ventilator-induced lung injury but may increase arterial carbon dioxide (PaCO2), resulting in intracranial hypertension and impaired cerebral perfusion. Conversely, strict control of PaCO₂ and optimisation of cerebral perfusion may necessitate deviations from conventional ARDS strategies. Oxygenation targets further illustrate this tension, as both hypoxaemia and hyperoxaemia can exacerbate secondary brain injury. We synthesised current evidence on respiratory support, including non-invasive strategies, invasive mechanical ventilation, rescue therapies such as prone positioning and extracorporeal support, and pharmacological interventions, with emphasis on their differential effects on pulmonary and cerebral physiology. Attention was also given to the role of multimodal neuromonitoring, including intracranial pressure and brain tissue oxygenation, as tools to individualise ventilatory management and reconcile competing organ priorities. Overall, available data support a shift from protocolised approaches towards physiology-driven, patient-specific strategies that integrate lung mechanics, gas exchange and cerebral haemodynamics in patients with concomitant ARDS and ABI. Future studies should incorporate combined lung and brain endpoints to define strategies that simultaneously minimise ventilator-induced lung injury and secondary brain injury.

Cardiovascular disease is the leading cause of morbidity and mortality in the elderly. Managing cardiovascular risk in this group is uniquely challenging due to physiological changes, multimorbidity, polypharmacy, and frailty, compounded by the under-representation of older adults in clinical trials Recent advances, including the SCORE2-OP risk stratification tool and emerging therapies such as sodium-glucose cotransporter-2 inhibitors and glucagon-like peptide-1 receptor agonists, have reshaped approaches to risk reduction. This review synthesizes the latest evidence and guideline recommendations for the management of hypertension, dyslipidaemia, diabetes, obesity, and antithrombotic therapy in older patients, with particular attention to frailty, adherence challenges, and individualized care. By addressing the complexities of cardiovascular risk management in older adults, this paper provides a practical framework for clinicians navigating this critical area.

Hypertension increases with age, with a very high prevalence in older patients. Since hypertension is a major contributor of cardiovascular diseases, this condition accounts for the majority of stroke and a relevant number of coronary artery disease cases in the older adults. Ageing is associated with frailty and multi-morbidity, often associated with poly-pharmacy, which may complicate the management of hypertension. Specific diseases like diabetes and Parkinson disease associated with autonomic dysfunctions, and the frail condition, should be carefully considered in order to avoid orthostatic hypotension. Aortic stenosis, cardiac hypertrophy, heart failure, reduced glomerular filtration rate, arrhythmias such as atrial fibrillation, obstructive coronaropathies, and cerebral vascular lesions constitute haemodynamic challenges and may be associated with increased adverse effects during anti-hypertensive treatments. Moreover, specific drugs and drug-drug interactions are associated with side-effects particularly deleterious in the older patients. The worsening of the state of health and the increase in the degree of frailty can result either as a consequence of target organ damage related to hypertension or caused by anti-hypertensive drugs. Therefore, in the older adults, a careful assessment of the individual risk/benefit profile and a personalized view of the patient are necessary to establish the appropriate blood pressure targets and the appropriate treatments.

Pulmonary hypertension (PH) is a life-threatening cardiovascular disorder characterized by irreversible pulmonary vascular remodeling and poor prognosis. RNA pseudouridylation, the most evolutionarily conserved RNA epigenetic modification, and its catalytic enzyme pseudouridine synthase 7 (PUS7) remained uncharacterized in PH, representing a major gap in the understanding of the epigenetic pathogenesis of the disease. We generated the first single-base resolution pseudouridine (Ψ) landscape in lung tissues of patients with PH using bisulfite-induced deletion sequencing. PUS7 expression was analyzed in hypoxic pulmonary artery endothelial cells, the lung tissues of patients with PH, and SU5416-hypoxia rodent model. The functional roles of PUS7 were investigated through genetic manipulation (PUS7-deficiency cells, adeno-associated virus serotype-mediated overexpression, endothelial cell-specific knockdown, and heterozygous knockout mice) and pharmacological inhibition with NSC107512. Bisulfite-induced deletion sequencing revealed global Ψ dysregulation in the lung tissues of patients with PH. Among PUS family members, PUS7 was the most markedly upregulated in these tissues and in the hypoxic pulmonary artery endothelial cells. Both gene knockdown and pharmacological inhibition with NSC107512 ameliorated PH, whereas adeno-associated virus serotype-mediated PUS7 overexpression exacerbated disease progression. RNA immunoprecipitation sequencing and mutagenesis studies demonstrated that PUS7 bound to and catalyzed Ψ at position 688 of TGFBI (transforming growth factor β-induced protein) mRNA, thereby stabilizing TGFBI and activating phosphatidylinositol 3-kinase-protein kinase B signaling pathway. Furthermore, hypoxia-inducible factor 2α bound directly to the PUS7 promoter, establishing a hypoxia-inducible factor 2α/PUS7/TGFBI/phosphatidylinositol 3-kinase-protein kinase B positive feedback loop that drives PH pathogenesis. PUS7-mediated pseudouridylation serves as a novel epigenetic driver of PH through the hypoxia-inducible factor 2α/PUS7/TGFBI/phosphatidylinositol 3-kinase-protein kinase B axis, positioning PUS7 as a promising therapeutic target for this devastating disease.

Liver sinusoidal microthrombosis (LST) is recognized as an initiating event in fibrogenesis and portal hypertension in chronic liver diseases. Liver sinusoidal endothelial cell (LSEC)-derived chemoattractants recruit neutrophils and macrophages, promoting LST in congestive hepatopathy (CH). However, the driving molecules from LSECs for LST remain unclear. This study aims to elucidate that LSECs inflammatory via cyclooxygenase-2 (COX-2) upregulation triggers metabolic reprogramming promoting thrombospondin-1 (TSP-1)-mediated LST and portal hypertension. A murine model of LST and portal hypertension was established by partial ligation of inferior vena cava (pIVCL). LST and portal hypertension were suppressed in both LSEC-specific COX-2 knockout mice (Ptgs2ΔLSEC) and celecoxib-treated wild-type mice induced by pIVCL. RNA sequencing of mouse liver tissue and untargeted metabolomics of human hepatic sinusoidal endothelial cells (HHSECs) revealed that COX-2 inhibition was concurrent with downregulation of the AKT/mTOR pathway, reduced lactate, and decreased TSP-1. In vitro, COX-2-derived prostaglandin E2 (PGE2) activated the AKT/mTOR pathway, driving glycolytic reprogramming and lactate production. In turn, the accumulation of lactate induced by COX-2 upregulation enhanced histone H3K9 lactylation, which transcriptionally upregulated Thbs1 (encoding TSP-1), thereby instigating a prothrombotic phenotype in LSECs. Collectively, this study uncovers a novel pathogenic axis in LST formation, where COX-2 drives a prothrombotic switch in LSECs via AKT/mTOR-mediated metabolic reprogramming and lactate-dependent epigenetic upregulation of TSP-1. Targeting LSEC COX-2 may represent a promising therapeutic strategy for mitigating LST and portal hypertension.

Fine-tuning of CaV1.2 calcium channel activity by binding proteins represents a novel mechanism for regulating smooth muscle contraction and blood pressure (BP). This study aimed to elucidate the role of Gal-3 (galectin-3), a newly identified CaV1.2-binding protein, in the pathogenesis of hypertension. In vitro, ex vivo, and in vivo experiments involving molecular and biochemical assays, in silico prediction, patch-clamp electrophysiologic recordings, immunohistochemistry, pressure myography, and tail-cuff BP measurements were used to evaluate the molecular mechanisms by which Gal-3 binds to and elevates membrane insertion of CaV1.2 channels. The experiments were performed in transfected HEK 293 cells, isolated smooth muscle cells, and arteries from smooth muscle-specific Gal-3 knockout mice and their wild-type littermates; spontaneously hypertensive rats; or human patients. In vivo experiments involving delivery of the blocking iGal3BP (inhibitory galectin-3-binding peptide) into spontaneously hypertensive rats were performed to investigate its effect on BP. We identified Gal-3 as a novel binding partner and unexpected positive modulator of the CaV1.2 channel through binding to the intracellular II-III loop. Gal-3 increased total and surface expression, current density, and open probability of CaV1.2 channels. Both CaV1.2 and Gal-3 were upregulated in hypertensive rat aortas and human pulmonary arteries. Conditional deletion of Gal-3 in smooth muscle markedly lowered CaV1.2 protein and BP in mice. With specific binding sites identified within both Gal-3 and the CaV1.2 II-III loop, the peptide iGal3BP, designed to block CaV1.2-Gal-3 interaction, significantly reduced BP in spontaneously hypertensive rats by decreasing CaV1.2 protein expression. Repeated iGal3BP administration resulted in cumulative peptide accumulation in mesenteric arteries and produced a sustained reduction in BP, which demonstrated greater long-lasting antihypertensive efficacy compared with amlodipine and losartan. Administration of iGal3BP in combination with a negative modulatory Gal-1 mimetic peptide that mimics Gal-1-CaV1.2 interaction returned systolic BP to normotensive levels within 4 hours and lowered BP in hypertensive rats in a sustained manner for 35 days. These results provide strong evidence that Gal-based CaV1.2 channel modulators are novel therapeutic pathways for normalizing BP.

Microbiome-derived deoxycholic acid (DCA) elevates serum 5-hydroxytryptamine (5-HT), a mediator of portal hypertension (PH). Rifaximin, a non-absorbable antibiotic, is known to reduce DCA levels. We aimed to elucidate the role of DCA in cirrhotic PH and evaluate the therapeutic potential of rifaximin. PH was induced in mice by thioacetamide (TAA) injection or bile duct ligation (BDL). Mice were treated with antibiotics (ABX) or rifaximin, with or without exogenous DCA supplementation. A cohort of 51 patients with cirrhosis and 19 healthy controls was analyzed to validate correlations among DCA, 5-HT, and hepatic venous pressure gradient (HVPG). Mice with tissue-specific knockout of gut epithelial Tph1 (Tph1VKO), vascular smooth muscle cell Htr1a (Htr1aΔVSMC), or Kcnj9 (Kcnj9ΔVSMC) were used for mechanistic studies. Fecal DCA positively correlated with portal pressure (PP) in TAA-induced PH mice (r = 0.631, p <0.001) and with HVPG in patients (r = 0.5874, p <0.001). ABX treatment reduced fecal DCA, serum 5-HT, and PP in TAA- or BDL-induced PH mice. Exogenous DCA reversed the ABX-induced reductions in serum 5-HT and PP, an effect abolished in Tph1VKO mice. GIRK3 (encoded by Kcnj9) was upregulated in portal veins from PH mice and patients. VSMC-specific Kcnj9 deletion attenuated PH and prevented 5-HT-induced PP elevation. Mechanistically, 5-HT triggered portal vein smooth muscle cell contraction via the HTR1A-GIRK3-Ca2+-MLC2 pathway. Rifaximin alleviated PH by reducing DCA in wild-type mice but showed no additional PP reduction in Tph1VKO, Htr1aΔVSMC, or Kcnj9ΔVSMC mice. Microbiome-derived DCA exacerbates PH by enhancing TPH1-dependent 5-HT biosynthesis, which activates portal vein smooth muscle cell contraction via HTR1A-GIRK3 signaling. Rifaximin alleviates cirrhotic PH by reducing DCA levels, highlighting a potential therapeutic strategy for clinical PH management. Portal hypertension is a key driver of cirrhosis-related complications, yet current therapies exhibit suboptimal efficacy. Herein, we elucidate the role of the gut microbial metabolite deoxycholic acid in the pathophysiology of cirrhotic portal hypertension through the TPH1-5-HT/HTR1A-GIRK3 axis and provide preclinical evidence that rifaximin ameliorates cirrhotic portal hypertension by reducing deoxycholic acid. These insights may open a new avenue for the clinical management of cirrhotic portal hypertension.

Tubulointerstitial fibrosis is the central pathological feature of hypertensive nephropathy, with cellular senescence being a key driver. Therefore, identifying therapeutic targets in senescent renal tubular epithelial cells is clinically important. The cytoplasmic FMR1-interacting protein (CYFIP) family, which comprises two evolutionarily conserved members, CYFIP1 and CYFIP2, plays crucial roles in neurological regulation. CYFIP2, a key member, is implicated in cytoskeletal dynamics and apoptosis within the nervous system; however, its renal expression pattern and function remain undefined. This study revealed that CYFIP2 expression was significantly upregulated in the renal cortex, particularly in the proximal tubules, of DOCA/salt-induced hypertensive mice, and was positively correlated with the extent of fibrosis. Consistently, CYFIP2 was highly expressed in the renal tubules of patients with hypertensive nephropathy, where its level inversely correlated with the estimated glomerular filtration rate (eGFR). Tubule-specific deletion of CYFIP2 attenuated hypertension-induced cellular senescence (reduced SA-β-gal, p53/p21, and SASP; increased Klotho) and mitigated renal dysfunction, collagen deposition, and epithelial‒mesenchymal transition (EMT). In vitro, CYFIP2 silencing alleviated TGF-β1-induced senescence and fibrosis in HK-2 cells. Mechanistically, CYFIP2 and p53 formed a positive feedback loop that promoted fibrosis by inhibiting the Hippo pathway and enhancing YAP nuclear translocation. The p53 agonist Nutlin-3a reversed the protective effect of CYFIP2 knockout, while the inhibitor Pifithrin-α mimicked this effect. These findings underscore the pivotal role of the CYFIP2/p53-Hippo/YAP axis in hypertensive renal injury, and identify CYFIP2 as a potential therapeutic target. CYFIP2/p53-Hippo signaling drives tubular senescence and renal fibrosis in hypertensive nephropathy.

We examine persistence with secondary prevention medication and longer-term mortality in a population-level cohort of ST-elevation myocardial infarction (STEMI) patients with and without standard modifiable cardiovascular risk factors (SMuRFs; hypertension, diabetes, hypercholesterolaemia, smoking). We utilized landmark analysis to study 65 059 first-time STEMI patients from the SWEDEHEART registry who were prescribed aspirin, lipid-lowering therapy (LLT), renin-angiotensin-aldosterone system (RAAS) inhibitors, or beta-blockers at hospital discharge. Persistence was assessed as a binary variable in patients alive 12 months after first dispensation (initiation, the landmark). The primary outcome was all-cause mortality 3 years after the 12-month landmark. Multivariable logistic regression models and Kaplan-Meier analyses were used to compare persistence, and Cox proportional hazards models to assess the impact of persistence on mortality. At 4 years after pharmacotherapy initiation, >50% of patients had discontinued prescribed aspirin, LLT, RAAS inhibitor, or beta-blocker. SMuRF-less patients were less likely to receive medications at hospital discharge; however, if prescribed, they were more likely to be persistent with aspirin and LLT at 12 months compared to SMuRF-positive patients. Discontinuing aspirin, LLT, or RAAS inhibitors within 12 months after initiation was associated with increased all-cause mortality 3 years later in both groups (HR between 1.45 and 2.02). Beta-blocker discontinuation was not associated with mortality in either group. Persistence with secondary prevention medication declined rapidly in this cohort. The increased longer-term mortality associated with 12-month non-persistence highlights the need to better understand drivers of medication discontinuation, and to work with patients and clinicians to support consistent use of guideline-recommended medications, regardless of risk factor status.

Spontaneous coronary artery dissection (SCAD) is characterized by a separation of the coronary artery wall, causing myocardial infarction and sudden death. This study is one of the first to clarify the impact of pathological genetic variants in candidate SCAD-related genes on the histopathological and morphological properties of human SCAD lesions. A total of 28 SCAD cases were selected from the CVPath Autopsy Registry. Histological differences in collagen and smooth muscle cells were compared among 3 groups: culprit SCAD (C-SCAD), defined as the coronary segment containing a dissection in cases with SCAD; nonculprit SCAD, defined as unaffected coronary segments (ie, healthy arteries) in cases with SCAD; and non-SCAD controls. Whole-exome sequencing was performed, and the identified variants were filtered to isolate pathogenic or likely pathogenic variants. Protein expression corresponding to the identified variants was assessed by immunostaining. Collagen content was significantly reduced in C-SCAD lesions compared with controls, and immunohistochemical staining for smoothelin was reduced in the media of C-SCAD lesions compared with controls, whereas there were no significant differences between C-SCAD and nonculprit SCAD. Further, the nuclear height/width ratio of smooth muscle cells was increased, suggesting smooth muscle cell phenotypic modulation. In whole-exome sequencing analysis, pathogenic or likely pathogenic variants were detected in 25% of cases, which showed a higher frequency of multivessel dissection. In SCAD cases with pathogenic or likely pathogenic variants in COL3A1 (collagen type III alpha 1), FBN1 (fibrillin-1), or FLNA (filamin A), the expression of the corresponding protein was reduced in the media. Reduced medial collagen and smooth muscle cell phenotypic modulation may be possible predisposing conditions for SCAD, regardless of the presence of pathogenic or likely pathogenic variants. The presence of pathogenic variants in extracellular matrix-related genes may further compromise arterial wall medial integrity, contributing to more severe disease. These findings provide novel pathological and genetic insights into the pathogenesis of SCAD and may inform future diagnostic and therapeutic strategies.

Intramyocardial hemorrhage (IMH) after reperfused ST-elevation myocardial infarction (STEMI) is associated with adverse outcomes, yet no therapy specifically targets it. Dexrazoxane (DXZ) may mitigate iron-mediated injury from IMH. SHIELD-MI was a single-center, non-randomized, placebo-controlled, sequential-cohort phase IIa study with participants and the cardiac MRI (CMR) core laboratory blinded to treatment. Twenty-five patients received intravenous DXZ 250 mg before primary PCI and at 4, 8, and 12 h thereafter. Twenty-five comparators, selected from 78 placebo-treated patients, were matched on total ischemic time, culprit territory, and pre-PCI occlusion status. Primary endpoints were left ventricular ejection fraction (LVEF) and IMH volume on CMR at 48-72 h, evaluating early ventricular function and hemorrhagic myocardial injury after reperfusion. In the matched analytic cohort (n=50), LVEF was higher in patients receiving DXZ (39.8±7.7% vs. 34.7±10.1%; P=0.048), permitting formal testing of IMH volume, which was lower with DXZ (2.0±3.4% LV vs. 6.3±6.0% LV; P=0.004). The prespecified fixed-sequence criterion was therefore met at both steps. Infarct size was lower with DXZ (29.1±13.1% LV vs. 43.8±18.6% LV; P=0.002). Hemorrhagic MI occurred in 6/25 (24%) versus 16/25 (64%) participants (P=0.010). No drug-related serious adverse events were observed. Peri-procedural intravenous DXZ was associated with lower IMH and infarct size and higher LVEF, without safety concerns. These exploratory findings identify IMH as a candidate therapeutic target warranting a randomized trial.

The fourth universal definition of myocardial infarction (UDMI) distinguishes type 1 from type 2 myocardial infarction (MI), but this framework does not fully capture the heterogeneity of underlying mechanisms and prognosis. To characterize the distribution and clinical features of MI causal endotypes in a large contemporary cohort with a descriptive assessment of associated 1-year outcomes. Consecutive patients from the prospective, multicenter AMIPE registry with an adjudicated diagnosis of MI according to the fourth UDMI were included between January 1, 2017, and December 31, 2023. Follow-up was 1 year; patients with available 1-year follow-up or who died within the first year were included. Type 3, 4, and 5 MI and nonischemic myocardial injuries were excluded. These data were analyzed from June 2025 to May 2026. Patients were classified according to the primary etiologic mechanism of MI into 4 causal endotypes: cardiac/coronary, cardiac/noncoronary, systemic, or indeterminate. The main measures were the distribution of causal endotypes and underlying etiologies. One-year outcomes included all-cause death, major adverse cardiovascular events ([MACE] cardiovascular death or recurrent MI), cardiovascular death, and recurrent MI. Cox and Fine-Gray models used the cardiac/coronary group as reference. Among 6282 patients, mean (SD) age was 69.8 (13.5) years and 2013 (32.0%) were women. Overall, 5330 patients (84.9%) had a cardiac/coronary cause, including 5158 with acute atherothrombosis and 172 with nonatherothrombotic coronary mechanisms, 302 had a cardiac/noncoronary cause (4.8%), most commonly tachyarrhythmia, 503 had a systemic cause (8.0%), and 147 had an indeterminate cause (2.3%). At 1 year, all-cause mortality was 9.8% in cardiac/coronary MI, 15.9% in cardiac/noncoronary MI, 25.8% in systemic MI, and 1.4% in indeterminate MI. Compared with cardiac/coronary MI, adjusted hazard ratios for all-cause death were 1.46 (95% CI, 1.08-1.96) for cardiac/noncoronary MI, 2.50 (95% CI, 2.05-3.05) for systemic MI, and 0.22 (95% CI, 0.06-0.89) for indeterminate MI. Higher mortality in systemic and cardiac/noncoronary MI was largely related to noncardiovascular death. MACE rates differed less markedly across endotypes, whereas recurrent MI was less frequent in cardiac/noncoronary and systemic MI than in cardiac/coronary MI. In this study, a causal endotype-based classification of MI identified distinct underlying mechanisms and clinical profiles that were not fully captured by the type 1/type 2 framework. This approach may complement the UDMI by improving characterization of MI heterogeneity.

Sex differences in treatment with Statins after Myocardial Infarction (MI) are widely recognised. This study aimed to assess differences in statin treatment initiation after MI by sex, age groups, and year of MI. We conducted a cohort study in Denmark using registries for patients with a first-time MI between 1st January 2000 and 31st December 2024, excluding patients already treated with lipid lowering drugs up to 180 days before their MI. Descriptive statistics and multivariable Poisson regression were used to explore the effect of sex on treatment initiation. A total of 154,591 patients were included in the study (37% females, median age 75 years for females and 65 years for men). Overall, 54% of females versus 72% of males had initiated statin treatment within 180 days (p < .001). For females ≥40 years, significantly lower proportions were found in every year interval (p < .001 for all). Within the age groups, the relative difference between the sexes increased from 2000-2002 until 2015-2019, whereafter a decrease was found from 2015-2019 to 2020-2024, except among 60-69-year-olds for whom the decrease began earlier, starting in 2010-2014. Females had a 25% lower relative risk (RR 0.75 [0.74;0.76]) of initiating treatment. These differences remained after adjusting for age groups and year interval (RR 0.87 [0.86;0.87]) and after further adjustment for baseline characteristics (RR 0.91 [0.85;99]). A smaller proportion of females received statins than males after a MI. Disparities in treatment persisted over the years.

Investigate sex-specific associations between exercise capacity and the risk of all-cause mortality and major adverse cardiovascular events (MACE) after myocardial infarction (MI), using nationwide real-world data. A prospective cohort study using the SWEDEHEART registry. Patients with an MI (2016-2020) were included. Exercise capacity (maximal workload in Watts) was assessed using bicycle ergometer testing performed before exercise-based cardiac rehabilitation, 2-8 weeks after hospital discharge. Outcomes were all-cause mortality and MACE (MI, stroke, and cardiovascular death), identified in national cause-of-death and patient registries (2016-2023). Associations between exercise capacity and outcomes were evaluated using adjusted Cox proportional hazard models. The functional form of the association was assessed using restricted cubic splines. There were 15,945 patients (78% men), with a median age of 64 (IQR: 56-70) years, included. During a median follow-up of 3.2 (2.3-4.3) years, 420 deaths and 948 MACE occurred. Higher exercise capacity (per 10-Watt increase) was associated with an 18% lower hazard of death in men and a 33% lower hazard in women, with a linear association for both sexes. Similarly, MACE hazard decreased by 8% in men and 18% in women per 10-Watt increase in exercise capacity, with a curvilinear association for men and linear association for women. Higher exercise capacity measured by routine clinical exercise testing was associated with lower risk of all-cause mortality and recurrent MACE, with stronger associations in women. These findings support the use of exercise capacity testing to identify patients at the highest risk.

Randomized trials conducted in the early 2000s established the survival benefit of primary prevention implantable cardioverter-defibrillator (ICD) therapy in patients with reduced left ventricular ejection fraction (LVEF) after myocardial infarction. However, management of myocardial infarction and heart failure has substantially evolved since that time. We investigated whether the estimated association between primary prevention ICD implantation in post-myocardial infarction patients with reduced LVEF and mortality reduction has changed over time. We analyzed individual participant data from 32,214 patients with LVEF ≤35% after myocardial infarction included in the PROFID pooled cohort, comprising 7,477 patients carrying a primary prevention ICD (ICD patients) and 24,737 patients without an ICD (non-ICD patients). The primary endpoint was all-cause mortality. Propensity scores were estimated using multivariable logistic regression including age, sex, LVEF, renal function, and diabetes, and overlap weighting was applied to balance treatment groups. Time period-specific analyses were performed across three prespecified time periods defined by inclusion year: 1995-2004, 2005-2014, and 2015-2020. Weighted cumulative mortality curves were generated for each time period. Temporal changes in the estimated association between ICD implantation and mortality reduction were assessed using a weighted Cox proportional hazards model. A total of 12,097 deaths occurred during a mean follow-up of 43.7 months. The estimated association between ICD implantation and mortality changed significantly across time (P for interaction <0.001). In weighted time period-specific analyses, the estimated mortality reduction associated with ICD implantation progressively decreased over more recent periods. The hazard ratio for ICD versus non-ICD patients was 0.54 (95% CI 0.47-0.62; P<0.001) in 1995-2004, 0.67 (95% CI 0.62-0.72; P<0.001) in 2005-2014, and 0.89 (95% CI 0.73-1.07; P=0.221) in 2015-2020, with negligible separation of the weighted cumulative mortality curves in the most recent time period. In this analysis including a large cohort of post-myocardial infarction patients with reduced LVEF, the estimated mortality reduction associated with primary prevention ICD implantation progressively decreased over time.

Myocardial infarction with non-obstructive coronary arteries (MINOCA) is a heterogeneous group of clinical entities requiring further investigation to assess aetiology. The European Society of Cardiology guidelines recommend advanced tests to establish an underlying mechanism. We evaluated advanced diagnostic testing utilization and real-world adherence to the current guideline in an international MINOCA registry. DOMINO is a prospective, multicentre, non-commercial registry enrolling 365 patients with MINOCA across 17 centres in 13 countries. Advanced testing was defined as cardiac magnetic resonance (CMR), intracoronary imaging, and/or invasive coronary functional assessment. The association between advanced testing and diagnostic resolution was assessed by multivariable logistic regression, with standard, cluster-robust, and generalized estimating equation (GEE) approaches to account for clustering by centre. Guideline-directed testing was performed in 254/365 (69.6%) and varied markedly by country (0-100%, P < 0.0001). A specific etiologic diagnosis was reached in 337/365 patients (92.3%). Advanced testing was associated with diagnostic resolution in the standard and GEE models, with a directionally consistent but non-significant cluster-robust estimate [standard odds ratio (OR) 3.94, 95% confidence interval (CI) 1.59-10.06; cluster-robust OR 3.75, 95% CI 0.95-14.72, P = 0.058; GEE OR 3.69, 95% CI 1.04-13.11]. Diagnostic resolution increased progressively with the extent of testing performed, from 85.6% with no advanced testing to 97.1% with CMR plus invasive/functional assessment (trend P = 0.02). Discharge pharmacotherapy varied significantly by etiologic diagnosis (P = 0.0001). Advanced diagnostic testing was associated with a higher likelihood of a determined etiologic diagnosis in MINOCA, despite marked international variability in its use; however, this association is partly definitional, as advanced testing directly contributes to diagnostic ascertainment for several etiologic categories. These findings nonetheless support closing the guideline-practice gap in advanced testing, while underscoring the need to distinguish mechanistically confirmed diagnoses from presumptive ones.

Vascular endothelial cells play a crucial role in maintaining the structural integrity and microcirculatory function of the coronary microvasculature. Endothelial dysfunction, a critical pathological process in various cardiovascular diseases including myocardial infarction (MI), leads to reduced myocardial blood flow due to a lack of nitric oxide gas inside blood vessel walls that ultimately causes inflammation, thrombosis and coronary artery obstruction. Therefore, the identification of molecular mechanisms that protect against endothelial cell injury is necessary for effective MI treatment. In this study, we identified a novel interaction between TEK receptor tyrosine kinase (TEK) and signal transducer and activator of transcription 3 (STAT3), promoting the phosphorylation and nuclear translocation of STAT3. In particular, the upregulation of STAT3 and p-STAT3 could be prevented by inhibiting the binding of STAT3 to TEK using specific STAT3 domain inhibitors. Additionally, chromatin immunoprecipitation (ChIP) analysis revealed that STAT3 acts as a transcription factor, binding to the promoter region of lysyl oxidase (LOX) and LOX propeptide (LOX-PP) and inhibiting their transcription. Notably, excessive LOX-PP has been shown to induce endothelial cell injury, leading to reduced nitric oxide synthesis, increased permeability, and impaired functionality in terms of proliferation, migration, and tube formation. These novel findings reveal a new mechanism of endothelial cell injury after myocardial ischemia and may offer new insights for developing future therapeutic approaches.

Myocardial infarction (MI) induces pathological remodeling that drives heart failure. Dual-targeted approaches addressing myocardial repair and angiogenesis are crucial for improving post-infarct prognosis. Previous research has demonstrated that hesperadin (Hes), a CaMKII inhibitor, exhibits anti-apoptotic activity, while vascular endothelial growth factor (VEGF) enhances angiogenesis following infarction. Although these two drugs may hold potential for combination therapy, their co-delivery is compromised by opposing physicochemical properties: Hes is highly hydrophobic, whereas VEGF is hydrophilic and can cause significant adverse effects when administered systemically. Here, we report a supramolecular hydrogel (SHV gel) constructed from hyaluronic acid (HA) and cucurbit[7]uril (CB[7]) to enable synchronized and sustained co-delivery of Hes and VEGF. CB[7] encapsulates Hes through host-guest recognition, thereby enhancing drug dispersibility and loading, while HA confines VEGF to preserve its bioactivity and prolong its release. In vitro and in vivo data reveal that SHV hydrogels combine favorable biocompatibility with sustained co-release of Hes and VEGF, showing superior synergistic efficacy against MI through anti-apoptosis, promoting angiogenesis, inhibiting myocardial remodeling and improving cardiac function compared to mono-component hydrogels. This supramolecular platform represents a promising multifunctional therapeutic strategy for precise MI intervention and clinical translation. STATEMENT OF SIGNIFICANCE: Myocardial infarction (MI) often progresses to heart failure because injured heart muscle dies and blood supply remains insufficient. Combining anti-apoptotic and pro-angiogenic therapies could improve recovery, but co-delivering a hydrophobic small molecule and a fragile, hydrophilic protein in one formulation is difficult, and systemic administration of vascular endothelial growth factor (VEGF) can cause adverse side effects. Here, we develop an injectable supramolecular hydrogel (SHV gel) built from hyaluronic acid and cucurbit[7]uril to synchronize delivery of hesperadin and VEGF. Cucurbit[7]uril encapsulates hesperadin to enhance solubility and loading, while the hyaluronic acid network confines VEGF to preserve bioactivity and prolong release. The resulting hydrogel shows good biocompatibility and synergistically reduces cardiomyocyte apoptosis, promotes angiogenesis, limits remodeling, and improves cardiac function in MI models.

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.

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.

Acute myocardial infarction (AMI) remains difficult to diagnose rapidly outside hospital settings because current evaluation still relies mainly on electrocardiography and blood-based biomarker testing. Here, we developed a coin-sized, Rapid Electrochemical Skin interstitial fluid microneedle device for multiplexed Cardiac-biomarker detection Utilizing deep-learning-based Evaluation (RESCUE). The RESCUE system integrates a mesoporous gold-coated microneedle electrode patch (MNE) with a miniaturized three-channel microelectrochemical workstation (MEW) and Bluetooth data link to enable fully portable operation. Antibodies immobilized on amino-functionalized multiwalled carbon nanotubes enabled simultaneous detection of C-reactive protein (CRP), cardiac troponin I (cTnI), and myoglobin (Myo). Electrochemical measurements showed log-linear responses, with limits of detection of 4.09 ng/mL, 0.078 ng/mL, and 1.642 pg/mL for C-reactive protein, cardiac troponin I, and myoglobin, respectively. In simulated skin and artificial interstitial fluid, the device showed good selectivity and average recoveries above 98%. Biocompatibility studies demonstrated preserved fibroblast viability, rapid closure of microneedle-induced micropores, and no detectable histological or serum biochemical toxicity in mice. In murine model of AMI induced by left anterior descending coronary artery ligation, RESCUE tracks ISF trajectories of all three biomarkers. A seven-feature one-dimensional convolutional neural network (CNN1D) trained on interstitial-fluid and blood biomarker features classified infarct size with 80% accuracy. These results support the feasibility of integrated interstitial-fluid sensing for preclinical AMI stratification.

Stem cell therapies are emerging as promising strategies for repair after myocardial infarction (MI), but the repair efficacy is limited by the poor cardiac microenvironment represented by the inflammatory response, as well as oxidative stress, and adverse electrical coupling. Here, we developed an injectable supramolecular hydrogel (HCPA) that modulates the infarct microenvironment and accelerates myocardial repair by encapsulating human induced pluripotent stem cells derived cardiomyocytes (hiPSC-CMs). HCPA hydrogel not only exhibited excellent reactive oxygen species (ROS) response in order to minimize oxidative stress but also possessed desirable electrical conductivity for the reintegration of electrical impulses. Critically, RNA sequencing demonstrated that the PPARα/NFκB pathway contributed significantly to the HCPA hydrogel-promoted macrophage polarization from M1-type to M2-type, thus alleviating inflammatory responses. HCPA hydrogel harboring hiPSC-CMs increased retention of hiPSC-CMs and improved cardiac function in MI mice. This study represents a new integrated therapeutic option for MI and provides insights for the development of novel biomaterials in the field of tissue engineering.

Myocardial infarction (MI) continues to be a leading cause of global mortality. Resibufogenin (RBG), a principal bioactive constituent derived from Venenum Bufonis, is well recognized for its potent cardiotonic properties. Nevertheless, the therapeutic potential of RBG in the context of MI remains to be fully elucidated. This study revealed that RBG exerted significant cardioprotective effects in a murine model of MI by preserving cardiac function, attenuating myocardial injury, and increasing vascular density. Proteomic analysis revealed that angiogenesis was the predominant biological process associated with RBG-responsive proteins. Integrated proteomic analysis and mechanistic validation demonstrated that RBG activated the ITGA5-VEGF signaling axis, a pathway essential for its therapeutic efficacy, in a macrophage-dependent manner. Notably, both pharmacological inhibition of ITGA5 and depletion of macrophages completely abrogated RBG-mediated cardioprotection in the MI model. Furthermore, RBG significantly increased endothelial cell proliferation, migration, and tube formation in a macrophage-endothelial cell coculture system. More importantly, RBG upregulated ITGA5 expression in macrophages through activation of the VAV3/CDC42 signaling pathway. Collectively, these findings demonstrate that RBG is a promising therapeutic agent for myocardial infarction and acts via the macrophage-specific VAV3/CDC42-mediated ITGA5/VEGF signaling pathway to promote reparative angiogenesis. This study elucidates the cardioprotective effects and underlying mechanisms of RBG and establishes a scientific basis for the discovery of novel therapeutic agents from natural products.

Despite significant advances in stent technology, long-term complications-such as restenosis and stent thrombosis-remain relatively common and clinically impactful due to their association with recurrent myocardial infarction and adverse outcomes. Among the causes of stent failure, neoatherosclerosis has gained recognition as a key pathological mechanism, driven by impaired vascular healing, chronic inflammation, platelet activation, and immune responses following coronary stenting. Advances in diagnostic accuracy, particularly intracoronary imaging, have provided new insights into its development. In response, emerging strategies-including refined pharmacotherapy, targeted intraprocedural interventions, novel stent designs, and alternative drug-delivery systems-are being explored. This review presents recent preclinical, diagnostic, and clinical advances in understanding and addressing neoatherosclerosis and discusses current and emerging therapeutic approaches (Graphical Abstract).

Guideline-recommended clinical risk scores such as AusCVDRisk underestimate cardiovascular disease (CVD) risk in a substantial proportion of individuals who later experience events, with up to 65% initially classified as low or intermediate risk. This limitation is most consequential in the intermediate-risk group, where treatment decisions are uncertain and additional risk refinement could alter management. Circulating lipid species and inherited genetic variation capture complementary molecular aspects of atherosclerotic risk that are not fully reflected by conventional clinical variables, but are not routinely incorporated into primary-care risk assessment. We investigated whether selective integration of lipidomic and genomic risk signals into AusCVDRisk improves 5-year CVD prediction and reclassification, with a focus on individuals at intermediate clinical risk. A lipidomic score comprising 689 lipid species measured by liquid chromatography-tandem mass spectrometry was derived using regularised Cox regression in 8082 participants from the Australian Diabetes, Obesity and Lifestyle Study (1999-2000). A genome-wide coronary artery disease polygenic score (PGS002048; 762,124 variants) was optimised in 3328 participants from the Busselton Health Study (1994-95). Each score was adjusted for AusCVDRisk predictors to isolate independent effects and incorporated into Cox models retaining the AusCVDRisk linear predictor as a fixed offset, generating lipidomic-enhanced (L.CVDRisk), genomic-enhanced (G.CVDRisk), and combined (LG.CVDRisk) scores. Internal and external validation was performed across five Australian cohorts totalling 13,521 adults without baseline CVD. Discrimination (Harrell's concordance index; C-statistic), calibration, categorical net reclassification improvement (NRI), and decision-curve analyses were assessed. LG.CVDRisk showed modest gains in discrimination compared with AusCVDRisk (pooled ΔC among intermediate-risk individuals 0.071, 95% CI 0.033-0.109; overall 0.012, 95% CI 0.000-0.024). Risk classification improved substantially (pooled NRI in the intermediate-risk group 0.305, 95% CI 0.212-0.397; overall 0.080, 95% CI 0.031-0.129), with net event and non-event reclassification of 38.2% (95% CI 29.3-47.0%) and -6.8% (95% CI -9.3 to -4.2%) among intermediate-risk individuals. Decision-curve analysis showed the greatest net benefit when molecular profiling was selectively applied to individuals with intermediate AusCVDRisk (5-<10%). In a coronary imaging cohort, LG.CVDRisk reclassified 17 (41%) of 41 intermediate-risk individuals with extensive coronary calcification into the high-risk category. Selective augmentation of an established clinical risk algorithm with lipidomic and genomic information improves cardiovascular risk stratification among individuals at intermediate baseline risk. This approach supports targeted molecular testing within existing primary-care pathways to inform personalised prevention. National Heart Foundation, Australia, Australian Government Medical Research Future Fund, National Health and Medical Research Council, Victorian Government.

LDL-cholesterol (LDLC) to apolipoprotein B (ApoB) ratio is an accessible and reliable proxy for the LDL-particle size. The aim of the present study was to investigate whether type 2 diabetes mellitus (T2DM) modulates the prognostic value of LDL-C/ApoB ratio in statin-treated patients with coronary artery disease (CAD). The study included 21,382 patients with CAD who had received statin therapy at baseline with a median follow-up of 3.1 years. The primary endpoint was major adverse cardiac events (MACE), including all-cause mortality, non-fatal myocardial infarction (MI), and ischemia-driven revascularization. Higher LDL-C/ApoB level (≥1.2) was associated with a decreased risk of MACE in the T2DM group (adjusted HR: 0.81, 95% CI: 0.69-0.96). A stepwise increase of 0.1 unit in LDL-C/ApoB ratio was associated with a 5% decrease for MACE only in the T2DM group. Among participants without T2DM, there was no clear association between LDL-C/ApoB and MACE (p for interaction < 0.05). No significant association was identified between MACE risk and LDL-C or ApoB in the T2DM group. Our data demonstrated that in CAD patients who had received statin therapy, LDL-C/ApoB ratio was related to adverse prognosis only in those with T2DM. Among patients with CAD and T2DM who are receiving statin treatment, LDL-C/ApoB may be a better indicator of residual cholesterol risk than LDL-C.

Exposure to metals has been associated with elevated oxidative stress, which may contribute to diabetic macrovascular complications. However, current methods for evaluating oxidative stress, which mainly rely on quantifying individual byproducts of oxidative damage, may not fully characterize the effects of metal exposure on global redox imbalance, especially in the setting of type 2 diabetes mellitus (T2DM). Here, by assessing global redox status using the novel marker oxidation-reduction potential (ORP) and performing elemental profiling of 35 plasma metals/metalloids in a large cohort of 3142 patients with T2DM, we successfully identified a mixture of 5 redox-related metals (including nickel, zirconium, titanium, strontium, and vanadium), which showed strong associations not only with ORP, but with conventional markers of protein, lipid, and DNA oxidation. Importantly, high exposure to the redox-related metal mixture cross-sectionally correlated with obstructive coronary artery disease (CAD) and prospectively predicted adverse events after percutaneous coronary intervention (PCI) in patients with T2DM. Further cytokine profiling found that changes in cytokines within the nuclear factor-kappa B (NF-κB) pathway might mediate the associations of the redox-related metal mixture with obstructive CAD and post-PCI outcomes. Notably, ex vivo experiments of peripheral blood mononuclear cells (PBMCs) showed that exposure to redox-related metals induced a specific pattern of bioenergetic dysfunction characterized by impaired respiration of mitochondrial complexes I and III, leading to mitochondrial oxidant overproduction and consequent NF-κB activation. Collectively, our findings indicate ORP as a promising marker of metal-induced oxidative stress and support the links of redox-related metals to cardiometabolic risk in patients with T2DM.

Comprehensive evaluation by invasive coronary function test (CFT) of patients with angina and non-obstructive coronary artery disease is recommended in current guidelines. The prognosis of patients with CFT-proven coronary vasomotor dysfunction (CVDys) is less well-known. Patients that provided consent for the previously published NL-CFT registry who underwent clinically indicated invasive CFT between February 1st, 2019 and June 1st, 2024 were included. Patients with CVDys defined as an abnormal spasm provocation test and/or microvascular functional assessment, were compared to patients with normal CFT. The primary outcome of major adverse cardiovascular events and emergency room visits for angina (MACE-EA) was defined as a composite of all-cause death, acute coronary syndrome, stroke/transient ischaemic attack, revascularization, repeat angiography without intervention, heart failure hospitalizations and unplanned hospitalizations or emergency room visits due to angina. In total, 1355 patients were included. In 79.8%, CFT was abnormal, vasospasm was the most prevalent endotype. In 1252 patients follow-up of clinical events was complete. During a mean follow-up of 33±13 months, CVDys patients had almost double the number of primary outcome events compared to patients with a normal CFT (31.2% vs 16.8%, p<0.001), driven by emergency care visits for angina. Secondary clinical endpoints including death, myocardial infarction, stroke or revascularization were low and comparable between the groups. The long-term risk of MACE-EA is doubled in ANOCA patients with CFT-confirmed CVDys compared to normal CFT results. Events are dominated by emergency room visits due to angina, illustrating the high disease burden of CVDys. Their (angina-related) health status is significantly worse at follow-up.

All apolipoprotein B-containing lipoproteins are established causal factors for coronary artery disease (CAD). This study aimed to identify robust proteomic signatures of low-density lipoprotein (LDL), triglyceride-rich lipoproteins (TRL), and lipoprotein(a) [Lp(a)] and to evaluate whether these signatures illuminate biological processes underlying differences in per-particle atherogenicity. Plasma proteins associated with LDL, TRL, and Lp(a) concentrations were identified using multivariable-adjusted regression across 2918 proteins in a primary prevention cohort based on UK Biobank (n=35,269), and findings were corroborated using one-sample Mendelian randomization. Proteins consistently identified by both approaches were summarized into lipoprotein-specific multi-protein scores and associated with incident CAD (n=1599 events) using Cox regression. High-dimensional mediation analysis quantified the proportion of lipoprotein-associated CAD risk explained by proteomic alterations. Findings were replicated in the Multi-Ethnic Study of Atherosclerosis (n=5915). Requiring concordance between observational and Mendelian randomization analyses (both Bonferroni-adjusted P<0.05), 30 proteins were identified as associated with LDL, 471 with TRL, and 53 with Lp(a). The TRL and Lp(a) signatures were distinct from the LDL signature yet overlapped substantially with each other (36 shared proteins), with common enrichment in inflammatory pathways. After adjustment for potential confounders and measured lipoprotein concentrations, the multi-protein scores for TRL (hazard ratio per 1-SD [HRSD], 1.16; 95% confidence interval [95%CI]: 1.08-1.24) and Lp(a) (HRSD, 1.09; 95%CI: 1.03-1.15), but not LDL (HRSD, 0.95; 95%CI: 0.89-1.02), were associated with incident CAD. Mediation analysis was consistent with immune activation and vascular remodeling markers mediating TRL-associated CAD risk (proportion mediated, 62%) and, in part, Lp(a)-associated risk (14%). Beyond arterial lipid deposition, TRL and Lp(a) converge on inflammatory and vascular remodeling pathways that, under the assumptions of observational mediation analysis, may explain their excess per-particle atherogenicity compared with LDL.

Interleukin-6 (IL-6) has been linked to major adverse cardiovascular events (MACE) in the general population. Among women with angina and no obstructive coronary artery disease (ANOCA), IL-6 has been associated with coronary microvascular dysfunction (CMD), a known driver of risk in this population. We aimed to investigate whether IL-6 identifies a cardiometabolic high-risk phenotype and predicts long-term cardiovascular outcomes in women with ANOCA, and whether its prognostic value is modified by CMD. The iPOWER cohort included 1853 women with stable angina and <50% coronary stenosis at coronary angiography. Of these, 1636 had measures of plasma IL-6 at baseline. The primary outcome was a composite of cardiovascular death, myocardial infarction, revascularization, ischaemic stroke, and heart failure. Associations with outcomes were assessed using Cox proportional hazards models adjusted for age and cardiovascular risk factors, with prespecified subgroup analyses, including assessment of potential effect modification by CMD assessed by TTE-derived coronary flow velocity reserve (CFVR). Higher IL-6 was associated with a cardiometabolically shifted phenotype characterized by adiposity, diabetes, a high triglyceride-high-density lipoprotein-cholesterol lipid profile, and reduced CFVR. During a median follow-up of 10.8 years, 250 women (15.3%) experienced MACE. IL-6 predicted MACE [hazard ratios (HR) 1.23, 95% confidence interval 1.07-1.41]. The association did not vary by CMD status (HR 1.25 vs. 1.16). IL-6 identifies an inflammation-driven cardiometabolic high-risk phenotype in women with ANOCA and independently predicts MACE. The prognostic value of IL-6 does not depend on CMD, underscoring IL-6 as a clinically relevant marker of long-term cardiovascular risk.

Inflammation influences outcomes after percutaneous coronary intervention (PCI) in coronary artery disease (CAD). This study aimed to evaluate the relative and combined prognostic value of local coronary inflammation, and systemic inflammation for adverse outcomes. In a prospective cohort of 1,987 patients with CAD undergoing PCI, local inflammation, quantified by the pericoronary fat attenuation index (FAI), and systemic inflammation, measured by high-sensitivity C-reactive protein (hs-CRP), were assessed. The patient-level primary endpoint was major adverse cardiovascular events (MACE) including all-cause mortality, non-fatal myocardial infarction, and unplanned repeat revascularization. The vessel-level endpoint was the vessel-oriented composite endpoint (VOCE). Over a median 3-year follow-up, 164 patients (8.3%) experienced MACE and 118 of 2,436 vessels (4.8%) experienced VOCE. Extreme Gradient Boosting with SHAP analysis ranked FAI-MAX as the most important local inflammatory feature for both MACE and VOCE. High FAI-MAX (? -70 HU) was strongly associated with MACE (HR 3.25, 95% CI 2.29-4.61) and VOCE (HR 3.15, 95% CI 2.06-4.82). Patients with high FAI-MAX and elevated hs-CRP had the highest risk (MACE HR 4.00, 95% CI 2.47-6.32; VOCE HR 4.15, 95% CI 2.37-7.25). High local inflammation with low systemic inflammation conferred substantially greater risk than the converse phenotype (MACE HR 2.88, 95% CI 1.85-4.49 vs 1.09, 95% CI 0.55-1.85; VOCE HR 2.64, 95% CI 1.55-4.50 vs 1.08, 95% CI 0.55-2.13). Addition of both markers significantly improved model discrimination compared with either alone (DeLong P < 0.05). In sensitivity analysis excluding revascularization, the advantage of isolated high FAI-MAX was attenuated, while the dual-high phenotype remained significant. Local coronary inflammation shows a stronger association with adverse outcomes after PCI than systemic inflammation. Integrating both markers improves risk stratification and may support inflammation-guided management in patients with CAD.

Microvascular resistance reserve (MRR) is a novel index for assessing coronary microvascular function that is independent of epicardial coronary artery stenosis and subtended myocardial mass. However, limited data are available regarding the clinical relevance of coronary microvascular dysfunction, defined by MRR in patients undergoing clinically indicated invasive coronary angiography. This study sought to evaluate the incidence and prognostic impact of coronary microvascular dysfunction defined by MRR in routine practice. In the prospective, multicentre FLOW-CMD Registry, 1003 consecutive patients with suspected ischaemic heart disease who underwent clinically indicated invasive coronary angiography with comprehensive coronary physiologic assessment were prospectively enrolled. Coronary microvascular dysfunction was defined as MRR ≤2.5 in any evaluated vessel. The primary endpoint was a composite of all-cause death, myocardial infarction, clinically-driven repeat revascularisation, or hospitalisation for heart failure. Coronary microvascular dysfunction was identified in 334 of 1003 patients (33.3%). MRR as a continuous variable was associated with the risk of the primary endpoint (hazard ratio [HR] per 1-unit decrease, 1.16; 95% confidence interval [CI] 1.03-1.32; P=0.026). At a median follow-up of 1.9 years, the primary endpoint occurred in 47 of 334 patients (18.2%) with coronary microvascular dysfunction and 49 of 669 patients (8.6%) with preserved microvascular function (HR 1.94; 95% CI 1.30-2.90; P=0.001). On multivariable analysis, coronary microvascular dysfunction defined by MRR ≤2.5 was independently associated with the primary endpoint (adjusted HR 1.78; 95% CI 1.06-2.99; P=0.030). In patients with suspected ischaemic heart disease undergoing invasive coronary angiography, coronary microvascular dysfunction defined by MRR ≤2.5 was observed among one-third of patients, and was associated with an increased risk of a composite of all-cause death, myocardial infarction, clinically-driven repeat revascularisation, or hospitalisation for heart failure (Multicenter FLOW-CMD Registry ClinicalTrials.gov number, NCT05369182).

Cardiovascular disease (CVD) risk assessment and risk-guided lipid management are cornerstones of primary prevention of atherosclerotic coronary artery disease (ACAD). However, the 10-year CVD risk is often limited by individual-level inaccuracy and poor adherence. This trial aimed to determine whether a coronary computed tomography angiography (CCTA)-guided strategy improves lipid management in asymptomatic populations. This pragmatic, open-label, assessor-blinded randomized trial was conducted in Nanjing, China. Asymptomatic community-dwelling adults aged 40-69 years with no history of CVD or prior use of lipid-lowering medication (LLM) were recruited. Participants were randomized to receive individualized LLM recommendations based either on CCTA findings (CCTA group) or on 10-year CVD risk (usual-care group). The primary outcome was the proportion of participants with regular LLM use (≥24 of preceding 30 days) at both the 6-month and 12-month follow-up visits. Of 3503 randomized participants, 3491 (1748 CCTA, 1743 usual-care) were included in the primary analysis (median [IQR] age, 55 [48-61] years; 60.2% women). Among 1516 participants undergoing CCTA, ACAD was detected in 565 (37.3%). The median follow-up was 12.5 months. Regular LLM use was higher in the CCTA group than in the usual-care group (12.5% [218/1748] vs. 8.1% [141/1743]; adjusted risk ratio, 1.57 [95% confidence interval, 1.29-1.91]; P < 0.001). During follow-up, invasive coronary procedures were more frequent in the CCTA group than in the usual-care group (29 procedures vs. 1). In asymptomatic populations, a CCTA-guided strategy modestly improved lipid management, though it increased invasive coronary procedures. Longer follow-up is needed to determine its effect on clinical events. Study Registration  http://www.clinicaltrials.com; Identifier: NCT05725096.

Age is a nonmodifiable risk factor for atherosclerosis and cardiovascular disease (CVD), with their prevalence increasing over time. Dyslipidaemia plays a key role in coronary artery disease (CAD) across all age groups, including older adults. However, limited evidence exists regarding the efficacy of lipid-lowering therapy, particularly statins, for primary prevention in older populations. This review underscores the significance of statins for primary prevention in older adults. The PROSPER study and similar trials demonstrated a 24% reduction in CAD mortality with statins, without notable cognitive or functional impairments. Similarly, the EWTOPIA 75 trial reported a 34% reduction in major cardiac events with ezetimibe, though benefits diminished in those aged >85 years. A meta-analysis revealed a 26% reduction in major vascular events per 1 mmol/L decrease in low-density lipoprotein cholesterol in older adults, with no heightened risks of cancer, haemorrhagic stroke, or cognitive decline. The Danish Contemporary Primary Prevention Cohort identified individuals aged 80-100 years as having the highest myocardial infarction risk, emphasizing the benefits of statin therapy in this group. Ongoing STAREE and PREVENTABLE trials aim to provide further evidence on statins for primary prevention in older adults. Effective CVD management in older populations should begin early, prioritizing a healthy lifestyle and addressing modifiable risk factors. Statin therapy should not be discontinued based on age alone and requires careful consideration for individuals with established CVD.

Complex tubular structures are essential in medical imaging and computer-assisted diagnosis, where their integrity enhances anatomical visualization and lesion detection. However, existing segmentation algorithms struggle with structural discontinuities, particularly in severe clinical cases such as coronary artery stenosis and vessel occlusions, which leads to undesired discontinuity and compromising downstream diagnostic accuracy. Therefore, it is imperative to reconnect discontinuous structures to ensure their completeness. In this study, we explore the tubular structure completion based on point cloud for the first time and establish a Point Cloud-based Coronary Artery Completion (PC-CAC) dataset, which is derived from real clinical data. This dataset provides a novel benchmark for tubular structure completion. Additionally, we propose TSRNet, a Tubular Structure Reconnection Network that integrates a detail-preservated feature extractor, a multiple dense refinement strategy, and a global-to-local loss function to ensure accurate reconnection while maintaining structural integrity. Comprehensive experiments on our PC-CAC and two additional public datasets (PC-ImageCAS and PC-PTR) demonstrate that our method consistently outperforms state-of-the-art approaches across multiple evaluation metrics, setting a new benchmark for point cloud-based tubular structure reconstruction. Our benchmark is available at https://github.com/YaoleiQi/PCCAC.

Thyroid-stimulating hormone (TSH), elevated in conditions like subclinical hypothyroidism, has been clinically linked to a higher risk of morbidity and mortality in patients with coronary artery disease (CAD). Here, we aim to investigate the effects of TSH on CAD-associated platelet activation and arterial thrombosis, along with the underlying mechanisms. Clinical study demonstrated that higher TSH levels are associated with an increased risk of major adverse cardiovascular events in CAD patients. In vitro human and mouse platelet function studies found that TSH potentiates agonist-induced platelet aggregation, dense granule adenosine triphosphate release, integrin alpha-IIb beta-3 activation, P-selectin release from α-granules, platelet spreading, and clot retraction. Furthermore, in vivo animal studies demonstrated that TSH enhances thrombosis, whole blood thrombus formation, and middle cerebral artery occlusion-induced brain injury. Mechanistic studies revealed that platelets express the TSH receptor (TSHR). TSH binds to platelet TSHR and activates both the Gs/cAMP/PKA and Gq/Ca2+/PKC/MAPK signaling pathways. Activation of the Gq pathway is more pronounced than that of the Gs pathway, thereby potentiating platelet activation. Finally, our in vivo work showed that TSH aggravates microvascular obstruction and promotes myocardial infarction expansion in a mouse myocardial ischeamia/reperfusion injury model. TSH augments platelet activation and in vivo thrombus formation through engagement of platelet TSHR, subsequently activating downstream signaling cascades involving Gs/cAMP/PKA and Gq/Ca2+/PKC/MAPK pathways.

In transthyretin amyloid cardiomyopathy (ATTR-CM), tricuspid regurgitation (TR) severity may be underestimated by conventional (semi-)quantitative echocardiographic criteria derived from nonamyloid populations, given the restrictive, low-flow hemodynamics characteristic of the disease. To derive and validate disease-specific prognostic, quantitative TR risk thresholds in ATTR-CM and to compare their prognostic performance with current guideline definitions and the Tricuspid Valve Academic Research Consortium (TVARC) 5-grade extension. This international, multicenter cohort study was conducted from January 2016 to February 2026 at 8 high-volume tertiary referral centers across Austria, Italy, Germany, and the Netherlands, with data analysis February to May 2026. Patients with newly diagnosed ATTR-CM were enrolled and underwent standardized transthoracic echocardiography with blinded core laboratory quantitative analysis of echocardiography TR severity parameters (vena contracta width [VCW], effective regurgitant orifice area [EROA], and regurgitant volume [RegVol]). TR severity defined by VCW, EROA, and RegVol from blinded core laboratory quantitative analysis and TR severity according to 2025 European Society of Cardiology/European Association for Cardio-Thoracic Surgery, 2020 American Heart Association/American College of Cardiology, 2017 American Society of Echocardiography, and 2023 TVARC grading schemes. Outcomes were all-cause mortality (primary end point) and time to first heart failure hospitalization (HFH; secondary end point). A total of 1124 patients with newly diagnosed ATTR-CM were enrolled (derivation cohort: n = 745; validation cohort: n = 379). Median (IQR) patient age was 80 (75-84) years, and 260 patients (23.1%) were female. Over a median (IQR) follow-up of 25.2 (12.2-43.2) months, 324 patients (28.8%) died and 251 (22.3%) experienced HFH. All TR metrics independently predicted both end points. Spline-derived thresholds delineated intermediate (VCW ≥3 mm; EROA ≥0.15 cm2; RegVol ≥10 mL), high (≥5 mm; ≥0.25 cm2; ≥20 mL), and extreme risk (≥8 mm; ≥0.50 cm2; ≥40 mL), with stepwise Kaplan-Meier separation in both cohorts. Whereas the guideline-based and TVARC schemes each classified 130 patients (11.6%) as having severe TR, the proposed framework classified 334 patients (29.7%) as having at least high or extreme risk (P < .001 for comparison to all other definitions). The framework was independently associated with both end points, with the highest point estimate among the schemes (mortality: hazard ratio [HR], 1.41; 95% CI, 1.23-1.62; HFH: HR, 1.31; 95% CI, 1.12-1.54), and showed superior discrimination over guideline definitions, particularly at later time points. In this multicenter cohort study among patients with ATTR-CM, a validated, risk-based conceptual framework of echocardiographic parameters to quantify TR improved prediction of mortality and HFH over standard classification of TR severity, better reflecting restrictive low-flow pathophysiology and supporting disease-specific TR grading in ATTR-CM.

This large contemporary cohort included 3,035 patients (median age 58 years, 57% men); 56% had LGE, including 242 (8%) with LGE > 10%. Most patients have obstructive HCM (71%), 1498 (69%) of which subsequently underwent septal reduction therapy (SRT) at a median of 43 days (interquartile range [IQR] 5-107) from the CMR date (1,485 myectomies and 13 alcohol septal ablations). Over a median of 8.8 years, 331 (11%) primary endpoints occurred (295 cardiovascular deaths [9.7%] and 36 appropriate ICD discharges [1.3%]). On multivariable Cox proportional hazards analysis (adjusted for standard clinical and CMR variables, higher %LGE (1.05 per 1% increase, 95% CI 1.03-1.06; p < 0.001) was associated with primary events. Compared with no LGE, LGE ≥10% was associated with higher risk of the composite endpoint.

Aficamten significantly improved both functional capacity and patient-reported health status in patients with symptomatic nonobstructive hypertrophic cardiomyopathy in the phase 3 randomized, placebo-controlled ACACIA-HCM trial (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints in Adults with Non-Obstructive HCM; NCT06081894). Serial echocardiographic examinations may provide insights into the mechanisms underlying the therapeutic effect of aficamten in this prespecified exploratory analysis. Symptomatic patients with nonobstructive hypertrophic cardiomyopathy were randomized 1:1 to receive aficamten (range, 5-20 mg, titration based on left ventricular [LV] ejection fraction) or placebo for up to 72 weeks (end of treatment). The effect of aficamten on echocardiographic measures at 36 weeks (time of primary end point) and end of treatment was assessed with linear regression models adjusted for baseline values, intracavity obstruction, and baseline atrial fibrillation. Among 517 participants (mean±SD: age, 55±16 years; 54% female, 75% White, 13% Asian), mean baseline LV ejection fraction was 68±4% with abnormal measures of diastolic function. Compared with placebo, aficamten decreased LV ejection fraction (-4.6% [-5.5, -3.6]; P<0.001) at 36 weeks and increased LV volumes. Aficamten improved measures of diastolic function, including lateral e' and septal e' velocities, at 36 weeks (0.9 cm/s [0.6, 1.2] and 0.7 cm/s [0.4, 0.9], respectively; P<0.001 for both) and at end of treatment (0.9 cm/s [0.5, 1.2] and 0.9 cm/s [0.6, 1.1], respectively; P<0.001 for both) and septal E/e' by end of treatment (-1.4 [-2.1, -0.6]; P<0.001, respectively). Peak tricuspid regurgitation velocity improved at 36 weeks (-10.4 cm/s [-19.9, -1.0]; P=0.030) with a sustained effect through end of treatment. Left atrial volume index did not significantly improve at 36 weeks (-1.3 [95% CI, -2.6, 0.04]; P=0.06) but showed a trend towards improvement with longer treatment exposure (-1.7 [-3.2, -0.3]; P=0.022). Aficamten demonstrated incremental improvements in measures of LV structure and function compared to placebo as doses were increased, with improvement in diastolic indices evident by week 2 of titration. In patients with nonobstructive hypertrophic cardiomyopathy, aficamten improved echocardiographic measures of diastolic function. These findings suggest that the benefits of aficamten extend beyond the effects of LV outflow tract gradient reduction observed in prior studies. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06081894.

Transthyretin cardiac amyloidosis (ATTR-CM) is associated with poor prognosis and significant morbidity and mortality, yet existing staging systems have limited ability to accurately predict outcomes in contemporary patient populations. To develop and validate a machine learning (ML)-based prognostic model for patients with ATTR-CM. This multicenter cohort study, including specialized referral centers for cardiac amyloidosis, used data from patients with confirmed ATTR-CM in the Swiss Cardiac Amyloidosis Registry (February 2018 to November 2025) and the Cardiac Amyloidosis Registry of the Medical University of Vienna (July 2014 to February 2025). A random survival forest model was developed and evaluated through internal-external cross-validation, with each center iteratively held out for validation. The model was compared with the National Amyloidosis Centre and Mayo Clinic staging systems. Data analysis was conducted from December 2025 to February 2026. Clinical, demographic, medication, laboratory, and echocardiographic variables were used to train an ML-based time-to-event prediction model. The primary outcome was defined as a composite event of all-cause mortality and hospitalization for heart failure. A total of 850 patients (median [IQR] age, 79 [74-83] years; 750 [88.2%] male) were included across 3 cohorts (from Bern, Switzerland [Bern-Swiss cohort], n = 352; the other centers from Switzerland combined [Other-Swiss cohort], n = 260; and Vienna, Austria [Vienna cohort], n = 238). The random survival forest model demonstrated good discrimination across all held-out cohorts, with Harrell concordance indices of 0.74 (95% CI, 0.69-0.78), 0.77 (95% CI, 0.69-0.83), and 0.72 (95% CI, 0.67-0.77) for the Bern-Swiss, Other-Swiss, and Vienna cohorts, respectively, and 3-year area under the curve (AUC) of 0.73 (95% CI, 0.66-0.80), 0.80 (95% CI, 0.70-0.88), and 0.75 (95% CI, 0.67-0.83), respectively. The model showed improved discrimination compared with the National Amyloidosis Centre and Mayo Clinic staging systems, with Harrell concordance indices 2% to 10% higher and 3-year AUC improvements ranging from 3% to 19% across cohorts and scoring systems. Calibration was generally acceptable across cohorts and time points. Model performance remained satisfactory in the subgroup of patients receiving disease-modifying therapy. Explainability analyses identified clinically plausible drivers of risk. An ML-based time-to-event prediction model demonstrated promising predictive performance and showed improved discrimination compared with established staging systems in patients with ATTR-CM, supporting its potential for individualized prognostication.

Myocarditis is an important and frequently underrecognized cause of atrioventricular conduction disease and ventricular arrhythmias and may also be associated with atrial arrhythmias and sinus node dysfunction. Arrhythmic risk evolves over time as a result of the interplay between myocardial inflammation, fibrosis, and genetic predisposition. Despite its clinical relevance, guidance for the diagnosis, treatment, and follow-up of arrhythmias in myocarditis has remained limited. This consensus statement provides a structured framework for the management of arrhythmias in myocarditis and inflammatory cardiomyopathy (Infl-CMP), integrating disease phase and genetic background into clinical decision-making. It offers practical guidance across the disease spectrum, including diagnostic evaluation, therapeutic strategies, and longitudinal follow-up. The document was jointly developed by the European Heart Rhythm Association of the European Society of Cardiology (ESC) in collaboration with the Heart Failure Association of the ESC, the ESC Working Group on Myocardial & Pericardial Diseases, and the European Association of Preventive Cardiology of the ESC, together with the Heart Rhythm Society, the Asia Pacific Heart Rhythm Society, and the Latin American Heart Rhythm Society. Consensus advice is organized using a phase-aware framework distinguishing hot, hot-to-cold, and cold phases, with clinical consensus statements graded according to opinion-, observational-, or randomized trial-based evidence and supported by formal author voting. Arrhythmia management is stratified by disease phase. During active inflammation, antiarrhythmic therapy is combined with aetiology-targeted treatment or immunosuppression when indicated. In later stages, substrate-based strategies include pharmacological therapy, device implantation, or ablation. Emphasis is placed on hot-to-cold transition as an arrhythmogenic window and on risk stratification.

Cardiac hypertrophy is a major contributor to heart failure development, making its prevention and treatment critical for reducing heart failure-associated mortality. Although alternative splicing is recognized as a key regulatory mechanism in myocardial hypertrophy, the precise pathways involved remain incompletely defined. To investigate the role of MBNL2 (muscleblind-like protein 2) in the heart, we overexpressed MBNL2 in cardiomyocytes via adeno-associated virus serotype 9 delivery. In addition, cardiomyocyte-specific MBNL2 knockout mice were generated, and transverse aortic constriction surgery or isoproterenol injection was performed to induce cardiac hypertrophy and dysfunction in mice. The underlying mechanisms were further investigated using RNA sequencing, alternative splicing analysis, and RNA immunoprecipitation. MBNL2 expression was significantly increased in the heart tissues from patients with ischemic cardiomyopathy and in mice with cardiac hypertrophy. Cardiac-specific overexpression of MBNL2 induced cardiac hypertrophy and dysfunction. Mechanistically, MBNL2 promoted exon 9 skipping of TPM3 (tropomyosin 3), generating the TPM3 isoform lacking exon 9 (TPM3-Δe9). In neonatal mouse cardiomyocytes, TPM3-Δe9 knockdown partially reduced oxidative stress and mitigated mitochondrial damage induced by MBNL2 overexpression. Adeno-associated virus serotype 9-mediated knockdown of TPM3-Δe9 partially attenuated cardiac hypertrophy in MBNL2-overexpressing mice. Notably, cardiac-specific MBNL2 knockout or TPM3-Δe9 knockdown in mice attenuated cardiac dysfunction induced by transverse aortic constriction. Further, we found that elevated TPM3-Δe9 was associated with RNF20 (ring finger protein 20) and was accompanied by reduced RNF20 interaction with NCoR1 (nuclear receptor corepressor 1), increased NCoR1 expression, and decreased PPARα (peroxisome proliferator-activated receptor alpha) signaling. The protective effects of MBNL2 or TPM3-Δe9 knockdown in hypertrophic cardiomyocytes were partially reversed by treatment with the PPARα inhibitor GW6471. This study uncovers a novel, critical role for MBNL2 in pathological cardiac hypertrophy through regulation of TPM3 alternative splicing and mitochondrial function, highlighting MBNL2 as a potential therapeutic target for cardiac hypertrophy and dysfunction.

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 bound to and deubiquitinated sorting nexin 13 (SNX13), thereby stabilizing the SNX13 protein. SNX13 promoted 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 enhanced 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.

Arrhythmogenic right ventricular cardiomyopathy (ARVC) is an inherited cardiomyopathy characterized by progressive fibrofatty replacement of the right ventricular myocardium, ventricular arrhythmias, and an increased risk of sudden cardiac death. Pathogenic variants of desmosomal genes have been implicated in ARVC pathogenesis and may disrupt desmosomal protein function. However, whether and how desmosomal protein dysfunction directly activates cardiac fibroblasts to mediate fibrosis remains poorly understood. To address this, we combined genetic analysis with in vivo and cellular models to investigate the role of desmosomal dysfunction in cardiac fibrosis. The systematic genetic analysis revealed that desmosomal gene variants are predominant in ARVC, accounting for 67.4% of cases in cohort studies and 96.1% of pathogenic variants in ClinVar. We used desmocollin-2 (DSC2) knockout mice to recapitulate key features of ARVC, including right ventricular fibrosis, enlargement, and dysfunction. In vitro, DSC2 deficiency directly activates cardiac fibroblasts, resulting in increased cell proliferation, migration, and fibrosis marker expression. Further analysis identified transforming growth factor beta-2 (TGF-β2) as a critical signaling mediator in cardiac fibrosis of DSC2 deficiency-mediated ARVC. Mechanistically, DSC2 deficiency upregulated transcription factor 7 (TCF7) expression, promoting its binding to TGF-β2 promoter regions to enhance TGF-β2 transcription in cardiac fibroblasts. Pharmacological inhibition of TGF-β2 with pirfenidone (PFD) effectively attenuated cardiac fibrosis and improved right ventricular function in DSC2-deficient hearts. The results of the present study identified DSC2 deficiency-mediated TCF7-TGF-β2 signaling in cardiac fibroblasts, which contributed to ARVC development. Thus, targeting TGF-β2 signaling may be a promising therapeutic strategy for desmosome gene mutation-related ARVC.

Impaired branched-chain amino acid (BCAA) catabolism has been implicated in obesity cardiomyopathy (OCM), and systemic inhibition of branched-chain ketoacid dehydrogenase kinase (BCKDK), a key negative regulator of BCAA oxidation, improves cardiac function. However, whether cardiomyocyte-specific manipulation of BCAA catabolism is sufficient to confer cardioprotection remains unknown. Cardiomyocyte-specific BCKDK knockout and overexpression mouse models were generated and subjected to high-fat diet feeding, followed by echocardiography, transcriptomic, metabolomic, and molecular analyses. The mechanistic findings were further validated using in vitro experiments. Despite reduced myocardial BCAA levels, cardiomyocyte-specific BCKDK deletion unexpectedly exacerbated cardiac dysfunction and ventricular remodelling in OCM. Consistently, cardiac BCKDK expression was reduced in OCM. In contrast, cardiomyocyte-specific BCKDK overexpression improved cardiac function and remodelling, accompanied by a further reduction in myocardial BCAA levels, attenuation of mitochondrial oxidative stress, and suppression of MAPK-driven inflammatory signalling. Mechanistically, BCKDK reprogrammed mitochondrial metabolism to restrain oxidative stress. Moreover, mitochondrial ROS scavenging with MitoTEMPO alleviated mitochondrial dysfunction, and reversed the MAPK activation induced by BCKDK deficiency in vitro. These findings reveal an unexpected BCAA-independent role of BCKDK in preserving cardiomyocyte mitochondrial function and restraining inflammatory signalling in OCM. Our study identifies cardiomyocyte-intrinsic BCKDK as a potential therapeutic target, while cautioning against overestimating the cardioprotective effects of systemic BCKDK inhibition, which may be driven primarily by extracardiac mechanisms.

Cardiac aging involves progressive mitochondrial dysfunction, contributing to heart failure. Cardiolipin (CL), essential for mitochondrial function, is increasingly depleted in aging cardiomyocytes, promoting mitochondrial decline. Lysosomal degradation relies on v-ATPase (vacuolar-type H+-ATPase)-mediated acidification, and although lysosomes regulate phospholipid metabolism, their roles in CL homeostasis during aging remains unclear. This study examines whether v-ATPase dysfunction drives age-related cardiac changes by disrupting CL metabolism and mitochondrial function. To investigate underlying mechanisms and causality, we use RNA sequencing, targeted lipidomics, immunofluorescence microscopy, co-immunoprecipitation, proximity ligation assays, subcellular fractionation, mitochondrial respiration analysis and echocardiography, a cardiolipin synthase-1 (Crsl1) knockout mouse model, and 2 v-ATPase knockout models. In addition, we assess whether a nutraceutical intervention targeting v-ATPase dysfunction can mitigate heart failure in aging mouse models and elderly people. Our present findings reveal a sequence of events driving age-related cardiomyopathy: declining cardiac nicotinamide adenine dinucleotide levels impair v-ATPase-mediated lysosomal acidification by weakening the interaction between nicotinamide adenine dinucleotide-dependent glycolytic enzyme aldolase and v-ATPase. This disruption increases lysosomal membrane permeability by reducing lysosomal acidification, allowing cathepsin B to leak into mitochondria. There, cathepsin B disrupts mitochondrial CRLS1 (cardiolipin synthase I), impairing CL synthesis and remodeling. The resulting CL deficiency causes mitochondrial oxidative stress and programmed cell death, leading to mitochondrial and cardiac dysfunction. Genetic or chemical inhibition of v-ATPase and of CRLS1 in mouse models reproduce these age-related defects, highlighting their central roles in cardiac aging. Restoring nicotinamide adenine dinucleotide levels rescues lysosomal acidification and CL metabolism, protecting against age-related cardiomyopathy in rodents and humans. Augmenting v-ATPase-mediated lysosomal acidification offers novel therapeutic strategies to combat age-related cardiomyopathy by rewiring CL homeostasis.

Inflammatory cardiomyopathy (iCMP) is a leading cause of heart failure, with limited therapeutic options. Excessive cytokine levels are implicated in adverse outcomes, but their pathomechanism in iCMP is poorly understood. We sought to identify key cytokines involved in severe iCMP and elucidate their potential contribution to cardiomyocyte injury. Cytokines were analysed in patients with severe biopsy-proven iCMP (n = 63; LVEF ≤ 35%) and validated in a national cohort (n = 425). In vitro experiments examined the effect of the top cytokines observed in severe iCMP with regards to production of reactive oxygen species (ROS) and calcium homeostasis in induced human pluripotent stem cell-derived cardiomyocytes (iPSC-CMs) and human aortic endothelial cells (HAECs). Three proteins (COLEC-12, CRIM-1, IL-6) were associated with severe iCMP. In iPSC-CMs, these proteins increased ROS (H2DCFDA assay) and intracellular Ca2+ levels (Fluo-4AM assay), indicating cellular stress. Effects were less pronounced in HAEC. Finally, real-world data from electronic medical records suggested a possible cardioprotective effect of clinically available inhibitors targeting these cytokines, although these findings remain exploratory and require confirmation in controlled studies. COLEC-12, CRIM-1, and IL-6 are elevated in severe iCMP and induce oxidative stress and calcium dysregulation in cultured cardiomyocytes. These findings highlight their potential as possible future therapeutic targets. ClinicalTrials.gov Identifier: NCT04265040, NCT02187263.

From bench to bedside—how basic science in myosin function and structure informed the development of precision therapy for hypertrophic cardiomyopathy ELC, essential light chain; HCM, hypertrophic cardiomyopathy; KCCQ, Kansas City Cardiomyopathy Questionnaire; LV, left ventricular; LVOT, LV outflow tract; MyBPC, myosin-binding protein C; nonobs HCM, nonobstructive hypertrophic cardiomyopathy; NT-proBNP, N-terminal pro-B-type natriuretic peptide; NYHA, New York Heart Association Functional Classification; obs HCM, obstructive hypertrophic cardiomyopathy; RLC, regulatory light chain; S1, subfragment 1; S2, subfragment 2.

Screening endoscopy can be spared in patients with compensated cirrhosis when spleen stiffness measurement (SSM) by vibration-controlled transient elastography (VCTE) is ≤40 kPa, as they have a low probability of high-risk varices (HRV). Conversely, endoscopy is required in all patients with chronic portal vein thrombosis (PVT) without cirrhosis. The objective was to evaluate the performance of SSM-VCTE to exclude HRV in patients with chronic PVT. We retrospectively included patients with chronic PVT without cirrhosis, who underwent an upper endoscopy within 2 years before or after SSM-VCTE in 16 VALDIG centers, divided into a derivation and a validation cohort. 159 patients were included in the derivation cohort; 43% had HRV. 187 patients were included in the validation cohort; 32% had HRV. By univariable analysis, myeloproliferative neoplasm, ascites, hemoglobin, bilirubin, albumin, splenomegaly, portosystemic collaterals, liver stiffness - spleen diameter to platelet ratio score, liver stiffness measurement and SSM-VCTE were associated with HRV in both cohorts. By multivariable binary logistic regression analysis, only SSM-VCTE (p <0.005) remained associated with HRV in both cohorts. In the derivation cohort, SSM-VCTE ≤ 40 kPa had a sensitivity of 97% to rule out HRV, and could spare 41% of endoscopies, with 3% of HRV missed, and a 97% negative predictive value (NPV). In the validation cohort, SSM-VCTE ≤ 40 kPa could spare 43% of endoscopies, with 5% of HRV missed, and a 96% NPV. This study gathering a total of 346 patients with chronic PVT without cirrhosis showed that SSM-VCTE ≤ 40 kPa can be used to identify patients with a probability of HRV ≤5%, in whom endoscopy can be spared. Patients with chronic portal vein thrombosis who do not have cirrhosis usually have low liver stiffness measurement values; the liver stiffness cut-offs used to rule out high-risk varices in patients with cirrhosis cannot therefore be used in this population. We show here that spleen stiffness measurement by vibration-controlled transient elastography ≤40 kPa is able to identify patients with chronic portal vein thrombosis with a very low probability of high-risk varices, in whom screening endoscopy can be spared. Annual surveillance of spleen stiffness measurement could reduce the need for repeated screening endoscopies throughout a person's lifetime. This approach could enhance quality of life while also reducing risks associated with endoscopic procedures, particularly those related to anesthesia.

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.

Colchicine, an ancient anti-inflammatory alkaloid, has been successfully repurposed as a cardiovascular therapeutic agent. This review synthesizes the evolving clinical evidence and mechanistic underpinnings of colchicine's action across a spectrum of cardiovascular diseases. Robust data from randomized trials support its efficacy in reducing recurrences of acute and recurrent pericarditis. In atherosclerotic coronary artery disease, long-term, low-dose colchicine has been shown to significantly reduce major adverse cardiovascular events in patients with chronic coronary syndromes, prompting its inclusion in international guidelines. However, not all trials have yielded consistent results; for instance, in the setting of recurrent myocardial infarction, some studies have failed to demonstrate significant benefit, highlighting issues of reproducibility and patient heterogeneity that have emerged across cardiovascular outcome trials. Evidence for its utility in other settings, such as preventing postoperative atrial fibrillation or ischemia-reperfusion injury, remains inconsistent, and a clear dose-response relationship has yet to be established. The therapeutic benefits are primarily attributed to the pleiotropic anti-inflammatory mechanisms, including microtubule disruption, inhibition of the NLRP3 inflammasome, and modulation of neutrophil and macrophage functions. Despite a narrow therapeutic index, low-dose regimens are generally well-tolerated, with gastrointestinal disturbances being the most common adverse effect. Its pharmacokinetics, notably metabolism via CYP3A4 and transport by P-glycoprotein, necessitate caution regarding drug interactions and use in renal/hepatic impairment. Future research should focus on precise patient stratification, combination therapies, and exploring its potential in emerging cardiovascular indications, solidifying its role in anti-inflammatory therapy.

General population distributions of lipoprotein(a) (Lp(a)) are well-characterized. However, less is known about its distributions and associated event rates within high-risk populations, including individuals with atherosclerotic cardiovascular disease (ASCVD), chronic kidney disease (CKD) and varying levels of subclinical atherosclerosis and calcific aortic valve disease. Yet, such insights will facilitate clinical implementation of Lp(a) testing and enhance the design of clinical trials with Lp(a)-lowering agents. Data from 5,129 participants in the population-based Rotterdam Study were used to assess Lp(a) distributions, prevalence of Lp(a) levels exceeding thresholds used in ongoing trials (i.e. >150, >175, and >200 nmol/L), accompanying numbers needed to screen (NNS), and major adverse cardiovascular event (MACE) rates across high-risk groups. Lp(a) distributions were right skewed across all groups. Among participants with ASCVD, 13.5% (11.9-15.3%) had Lp(a) >150 nmol/L and 6.5% (5.3-7.8%) had >200 nmol/L, with corresponding NNS 7.4 and 15.4. Similar distributions were observed between participants with coronary artery calcium (CAC) score >300 and participants with coronary heart disease (CHD). Prevalence in participants with aortic valve calcification (AVC) scores >300 was double that of the general population: 20.2% (13.0-27.4) at >150 nmol/L and 11.8% (6.6-19.0) at >200 nmol/L, with the lowest NNS across all groups (5.0-8.5). MACE rates varied by group and increased progressively with higher Lp(a) thresholds. Lp(a) distributions and MACE rates substantially vary across high-risk groups in the general population. These findings can facilitate design and recruitment strategies of studies with emerging Lp(a)-lowering therapies, while also aiding in identification of populations who may benefit from such therapies.

Evolocumab, a PCSK9 (proprotein convertase subtilisin-kexin type 9) inhibitor, significantly reduced the risk of cardiovascular events in patients without previous myocardial infarction or stroke in the VESALIUS-CV trial (Effect of Evolocumab in Patients at High Cardiovascular Risk without Prior Myocardial Infarction or Stroke). However, mortality results have yet to be fully characterized. VESALIUS-CV was a double-blind study of 12 257 patients (median age, 66 years [interquartile range, 60-71]; 43% women) with qualifying atherosclerosis or high-risk diabetes without previous myocardial infarction or stroke, and low-density lipoprotein-cholesterol ≥90 mg/dL (or non-high-density lipoprotein-C ≥120 mg/dL or apolipoprotein B ≥80 mg/dL) who were randomized to evolocumab or placebo. Prespecified mortality outcomes of interest included all-cause mortality, subtypes of death (including cardiovascular [CV] and non-CV), and timing of events. Non-CV mortality was further investigated using multistate modeling to assess the contribution of prevention of nonfatal CV events (myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization) to non-CV mortality. Over a median of 4.6 years (interquartile range, 4.0-5.2), 973 (7.9%) patients died: 351 (36%) of CV causes, 497 (51%) of non-CV causes, and 125 (13%) of undetermined cause. All-cause mortality rates were 20% lower with evolocumab compared with placebo: 434 deaths (5-year Kaplan-Meier rate of 7.9%) with evolocumab versus 539 deaths (9.7%) with placebo (hazard ratio, 0.80, 95% CI, 0.70-0.91; P=0.0005). There was consistency of benefit for CV death (156 deaths [2.8%] versus 195 [3.6%]; hazard ratio, 0.79; 95% CI, 0.64-0.98), non-CV death (229 [4.2%] versus 268 [5.0%]; hazard ratio, 0.85; 95% CI, 0.71-1.01), and deaths of undetermined cause (49 [1.1%] versus 76 [1.4%]; hazard ratio, 0.64; 95% CI, 0.45-0.92). Results were consistent regardless of age, sex, region, race, qualifying atherosclerosis or high-risk diabetes, baseline low-density lipoprotein-cholesterol, or background lipid therapy. Postrandomization nonfatal myocardial infarction, ischemic stroke, and ischemia-driven arterial revascularization were associated with increased risk of subsequent non-CV death within the next 4 years, with the majority occurring during the first year after the event. Multistate modeling suggested the observations regarding non-CV death with evolocumab was largely (78%; bootstrap interquartile range, 71-92%) driven by the prevention of antecedent nonfatal CV events. These results support using evolocumab to improve survival in high-risk patients who have not experienced a previous myocardial infarction or stroke, including those with high-risk diabetes without qualifying atherosclerosis with low-density lipoprotein-cholesterol ≥ 90 mg/dl (or non-high-density lipoprotein-cholesterol ≥ 120 mg/dl or apolipoprotein B ≥ 80 mg/dl). URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.

To evaluate the association between cardiorespiratory fitness (CRF), directly measured as peak oxygen uptake (VO2peak), and the risk of major adverse cardiovascular events (MACE) in older Norwegian adults. A total of 1547 individuals aged 70-77 years (784 women) from the Generation 100 Study, examined in 2012 and 2013, were studied. We defined MACE as the first occurrence of acute myocardial infarction, stroke, heart failure, or cardiovascular death. Sex- and cohort-specific VO2peak categories (20% least fit, 80% fit) were established based on baseline VO2peak and changes over one year. Associations between baseline VO2peak, one-year fitness trajectories, and MACE were assessed using competing risk regression to estimate subdistribution hazard ratios (sHRs) and 95% confidence intervals (CIs). During follow-up (median, 10.0 years; IQR, 9.2-10.0 years), 294 individuals experienced MACE (185 men, 109 women). Higher baseline VO2peak was inversely associated with MACE in both sexes. Compared with unfit participants, those with a VO2peak ≥26.0 mL/kg/min in men and ≥22.2 mL/kg/min in women had lower risk of MACE (men: sHR, 0.76; 95% CI, 0.54-0.99; women: sHR, 0.59; 95% CI, 0.39-0.90). Compared with those who remained unfit over one year, men and women who remained fit had 36% (sHR, 0.64; 95% CI, 0.42-0.99) and 42% lower risk (sHR, 0.58; 95% CI, 0.33-0.99), respectively. In older Norwegian adults, higher CRF was inversely associated with long-term risk of MACE. Although external validation is needed, the cohort-specific lowest quintile VO2peak cut-points of 26.0 mL/kg/min in men and 22.2 mL/kg/min in women may aid cardiovascular risk stratification in older adults.

Inherited variants in the LDL (low-density lipoprotein) receptor (LDLR) gene are the most common cause of familial hypercholesterolemia, significantly increasing coronary artery disease risk. Early identification of pathogenic LDLR variants enables prompt lipid-lowering therapy and cascade testing of at-risk relatives; however, most LDLR variants observed in the population have uncertain or absent clinical classifications, leaving many patients without actionable information. We developed the first activity-normalized prime editing screening pipeline to measure the impact of 5184 LDLR coding variants on LDL-cholesterol (LDL-C) uptake. Each prime editing guide RNA is paired with a genotypic outcome reporter to correct for variable editing efficiency, overcoming a key limitation of previous pooled genome editing screens. A statistical framework further improves variant effect estimates by jointly analyzing all missense variants at each amino acid position. We show that prime editing of the reporter construct correlates with endogenous variant installation frequency, validating the activity normalization approach. The resulting scores capture a continuous spectrum of functional effects, robustly separate pathogenic versus benign ClinVar variants, and show concordance with LDL-C levels in UK Biobank participants. We calibrate functional evidence strengths to the ACMG/AMP variant interpretation framework, enabling integration into a clinical variant classification workflow. By combining functional, computational, population, and contextual evidence, 322 of 434 LDLR variants currently classified as variants of uncertain significance, conflicting, or absent from ClinVar appear to meet evidence thresholds for reclassification and can be prioritized for expert review, substantially expanding the pool of actionable variant classifications. The screen also reveals a cluster of gain-of-function variants in LDLR class A repeat 5, at least some of which enhance LDL-C uptake through increased apolipoprotein B interaction, with implications for therapeutic genome editing. Last, prime editing uniquely detects splice-altering coding variants missed by cDNA-based screens and pathogenicity predictors, revealing an advantage of endogenous variant installation. Altogether, activity-normalized prime editing provides a scalable framework for LDLR variant classification that substantially expands the proportion of variants with evidence for genetic diagnosis and reveals novel biology with therapeutic relevance.

Metabolic syndrome is a global health concern characterized by obesity, insulin resistance, dyslipidemia, and hypertension - all of which increase risk of cardiovascular diseases and type 2 diabetes. CO-releasing molecules (CORMs) deliver low amounts of CO in vivo and have been reported to improve metabolic parameters in obese mice by inducing a transient mitochondrial uncoupling and improving insulin resistance. CO reduces oxygen-binding capacity of hemoglobin, which may cause tissue hypoxia and mediate metabolic alterations through the hypoxia-inducible factor (HIF) pathway. This study: 1) Analyzes whether the beneficial metabolic effects of CORMs are mediated by the HIF pathway, and 2) Evaluates the metabolic effects of long-term CORM-401 treatment in high-fat diet-fed mice. A 7-week-treatment of CORM-401 elicited a metabolic phenotype characterized by significantly reduced body weight and white adipose tissue (WAT) mass, increased energy expenditure and glucose tolerance, and higher LDL + VLDL cholesterol levels. CORM-treatment triggered lactatemia-induced metabolic acidosis which was compensated through increased respiration. No toxicity or organ damage was seen. HIF target mRNA levels were positively associated with carboxyhemoglobin levels in the CORM-401-treated tissues. CORM-401-treated mice exhibited elevated serum corticosterone levels, which showed associations with metabolic mRNAs in WAT and liver. These findings suggest a dual mechanism: glucocorticoid-driven stress activation as the primary mechanism accompanied by a low-grade, tissue specific HIF engagement underlying the observed metabolic effects of the CORM-401 treatment. Despite the mild beneficial effects on metabolism, the systemic hormonal effects of the long-term CORM-401 treatment warrant caution when evaluating its potential as a therapeutic for metabolic disorders.

Host-microbiota co-metabolism of tryptophan is increasingly recognized as a critical nexus linking diet, gut microbiota, immune function, serving as a core regulatory network governing cardiovascular function and systemic homeostasis. Its catabolism in vivo mainly proceeds through three distinct pathways: the kynurenine pathway, the serotonin pathway, and the gut microbiota-mediated indole pathway. Tryptophan metabolites exert multifaceted physiological and pathophysiological effects on the cardiovascular system via diverse specific receptors and non-receptor signaling pathways. Numerous clinical and basic studies have confirmed that the tryptophan metabolic network plays a dual role in the progression of cardiovascular diseases (CVDs), including atherosclerosis, myocardial ischemia/reperfusion injury, and heart failure. However, existing studies have largely focused on individual pathways or isolated metabolites, and an integrated, systematic view of the entire tryptophan metabolic network in CVDs remains lacking. This review summarizes the tryptophan metabolic pathways, the physiological effects of tryptophan metabolites including potential therapeutic targets, and their impacts on cardiovascular diseases. Furthermore, based on the complex pathophysiological regulatory mechanisms of tryptophan metabolism, we systematically elaborate therapeutic strategies including dietary intervention, gut microbiota modulation, and targeted pharmacological intervention against rate-limiting enzymes and core receptors. These multidimensional approaches hold promise for reshaping the tryptophan metabolic axis and providing novel therapeutic paradigms for the management and treatment of CVDs.

Population aging is increasing atrial fibrillation (AF) prevalence. In elderly patients with persistent AF, pulmonary-vein isolation (PVI) has limited success, but is widely used. Pacemaker-implantation with atrioventricular-node ablation (PM+AVNA) provides effective symptom control, but the relative effects of PM+AVNA versus PVI on hospitalisations and other outcomes in the elderly remain unknown. This investigator-initiated, multicentre, open-label trial randomised patients aged≥75 years with symptomatic persistent AF and normal left-ventricular ejection fraction to PM+AVNA or PVI treatment-strategies. The primary endpoint was a composite of hospitalisation for atrial arrhythmia or heart failure, outpatient electrical cardioversion or upgrade to cardiac resynchronisation therapy for left-ventricular dysfunction. Secondary endpoints included all-cause death, stroke, treatment-related complications and quality of life. Twelve centres in Germany and Austria randomised 196 patients (median age 82 years). At 12 months, a first primary endpoint event occurred in 24 of 98 patients (24%) assigned to PM+AVNA and 45 of 98 patients (46%) assigned to PVI (hazard ratio 0.45, 95% confidence interval 0.27 to 0.74; P=0.002). A total of 29 and 84 primary endpoint events occurred respectively, consisting principally of AF-hospitalisations and cardioversions in the PVI group (54 and 19 respectively, vs 3 and 1 in PM+AVNA group) and of heart failure-hospitalisations in the PM+AVNA Group (23, vs 11 in PVI group). The incidence of cardiovascular complications and mortality, as well as qualityof-life, were not statistically different. In elderly patients with persistent AF, PM+AVNA was associated with fewer primary endpoint events than PVI over a 12-month follow-up period.

The optimal long-term antithrombotic strategy after left atrial appendage occlusion (LAAO) remains undetermined. The present study aimed to investigate whether half-dose rivaroxaban (10 mg daily) could better reduce silent cerebral embolic lesions (SCEs) and preserve cognitive function compared to antiplatelet therapy after successful LAAO. In this investigator-initiated, prospective, multicenter, randomized controlled trial, patients with successful LAAO confirmed 45 days post-procedure were assigned 1:1 to half-dose rivaroxaban or antiplatelet therapy group. Diffusion-weighted magnetic resonance imaging and cognitive assessments were repeated at 90, 180 and 365 days after LAAO. The primary outcome was the patient-level incidence of any newly detected SCE during follow-up. Secondary outcomes included cognitive trajectories, SCE burden, and a composite of all-cause mortality, clinical thromboembolic events and major bleeding. Between December 2022 and February 2025, 164 patients were randomized. The patient-level incidence of new SCEs was significantly lower in the half-dose rivaroxaban group than in the antiplatelet therapy group (10/82 [12.2%] vs. 26/82 [31.7%]; P = 0.005). At 365 days, model-derived between-group differences favored the half-dose rivaroxaban group for both Mini-Mental State Examination (2.56; 95% confidence interval [CI] 1.11-4.01; P < 0.001) and Montreal Cognitive Assessment (2.67; 95% CI 1.07-4.26; P = 0.001) scores. The composite clinical outcome occurred in 2.4% of the half-dose rivaroxaban group vs. 11.0% of the antiplatelet therapy group (P = 0.057). In patients eligible for oral anticoagulation after successful LAAO, rivaroxaban 10 mg daily significantly reduced SCEs and better maintained cognitive function compared with antiplatelet therapy, with numerically fewer composite clinical events.

Adherence with a holistic or integrated care management of atrial fibrillation (AF) based on the AF better care (ABC) pathway has been associated with improved clinical outcomes. Two prospective randomized trials (mAFA and MIRACLE-AF) have evaluated this approach. The multicentre mAFA-II trial delivered the ABC pathway via mobile health using an mAFA App, while the MIRACLE-AF trial relied on village doctors supported by telehealth in rural communities. We conducted a pooled analysis of individual participant data to assess the overall efficacy of ABC pathway-based management in patients with AF. We combined patient-level data from the mAFA-II and MIRACLE-AF trials. The primary endpoint was defined as a composite of all-cause mortality, ischaemic stroke, haemorrhagic stroke, heart failure (HF), acute coronary syndrome (ACS), and major bleeding events. The secondary endpoints included individual components and two grouped outcomes: all stroke and HF/ACS. A one-stage marginal Cox proportional hazards model stratified by trial and with robust standard errors clustered at the site level was used, with adjustment for CHA2DS2-VASc and other clinically relevant baseline variables. Cumulative event rates were estimated using Kaplan-Meier methods. Subgroup and sensitivity analyses were conducted to assess the robustness of the findings. Between-trial heterogeneity was further explored using a two-stage approach, incorporating trial-level effect estimates and inverse-variance weighting. We studied 4363 patients with AF [mean age 70.3 (SD 12.8) years; 60.5% male]. During 0.8 [SD 0.4] years of follow-up, the primary endpoint occurred in 329 (7.5%). Kaplan-Meier curves demonstrated lower cumulative incidence of events in the intervention group. On multivariable mixed-effects Cox models, the intervention group demonstrated a significantly lower risk of the primary endpoint compared to the control group (adjusted hazard ratio: 0.72; 95% confidence interval: 0.56-0.93). Subgroup analyses suggested potential effect modification, whereas sensitivity analyses consistently supported the primary findings. A two-stage analysis showed directionally consistent effects across trials for the primary endpoint. In this pooled individual participant data from two prospective randomized trials, ABC pathway-based integrated care was associated with improved clinical outcomes in patients with AF vs. usual care, with the observed benefit primarily driven by reductions in HF/ACS-related events rather than classical AF-specific outcomes, supporting further implementation studies and context-specific adoption in clinical practice.

Randomized trials demonstrated that in patients with atrial fibrillation (AF) undergoing percutaneous coronary intervention (PCI) direct oral anticoagulants (DOAC) and a P2Y12 inhibitor reduce bleeding compared with vitamin K antagonist (VKA) plus dual antiplatelet therapy (DAPT) with no increase in ischemic risk; however, important gaps in knowledge remain, limiting certainty and generalizability of these findings. In this patient-level meta-analysis of randomized trials evaluating antithrombotic strategies in patients with AF undergoing PCI, Cox proportional hazard models, stratified by trial, were used to estimate hazard ratios and 95% confidence intervals (HR, 95%CI). The primary efficacy and safety outcomes were the composite of cardiovascular death, myocardial infarction, or stroke, and TIMI major bleeding, respectively. The study was registered in PROSPERO (CRD420251130025). Six trials (10,634 patients) comparing DOAC plus P2Y12 inhibitor (4,083), VKA plus single antiplatelet therapy (SAPT, 1,247), VKA plus DAPT (3,715), and DOAC plus DAPT (1,589) were included. The transition from DAPT to SAPT was recommended at 1 (1-3) and 3 (1-7) days in the DOAC plus P2Y12 inhibitor and VKA plus SAPT groups, respectively. At 1 year, the risk of the primary efficacy outcome did not differ across the antithrombotic strategies (reference group: VKA plus DAPT; DOAC plus P2Y12 inhibitor: HR 1.16, 95%CI 0.97-1.41; VKA plus SAPT: 1.14, 0.85-1.54, DOAC plus DAPT: 0.99, 0.75-1.30), without any statistically significant interaction between treatment effects and all prespecified subgroups, including age, sex, bleeding risk, and thrombotic risk. However, 14-day landmark analysis showed an increased risk of myocardial infarction and definite/probable stent thrombosis in patients receiving DOAC plus P2Y12 inhibitor or VKA plus SAPT in the early phase after PCI. DOAC plus P2Y12 inhibitor reduced the risk of the primary safety outcome compared with VKA plus DAPT (0.48, 0.38- 0.65) and VKA plus SAPT (0.62, 0.40-0.97); only a borderline reduction was observed compared to DOAC plus DAPT (0.66, 0.44-1.01). DOAC plus P2Y12 inhibitor reduced intracranial hemorrhage compared with VKA plus DAPT (0.21, 0.07-0.64). In patients with AF undergoing PCI, the risk of cardiovascular death, myocardial infarction, or stroke did not significantly differ according to whether patients received a DOAC or VKA, whereas a modest increase in risk with single compared with dual antiplatelet therapy cannot be excluded, given the higher risk of early coronary events. DOACs compared with VKAs reduced the risk of bleeding across all severity grades, including intracranial hemorrhage, whereas omission of a second antiplatelet agent reduced the risk of TIMI major or minor bleeding.

Hypokalaemia and low-normal plasma potassium levels are associated with increased risk of atrial fibrillation. This study examined if potassium-increasing treatment reduces the risk of atrial fibrillation-related clinical events. This is a prespecified analysis of the POTCAST trial. Adults with an implantable cardioverter-defibrillator (ICD) or cardiac resynchronization therapy-defibrillator (CRT-D) and plasma potassium ≤4.3 mmol/L were randomized to potassium-increasing treatment and standard care (high-normal potassium group) or standard care alone (control group). The endpoint was a composite of acute hospitalizations due to atrial fibrillation leading to a change in pharmacological treatment or due to inappropriate shock therapy, hospitalization for electrical cardioversion or ablation of atrial fibrillation, and loading with amiodarone for atrial fibrillation. The endpoint was evaluated in time-to-first-event analyses with death as competing risk. Among 1200 participants [600 in each group, median age 64 years (interquartile range, 56-72), 80.3% male], 390 (32.5%) had a history of atrial fibrillation. Plasma potassium increased by .3 mmol/L after uptitration in the high-normal potassium group compared with the controls. After a median follow-up of 3.3 person-years, the endpoint had occurred in 48 participants in the high-normal potassium group (8.0%, 2.80 events per 100 person-years), when compared with 73 participants in the control group (12.2%, 4.30 events per 100 person-years) (subdistribution hazard ratio, .65; 95% confidence interval, .45-.93, P = .02). The treatment effect appeared similar across subgroups, including those with vs without a history of atrial fibrillation. In adults with any cardiac disease, treated with an ICD or CRT-D, uptitration of plasma potassium levels within the normal range reduced the risk of atrial fibrillation-related clinical events.

The selection of the optimal antithrombotic regimen in patients with atrial fibrillation and acute coronary syndrome remains challenging. Previous trials have demonstrated that dual antithrombotic therapy (DAT), consisting of direct oral anticoagulants (DOACs) plus a P2Y12 inhibitor, reduces bleeding compared to a triple-therapy regimen using vitamin K antagonists. However, subsequent meta-analyses have suggested an increased risk of ischemic events with DAT, particularly within the first month of treatment. Clopidogrel has been the predominant P2Y12 inhibitor used across these studies, despite the risk of high on-treatment platelet reactivity when using this drug. In this study, we conducted an open-label, randomized controlled trial (EPIDAURUS) in patients with atrial fibrillation and acute coronary syndrome, designed to assess the efficacy and safety of a 1-month regimen of DOAC plus potent P2Y12 inhibitor (prasugrel or ticagrelor) compared to DOAC plus clopidogrel and in-hospital aspirin. The primary outcomes of the trial were an efficacy endpoint, recurrent ischemic events and safety endpoints, including death and major bleeding, which were evaluated 6 weeks after randomization using separate win-loss ratio analyses. The study was prematurely terminated after enrollment of 602 patients (154 female) of an expected 1,474 patients, owing to safety concerns raised by the Data and Safety Monitoring Board. Exploratory analyses of secondary safety endpoints, including bleeding type ≥2 and ≥3 according to the Bleeding Academic Research Consortium scale, revealed that, compared to clopidogrel and in-hospital aspirin, treatment with a potent P2Y12 inhibitor was associated with higher bleeding rates without a clear reduction in the risk of ischemic complications. These findings do not support the routine use of potent P2Y12 inhibitors in combination with DOACs in this patient population. ClinicalTrials.gov identifier: NCT04981041 .

Major bleeding remains a major barrier to optimal anticoagulation in patients with atrial fibrillation (AF). We aimed to develop and externally validate a weighted score that balances simplicity and prediction for 1-year major bleeding prediction. Using prospective multinational GLORIA-AF Phase II/III data, we developed the GLORIA-AF Bleeding Weighted Risk Score using LASSO-penalized regression with stability selection, coefficient-rescaling and internal validation. The score was externally evaluated in EORP-AF and APHRS-AF registries. Discrimination, calibration and clinical benefit were assessed using C-index, observed-to-expected ratio, calibration plot and decision-curve analysis, and compared with HAS-BLED, unweighted GLORIA-AF score and full multivariable Cox model. Among 20,250 eligible derivation cohort patients (69.9 [10.3] years; 9,092 female [44.9%]), 317 (1.6%) had major bleeding during 1-year follow-up. The derived score ranges from 0 to 22, with the highest weight (5) assigned to age >65 years, followed by abnormal kidney function (3). The derived score achieved C-index of 0.688 (95% CI: 0.660-0.717), outperforming HAS-BLED (C-index: 0.631, 95% CI: 0.604-0.658; P < 0.001), while preserving discrimination comparable to full multivariable regression (C-index: 0.690; 95%CI: 0.661-0.719; P = 0.084). Calibration was good (O:E ratio: 0.996) and DCA showed greater net benefit than HAS-BLED across 1% to 3% thresholds. Among 9,752 external validation patients, 148 (1.5%) had major bleeding. The derived score achieved C-index of 0.674 (95% CI: 0.643-0.705; P < 0.001), with better discrimination, calibration and clinical benefit than HAS-BLED. The GLORIA-AF Bleeding Score showed modestly higher discrimination than HAS-BLED for 1-year major bleeding prediction while retaining clinical interpretability and usability. External validation in independent European and Asia-Pacific registries further supports its transportability beyond the derivation population.

Atrial fibrillation (AF), the most common cardiac arrhythmia, affects one in three adults over 45 years of age. Improving its treatment requires a better understanding of bi-atrial anatomy. Existing benchmarks have focused on the left atrial (LA) cavity, overlooking the fundamental challenges posed by bi-atrial anatomy, most notably the thin atrial walls, which are critical for substrate-guided ablation planning in patients with atrial fibrillation. To address these limitations, the Multi-class Bi-Atrial Segmentation 2024 Challenge (MBAS2024) introduced the first large-scale, multi-class benchmark for simultaneous segmentation of the LA cavity, right atrial (RA) cavity, and bi-atrial walls from late gadolinium-enhanced (LGE) MRI. We systematically evaluated 13 state-of-the-art methods on the world's largest curated bi-atrial dataset, comprising 175 3D multi-center scans with expert-validated annotations, providing a comprehensive assessment of current methodological capabilities and limitations. Key findings include: segmentation of the LA and RA cavities is generally robust to image quality, whereas atrial wall delineation is highly sensitive to image degradation. Performance varies across centers, indicating limited generalization of atrial wall segmentation across different acquisition protocols. Model architecture, rather than hyperparameter tuning, is the primary driver of performance, with U-Net-based models and emerging state-space models (e.g., UMambaBot) achieving higher accuracy at modest computational cost. Segmentation accuracy also varies along the slice dimension, with central slices segmented more reliably. Finally, hybrid labeling strategies-separating LA and RA cavities while merging bi-atrial walls into a single class-consistently improve performance. The MBAS2024 challenge establishes a foundational benchmark for bi-atrial segmentation, providing validated baselines and actionable insights to guide the development of clinically relevant, efficient, and anatomically aware segmentation algorithms to improve targeted ablation in patients with AF.

Dissipation of body heat, essential to human life, is largely achieved through sweating. If sweating does not occur normally-as in patients with hypohidrosis (reduced sweating) or anhidrosis (lack of sweating)-the ability to dissipate heat via evaporative mechanisms is overwhelmed. Body temperature may rise, leading to heat-related illness, including heat intolerance, hyperthermia, heat exhaustion, heat stroke, and even death. In patients seen by a dermatologist, anhidrosis may underly and contribute to their symptoms and signs but may be difficult to detect given a limited availability of tools to measure anhidrosis. An association between anhidrosis and skin symptoms including flushing syndromes (eg, facial flushing and erythromelalgia) and widespread skin symptoms (eg, itching, burning, numbness, or tingling, and paresthesias) has recently been described. This review explores the existing dermatologic literature on anhidrosis including clues to the pathophysiology of these disorders, its relationship to skin diseases and symptoms, the tests currently available, and approaches to management. Recognition of an underlying anhidrosis by dermatologists may be important for providing optimal management for patients with heat-related symptoms.

Giant cell arteritis is associated with increased cardiovascular risk, potentially related to systemic inflammation, vascular injury, and glucocorticoid exposure. Whether steroid-sparing therapies differentially influence cardiovascular outcomes in giant cell arteritis remains uncertain. We conducted a nationwide observational cohort study emulating a target trial using the French National Health Data System from January 1, 2012, to December 31, 2024. We included patients hospitalized for incident giant cell arteritis who initiated tocilizumab or methotrexate within 6 months after discharge. The primary outcome was the first major adverse cardiovascular event, defined as any coronary event, ischemic stroke, or all-cause death. Treatment effects were estimated with a clone-censor-weight approach with inverse probability of censoring weighting. We estimated 2-year cumulative incidences, absolute risk differences, and hazard ratios with 95% CIs. In 1997 patients with incident giant cell arteritis (mean age, 73.1±8.3 years; 70.4% women), 1095 initiated tocilizumab and 902 initiated methotrexate within 6 months after discharge. At 2 years, the cumulative incidence of major adverse cardiovascular events was 6.4% (95% CI, 4.9%-7.9%) with tocilizumab and 10.7% (95% CI, 8.4%-12.9%) with methotrexate (risk difference, -4.3% [95% CI, -6.6% to -1.7%]). Tocilizumab initiation was associated with a lower risk of major adverse cardiovascular events (hazard ratio, 0.60 [95% CI, 0.48-0.75]), driven by fewer coronary events (hazard ratio, 0.55 [95% CI, 0.37-0.84]) and all-cause deaths (hazard ratio, 0.53 [95% CI, 0.36-0.74]). Results were consistent in sensitivity analyses using alternative grace periods, corticosteroid dose thresholds, restriction to the 2017 to 2024 period, and a per-protocol-analogous approach. Negative control outcomes did not differ meaningfully between treatment strategies. In this nationwide target trial emulation of incident giant cell arteritis, initiation of tocilizumab was associated with a lower risk of major adverse cardiovascular events compared with methotrexate, primarily through a reduction in coronary events and all-cause deaths. URL: https://www.clinicaltrials.gov; Unique identifier: NCT07459335.

Excitability is a fundamental dynamical paradigm underlying both local and collective activity across a broad range of living systems, from neurons and cardiomyocytes to pancreatic β-cells, cancer cells, and the emerging field of network physiology. This review summarizes the current state of research on coherence-incoherence patterns in coupled excitable systems, covering theoretical advances and experimental evidence for their roles in physiological and pathological processes. Particular emphasis is placed on how excitable dynamics modifies the mechanisms of pattern formation relative to coupled oscillator networks, highlighting the importance of inhibitory/repulsive interactions and the constructive role of noise through phenomena such as coherence resonance, in generating pattern classes characteristic of excitable media, including bumps, patched patterns, and noise-facilitated chimera states. We further discuss how existing theoretical concepts can be extended to biological systems characterized by heterogeneous local dynamics, complex coupling architectures, and metastable behavior. In addition, we survey state-of-the-art electrophysiological and optical imaging techniques for observing coherence-incoherence patterns and assess current evidence linking them to sleep, cognition, spatial navigation, epilepsy, cardiac arrhythmia, pancreatic islet dynamics, and cancer progression. Finally, we outline major open challenges, including characterization of chaos, long-term dynamics and finite-size effects, experimental validation, control of pattern emergence/termination and switching, and the development of biologically realistic theoretical frameworks.

Magnetic resonance imaging (MRI) is a cornerstone of neurological care, serving as the gold standard for diagnosing pathologies, such as brain tumors and, together with computed tomography, stroke. However, the high capital costs, specialized infrastructure requirements such as expensive and bulky radiofrequency-shielding cages, and the operational complexity of conventional high-field scanners (1.5T and 3T) largely confine MRI to centralized imaging facilities. This scenario often leads to reliance on brain computed tomography or ultrasound in point-of-care settings, despite MRI's superior soft-tissue contrast for diagnosis and prognosis. In the past decade, there has been renewed interest in compact and simplified ultra-low-field (under 0.1T) MRI scanners, fueled by advances in engineering and computing. Here, we review the recent developments in ultra-low-field brain MRI, which enable imaging in open environments and demonstrate initial clinical applicability in point-of-care settings. We also envision future developments along 3 focus areas (ie, hardware, imaging protocols, and data-driven image formation and analysis) to address the current limitations of image quality and contrast in ultra-low-field brain MRI systems.

Ischemia-reperfusion (I/R) injury is a major cause of tissue damage after myocardial infarction and ischemic stroke. Ferroptosis is an iron-dependent form of regulated cell death (RCD) marked by phospholipid peroxidation, and it is an important contributor to I/R-related injury. Although oxidative stress and lipid peroxidation are common features of I/R injury, they do not fully explain why ferroptosis sensitivity increases during reperfusion. Recent studies have shown that ferroptosis is also influenced by the ubiquitin system. Changes in ubiquitination and deubiquitination regulate key proteins involved in iron metabolism, lipid remodeling, and antioxidant defense, thereby altering cell susceptibility to ferroptosis under I/R stress. This review summarizes current evidence showing how ubiquitin-dependent regulation controls ferroptosis in both cardiac and cerebral I/R injury. We focus on mechanisms that disrupt iron homeostasis, weaken antioxidant defenses, increase oxidation-sensitive membrane lipids, and alter organelle stress responses. We also highlight the shared mechanisms in the heart and brain, while noting that the main ubiquitin-regulated control points differ between these tissues. In addition, we discuss emerging therapeutic strategies targeting selected E3 ubiquitin ligases and deubiquitinating enzymes. A better understanding of the ubiquitin-ferroptosis axis may support the development of more precise therapies for ischemic injury in the cardiovascular and cerebrovascular systems.

N-methyl-D-aspartate receptors (NMDARs) mediate excitatory signaling essential for synaptic plasticity and memory. Unlike GluN2-containing NMDARs, GluN3-containing receptors are activated solely by glycine and exhibit profound desensitization and paradoxical potentiation by GluN1-selective antagonists, including CGP-78608 (CGP). Although GluN3A-containing NMDARs regulate synapse pruning and excitotoxicity, and are associated with schizophrenia, autism and stroke, their native stoichiometry and gating mechanism are poorly defined. Here, using single-molecule pull-down analysis, we show that native GluN3A-containing receptors are diheteromeric assemblies. Cryogenic-electron microscopy analysis of GluN1-GluN3A receptors in antagonist-bound, preactive, active and desensitized states, augmented by electrophysiology and pharmacology experiments, show how glycine activates the receptor solely via GluN3A-dependent conformational changes, opening the gate with two-fold symmetry, and induces a roughly four-fold symmetric desensitized state. CGP-bound GluN1 restricts GluN3A rotation, promoting glycine-induced activation by blocking desensitization. These findings illuminate how CGP potentiates GluN1-GluN3A receptor activity, place the receptor gating mechanism on a structural foundation and define the molecular basis for pharmacological modulation.

Hypertrophic cardiomyopathy (HCM) has traditionally been considered a Mendelian disease driven by pathogenic or likely pathogenic variants in sarcomere-encoding genes (SARC-HCM-P/LP). However, these variants explain only one-third of cases, and variable penetrance suggests additional polygenic contributions. Existing HCM polygenic risk scores (PRSs), largely derived from European-ancestry cohorts, have limited generalizability. Here we develop a multiancestry PRS using summary statistics from the BioBank Japan, Million Veteran Program and a meta-analysis of seven European-ancestry cohorts and evaluate its association with HCM in a USA-based multiancestry population. Individuals with the highest PRS quintile had a 2.11-fold increased risk of HCM in the overall population and nearly 70-fold higher risk among SARC-HCM-P/LP carriers. The PRS improved risk stratification and showed trends toward improved ancestry-specific prediction. Among individuals with HCM, a higher PRS was also associated with adverse cardiovascular outcomes. These findings support the integration of multiancestry PRSs into HCM risk assessment and prognostication.

Takotsubo syndrome (TTS) closely mimics acute coronary syndrome (ACS). Early differentiation remains challenging because diagnosis currently relies on medical, psychiatric, and neurological history, repeated cardiac imaging, and exclusion of a culprit epicardial coronary artery lesion, generally with invasive coronary angiography (ICA). The aim of this study was to develop and externally validate a biomarker-based diagnostic score supporting the early differentiation of TTS from ACS before ICA. In this study, 3615 patients with ACS or TTS from overlapping registries were investigated. Circulating levels of established and emerging cardiovascular biomarkers were measured before ICA. A biomarker-based diagnostic score for TTS (BioTAK) was developed in a cohort of 1823 patients (ACS n = 1754; TTS n = 69) using machine learning-guided feature selection and logistic regression and externally validated in an independent cohort of 1792 patients (ACS n = 1715; TTS n = 77). The final five-item score incorporated biomarkers reflecting myocardial stress (N-terminal pro-B-type natriuretic peptide), vasoconstriction and anxiety regulation (peptidylglycine α-amidating monooxygenase), atherosclerotic plaque instability (soluble lectin-like oxidized low-density lipoprotein receptor-1), and lipid metabolism (low-density lipoprotein cholesterol), along with sex. BioTAK demonstrated excellent discrimination between TTS and ACS in the development cohort [area under the receiver operating characteristic curve (AUC) .97, 95% confidence interval (CI) .95-.98] and maintained high performance on external validation (AUC .93, 95% CI .90-.96), with good calibration. Using predefined rule-in and rule-out thresholds, the score stratified almost 90% of patients to a likely diagnosis prior to ICA. TTS is characterized by a distinct biomarker profile reflecting pathophysiological differences from ACS. The non-subjective biomarker-based BioTAK score can support the early identification of TTS, help streamline diagnostic pathways, and might reduce potentially avoidable invasive procedures in patients presenting with suspected ACS. NCT01000701, NCT01947621.

Nonobstructive hypertrophic cardiomyopathy (nHCM) is associated with significant morbidity with no approved treatment. Aficamten is a cardiac myosin inhibitor targeting excess contractility and diastolic impairment, the predominant mechanism responsible for adverse outcomes in nHCM. In the ACACIA-HCM trial (Assessment Comparing Aficamten to Placebo on Cardiac Endpoints in Adults With Non-Obstructive HCM; URL: https://www.clinicaltrials.gov; Unique identifier: NCT06081894), aficamten significantly improved outcomes in patients with nHCM versus placebo. To contextualize the observed treatment effects, we performed a responder analysis integrating multiple clinically relevant measures. Patients with symptomatic nHCM were randomized to daily aficamten (n=258) or placebo (n=259) assessed at week 36, including (1) symptom burden (≥1 improvement in New York Heart Association class or reported improvement in Patient Global Impression of Change); (2) exercise capacity (≥0.5 mL/kg per min in peak oxygen uptake); (3) >10% decrease in left atrial volume index; (4) >10% improvement in septal early diastolic mitral annular velocity (e'); (5) ≥50% reduction in NT-proBNP (N-terminal pro-B-type natriuretic peptide). Overall clinical response was classified by the number of favorable outcomes achieved: nonresponder (none), limited (1 or 2), partial (3 or 4), or complete (all 5). At 36 weeks, a greater proportion of patients treated with aficamten versus placebo experienced improvements in symptom burden (71% versus 53%), peak exercise capacity (45% versus 37%), left atrial volume index (31% versus 23%), septal e' (51% versus 26%), and NT-proBNP (63% versus 5%) (P<0.05 for all except peak oxygen uptake, P=0.1). Number needed to treat for aficamten ranged from 1.7 (NT-proBNP reduction) to 14 (peak oxygen uptake improvement) relative to placebo. A partial or complete clinical response (≥3 outcomes) was achieved in 53% of patients on aficamten versus 14% on placebo (P<0.001). In patients with nHCM, aficamten was associated with improvements across a broad range of clinically relevant measures including symptom burden and diastolic function. These results underscore a potential benefit of aficamten in the population of patients with nHCM. URL: https://www.clinicaltrials.gov; Unique identifier: NCT06081894.

The neonatal heart experiences rapid metabolic growth after birth to meet increasing energetic and biosynthetic demands. How mitochondrial cofactor availability limits this transition remains unclear. Here, we demonstrate that mitochondrial S-adenosylmethionine (mitoSAM) import through SLC25A26 becomes limiting shortly after birth and specifically restricts protein lipoylation, although other mitoSAM-dependent processes are partially preserved. Loss of Slc25a26 impaired lipoylation-dependent flux through pyruvate and α-ketoglutarate dehydrogenases, restricting tricarboxylic acid cycle carbon entry and depleting aspartate and nucleotide pools. Conversely, mitochondrial gene expression remained intact, and respiratory chain enzyme activities showed partial impairment, indicating that lipoylation is the most mitoSAM-sensitive pathway during postnatal heart adaptation. These metabolic limitations were linked to sustained cardiomyocyte cell-cycle activity, delayed structural maturation, and early cardiomyopathy. Supplementing with medium-chain triglycerides during the suckling-to-weaning transition partially stabilized metabolism and prolonged survival. Overall, our findings identify a stage-specific metabolic vulnerability in the postnatal heart characterized by hierarchical mitoSAM utilization within the mitochondria.

Despite optimal glycemic control, the heart failure burden remains substantial in diabetic patients. Metabolic remodeling is involved in this process, yet our current understanding is still in its infancy. Methylmalonic acid (MMA) is conventionally viewed as a marker of cobalamin (Cbl) deficiency. Paradoxically, MMA elevation-related cardiovascular mortality is more pronounced in diabetic patients with normal or high Cbl levels. This study investigated the mechanisms and translational significance of this contradictory MMA accumulation in the diabetic heart. We analyzed serum Cbl, MMA, and cardiac biomarkers in 12 751 participants and characterized Mmut (methylmalonyl-CoA mutase; a key enzyme in MMA catabolism) expression in failing human hearts with diabetes. Cardiomyocyte-specific Mmut knockout and Mmut-overexpressing mice were subjected to high-fat diet/streptozotocin-induced diabetes. Molecular mechanisms were elucidated using 13C-isotope tracing, RNA sequencing, immunoprecipitation, and biolayer interferometry. Elevated serum MMA was significantly associated with subclinical heart damage and adverse outcomes in diabetic adults, even in the absence of Cbl deficiency. Cardiac MMA overload and decreased protein expression of Mmut were observed in humans and mice with diabetes. Notably, MMA dysmetabolism preceded detectable cardiac dysfunction in diabetic mice and persisted even after glycemic normalization. Mechanistically, the hyperglycemic memory-associated molecule miR-499 binds to Mmut mRNA, suppressing its expression and driving MMA accumulation. Mmut deficiency amplified cardiac MMA overload and exacerbated disturbances in glycolipid metabolism and mitochondrial quality control, whereas adeno-associated virus-mediated Mmut overexpression attenuated cardiac MMA load and adverse remodeling in diabetic mice. Isotope tracing identified isoleucine and valine as the primary sources of cardiac MMA under diabetic conditions. Branched-chain amino acid-restricted diets alleviated diabetes-induced MMA accumulation and heart damage. Crucially, Cbl supplementation failed to alleviate MMA overload in diabetic mice, even at high doses or with activated forms. Strikingly, metformin, an established risk factor for Cbl deficiency, mitigated MMA-induced heart damage through dual mechanisms: activating AMPK (AMP-activated protein kinase)-dependent mitochondrial quality control to enhance tolerance to MMA, and directly promoting Mmut-Cbl cooperation to enhance MMA clearance. This study provides a foundation for understanding diabetes-related MMA dysmetabolism as a trigger for subclinical heart damage resistant to glycemic control and Cbl supplementation. Our findings challenge the prevailing clinical consensus regarding the impacts of Cbl and metformin use on MMA elevation in diabetic management.

Cigarette smoking is a major modifiable risk factor for cardiovascular disease. Despite the widespread use of coronary artery calcium (CAC) scoring as a risk stratifier for preventive therapy, smokers frequently present with acute coronary syndromes despite minimal coronary calcification. We performed a multimodality meta-analysis to quantify the association between smoking and coronary plaque burden and phenotype using CCTA, IVUS, and OCT. We systematically searched multiple databases through June 2026 for imaging studies comparing smokers with never-smokers. Random-effects meta-analyses using inverse-variance weighting were performed to pool odds ratios (ORs) for plaque presence and specific phenotypes; heterogeneity was assessed using the I2 statistic. Sixteen studies (n = 251,839; mean age 58 years; 65% male) met the inclusion criteria. In pooled analyses, smokers had higher odds of any detectable coronary plaque (OR 1.42; 95% CI 1.32-1.53). Smoking was associated with increased odds of both calcified plaque (OR 1.33; 95% CI 1.11-1.58) and non-calcified plaque (OR 1.59; 95% CI 1.47-1.73), with a more consistent and homogeneous association observed for non-calcified plaque. Mixed plaque was also more frequent in smokers (OR 1.52; 95% CI 1.31-1.78). Cigarette smoking is associated with greater coronary plaque burden and a relative excess of non-calcified plaque compared with never-smoking. These findings suggest that plaque phenotypes in smokers may not be fully reflected by CAC scoring alone. Prospective multimodality cohorts with individual-level CAC and plaque characterization are needed to further refine risk stratification in this population.

Coronary artery calcification (CAC) progression is a strong predictor of cardiovascular events. We investigated whether supplementation with vitamin K2 and vitamin D3 reduces CAC progression in patients with severe coronary calcification. In this multicenter, double-blind, placebo-controlled randomized trial, 400 participants with a CAC score ≥400 Agatston units (AU) were randomly assigned to vitamin K2 (720 μg/d) plus vitamin D3 (25 μg/d) or placebo for 24 months. Participants were enrolled from February 2023 to February 2024. Noncontrast cardiac computed tomography was performed at baseline, 12 months, and 24 months. The primary end point was change in CAC score at 24 months. Subgroup analyses by sex and baseline CAC subgroups (400-999 and ≥1000 AU) were performed. Change in plaque composition was assessed in a subset with CAC score <1000 AU who underwent coronary computed tomography angiography at baseline and 24 months. A total of 398 participants (30% women; median age, 71 years) were included. Median baseline CAC was 903 AU, and 44% had CAC ≥1000 AU. In the intention-to-treat analysis, the mean CAC increase was 196 AU (95% CI, 178-214) with vitamin K2 and D3 and 248 AU (95% CI, 225-271 AU) with placebo (between-group difference, -52 AU [95% CI, -79 to -24]). The treatment effect was consistent across sex and baseline CAC subgroups. In the 143 participants who underwent coronary computed tomography angiography, there were a similar increase in total plaque volume and no change in noncalcified plaque volume between groups; progression of calcified plaque volume was attenuated in the intervention group (between-group difference, -8 mm3 [95% CI, -13 to -2]). Among patients with severe CAC, supplementation with vitamin K2 and vitamin D3 reduced progression of CAC over 24 months. The reduction in calcification progression was not associated with an increase in noncalcified plaque volume. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05500443.

Atherosclerosis is a chronic inflammatory disease with a strong autoimmune component, marked by the detection of autoreactive T cells and autoantibodies. Recent single-cell RNA sequencing studies have shown that atherosclerotic plaques contain clonally expanded CD8+ T cells. One of the known atherosclerosis autoantigens is APOB (apolipoprotein B). However, autoreactive CD8+ T cells to APOB in humans have not been described. We studied CD8+ T-cell reactivity to human leukocyte antigen-A*02:01-restricted APOB epitopes, starting with in silico epitope prediction. We used peripheral blood mononuclear cells from human leukocyte antigen-A02:01+ healthy subjects to test the top 64-ranked peptides for their potential to elicit a CD8+ T-cell response. Antigen-specific responses were assessed using activation-induced marker assays, intracellular cytokine staining, and IFNγ (interferon gamma) ELISpot assays. Some APOB peptides triggered robust CD8+ T-cell activation with effector memory features, and expression of cytokines and cytotoxic molecules. Five immunodominant epitopes spanning 2 APOB regions accounted for most of the response and elicited significant T-cell activation in healthy donors that was increased in clinical samples from patients with severe coronary artery disease. The discovery of immunodominant major histocompatibility complex class I-restricted APOB epitopes suggests a new perspective for immune-based interventions to mitigate atherosclerosis.

Stroke is a leading cause of morbidity and mortality globally. Prehospital stroke care is a rapidly growing field to improve stroke outcomes. Methods to assess patients in the prehospital setting include clinical scales and portable neuroimaging that are usually restricted to mobile stroke unit computed tomography scanners, which are not widely available. Lightweight low-field magnetic resonance imaging devices at the <0.1T range offer an opportunity for portable lightweight imaging for the prehospital setting, with the advantage of greater tissue assessment to diagnose stroke. This review focuses on the current landscape and future direction for low-field magnetic resonance imaging in the prehospital setting, with a discussion of current and upcoming devices, and potential barriers to ambulance integration and how these may be overcome. Low-field magnetic resonance imaging provides an exciting opportunity for portable and safe imaging for the prehospital setting for the early diagnosis of stroke and the initiation of triage and treatment. These devices have the potential to be much more widely available and accessible than the current prehospital assessment model of mobile stroke units and provide additional detail for treatment decisions compared with non-imaging-supported telehealth prehospital assessments.

Thrombolysis is infrequently delivered to children with acute ischemic strokes (AIS). We explored potential eligibility for treatment with tPA (tissue-type plasminogen activator) for pediatric AIS. This retrospective, multicenter, observational, cohort study reviewed children aged 29 days to 17 years with symptomatic AIS identified via Children's Hospital Westmead, John Hunter Children's Hospital, and Sydney Children's Hospital between January 1, 2010, and December 31, 2019. Medical records were examined to evaluate eligibility for treatment with tPA based on established multinational and the 2026 American Heart Association guidelines, reasons for exclusion beyond delay to diagnosis, and long-term outcomes as pediatric modified Rankin Scale scores. We also explored additional exclusions and outcomes among children with small-vessel AIS and AIS in the context of brain tumors, who are currently excluded from tPA. A total of 135 patients with 139 symptomatic AIS were identified-median age, 6 years; 36% female; 73% presented via emergency departments; mean follow-up, 43 months; 12% deaths. Irrespective of delay to diagnosis, only 26 of 139 (19%) AIS were potentially eligible for treatment with tPA. Among patients potentially eligible for tPA, acute neuroimaging revealed large-vessel occlusions, unilateral focal cerebral arteriopathy, or extracranial dissections. Thirteen of 26 (50%) had nondisabled outcomes without tPA treatment. One hundred thirteen of 139 (81%) AIS were ineligible for treatment with tPA, irrespective of delay to diagnosis. All deaths occurred among patients excluded from tPA, predominantly related to underlying disorders. Fifty-four small-vessel AIS accounted for 39% of AIS. Eighteen (33%) had no additional ineligibilities to thrombolysis, among whom 10 had nondisabled outcomes without tPA. Based on current recommendations, 19% of symptomatic childhood AIS were potentially eligible for treatment with tPA, irrespective of delay to diagnosis. Selected patients with small-vessel AIS may offer an opportunity to extend the role of tPA. These observations may be relevant for optimizing pediatric stroke management strategies.

Low-field (LF) magnetic resonance imaging (MRI) plays a crucial role in assisting clinicians with rapid stroke diagnosis. However, its inherent limitations, such as low signal-to-noise ratio (SNR) and suboptimal image quality, make accurate stroke lesion identification challenging. To address this, we propose a Difference-Guided Conditional Diffusion Model (DGCD-3D) to enhance image quality of LF MRI while preserving structural integrity of stroke lesions. Specifically, the model incorporates a difference-adaptive forward diffusion process that guides the diffusion dynamics based on differences. During training, multi-scale intrinsic features from LF MRI and prior spatial information of stroke lesions are explicitly encoded into the generative process. Furthermore, a time-adaptive multi-loss optimization strategy dynamically balances pixel-wise and perceptual losses at different timesteps. DGCD-3D was evaluated on a large-scale, clinically scarce paired LF-HF MRI dataset (n = 974) acquired within a mean interval of 18.5 min. Experimental results demonstrate that DGCD-3D substantially improves LF MRI image quality (PSNR = 28.26, SSIM = 0.896) and achieves significantly higher consistency with HF MRI in stroke lesion assessment (Spearman's correlation coefficient ρ = 0.732) compared with the LF MRI (ρ = 0.680). Furthermore, a clinical authenticity assessment conducted by six experienced radiologists yielded a confusion rate of 51.6% and a confusion score of 5.64, further confirming the clinical reliability and broad applicability of the proposed approach. The codes and trained models will be released on GitHub: https://github.com/lihao9056/DGCD-3D.

Patients with catecholaminergic polymorphic ventricular tachycardia (CPVT) are at risk for potentially life-threatening arrhythmic events (AEs) even while treated with β-blockers. The aim was to develop a model for individualized prediction of AEs in patients with RYR2-mediated CPVT on β-blocker monotherapy. The derivation and independent validation cohorts included 743 and 129 patients, respectively. AEs were defined as arrhythmic syncope, appropriate implantable cardioverter-defibrillator shock, sudden cardiac arrest (SCA), and sudden cardiac death. Near-fatal or fatal AEs (nf/fAEs) included all AEs except for arrhythmic syncope. Prediction models using Cox regression were developed and internally and externally validated. A total of 102 (13.7%) patients in the derivation cohort and 24 (18.6%) patients in the validation cohort experienced ≥1 AE over a median follow-up of 5.1 [interquartile range (IQR), 7.7] and 2.4 (IQR, 4.4) years, respectively. Predictors of AE were arrhythmic syncope or SCA prior to diagnosis and age at β-blocker initiation. In the derivation and validation cohorts, the optimism-corrected C-indices of the models for AE were 0.67 [95% confidence interval (CI) 0.62-0.72] and 0.59 (95% CI 0.48-0.71), respectively. For nf/fAEs, ventricular arrhythmia severity before β-blocker initiation was a fourth independent predictor, and C-indices of the models in the derivation and validation cohorts were 0.74 (95% CI 0.68-0.80) and 0.60 (95% CI 0.47-0.72), respectively. In the derivation cohort, calibration slopes were 1.00 (95% CI 0.59-1.41) for AE and 1.00 (95% CI 0.69-1.32) for nf/fAE. These externally validated risk prediction models using clinical parameters accurately distinguished CPVT patients on β-blocker monotherapy at low and high risk for future AEs while treated with β-blockers. These models provide guidance for implementation of clinical management therapies to prevent AEs in patients with CPVT.

Brugada Syndrome (BrS) is an inherited arrhythmia disorder that causes an elevated risk of sudden cardiac death. Approximately 20% of patients with BrS have rare variants in SCN5A, which encodes the cardiac sodium channel NaV1.5. Genetic workup of BrS is often complicated by SCN5A variants of uncertain significance (VUS) and/or incomplete penetrance. This study deployed an SCN5A-BrS functional assay at cohort scale to facilitate the implementation of genetic and precision medicine. All 252 missense and in-frame insertion/deletion SCN5A variants from a previously published large cohort of BrS cases (n = 3335 patients) were analysed using a calibrated high-throughput automated patch-clamp (APC) assay. Variant functional Z-scores were assigned evidence levels ranging from BS3_moderate (normal function) to PS3_strong (loss-of-function), as defined by American College of Medical Genetics and Genomics criteria. Functional evidence was combined with population frequency, hotspot, case counts, protein-length changes, and in silico predictions. Odds ratios of BrS case-control enrichment and penetrance for BrS were calculated from variant frequencies in the BrS cohort and in gnomAD. Most variants (146/252) were functionally abnormal (Z ≤ -2), with 100 having severe loss-of-function (Z ≤ -4). Functional evidence enabled the reclassification of 110 of 225 VUS; 104 to likely pathogenic and 6 to likely benign. SCN5A variants with loss-of-function were mainly localized to the transmembrane domains, especially the regions comprising the central pore. SCN5A variant penetrance was proportional to the severity of loss-of-function; variants with Z ≤ -6 had penetrance of 24.5% (15.9%-37.7% CI) and an odds ratio of 501 for BrS. This cohort-scale APC dataset stratifies SCN5A variants found in BrS patients into normal function 'bystander' variants that have a low risk of BrS and loss-of-function variants that have a high risk for BrS. Functional data can be integrated with other criteria to reclassify a substantial fraction of VUS. The dataset helps clarify the SCN5A-BrS relationship and will improve the diagnosis and clinical management of BrS probands and their families.

Methadone is increasingly used for perioperative care. High-dose methadone, for opioid use disorder or chronic pain, can prolong the cardiac QTc interval, which increases the risk of dangerous cardiac arrhythmias. This investigation evaluated single-dose perioperative methadone effects on QTc. This prospective observational cohort study evaluated adults undergoing elective surgery under general anaesthesia. Patients received methadone i.v. or no methadone (typically fentanyl) at induction of anaesthesia (provider discretion). QTc was determined before and for 1 h after opioid administration and rate-corrected using Fridericia's formula (QTcF). The primary outcome was new-onset QTcF >500 ms. Secondary outcomes were any QTcF>500 ms; QTcF increase (ΔQTcF)>60 ms; QTcF>500 ms for >15 min; QTcF>450 ms (males) or >470 ms (females); maximum QTcF and ΔQTcF; and methadone dose vs QTcF or ΔQTcF. Patients were 59 (median; range 18-86) yr of age, and received methadone (n=282, median 20 mg, IQR [15-20], range 10-60 mg) or no methadone (n=265, typically fentanyl, 250 μg [100, 350], 0-750 μg). New QTcF>500 ms occurred in 2.5% of patients receiving methadone and 8.3% receiving no methadone (relative risk [RR] 0.34, 95% confidence interval [0.16-0.75] P=0.009). Secondary outcomes with methadone vs no methadone found that any QTcF>500 ms occurred less (3.5% vs 8.3%, RR 0.43); ΔQTcF>60 ms occurred less (4.6% vs 12.1%, RR 0.39); maximum ΔQTcF was less (28 ms vs 37 ms); and sex-specific thresholds were exceeded less (22.3% vs 33.6%) (all P<0.03). There was no correlation between methadone dose and QTcF or ΔQTcF. A single-dose at induction of methadone i.v. did not prolong QTcF. Methadone had no clinically meaningful QTcF effects, specifically or in comparison with no use of methadone.

Arrhythmia is one of the leading causes of mortality and lacks diagnostic and therapeutic options. Electrical activity at the cellular level is difficult to use as a basis for evaluating drug effects on cardiac rhythm. Cardiac organoids, as organized and functional cell clusters, offer significant advantages as models for the pathophysiological mechanisms of arrhythmia or as drug screening platforms. Here, we applied a standardized set of electrophysiological techniques to integrate electrophysiological activity of cardiac organoids, including multielectrode array (MEA), calcium signal optical mapping and patch clamp analysis. We first established cardiac organoids containing cardiomyocyte and endothelial cell components through hiPSC (human induced pluripotent stem cell) induction. Then by this electrophysiological detection protocol, we found that the characteristics of electrical activity and calcium transient signal of cardiac organoids under E-4031, cisapride or ATX-II induction were more similar to cardiac tissue rather than to cardiomyocytes cultured in vitro. Finally, the patch clamp analysis revealed the existence of subpopulations of ventricular-like cardiomyocytes with different electrical activity phenotypes in cardiac organoids, which aligns with the theoretical basis for cardiac rhythm formation. Our findings systematically validated the tissue-like characteristics of cardiac organoids and can be applied to the testing of molecules' effects on cardiac rhythm, thereby screening for novel antiarrhythmic drugs.

Emerging evidence implicates intestinal barrier dysfunction and translocation of microbial factors as key drivers of post-myocardial infarction inflammation and cardiac remodeling, yet therapeutic strategies targeting the gut-heart axis remain underdeveloped. Here we demonstrate that ALY688, an adiponectin receptor agonist peptide, confers robust cardioprotection in rat myocardial ischemia-reperfusion (IR) injury through coordinated immunoregulatory programs in cardiac and intestinal tissues. ALY688 administration during ischemia or at reperfusion and subsequently daily for 28 days significantly preserved cardiac function with improved ejection fraction and fractional shortening, reduced infarct size, and decreased cardiac troponin-I levels. Mechanistic investigation revealed tissue-specific immune reprogramming: in the myocardium, ALY688 directly activated macrophages to secrete TGFβ1, which promoted regulatory T cell (Treg) differentiation from naïve CD4 + T cells as validated in macrophage-T cell co-culture systems. This macrophage-to-Treg axis suppressed inflammasome activation and IL-1β/IL-23/IL-6 signaling while enhancing anti-inflammatory macrophage polarization. Simultaneously, ALY688 strengthened intestinal barrier integrity through activation of the RORγt/IL-17 pathway, upregulating tight junction proteins (Claudin-1, ZO-1) and mucins (MUC19, MUC22), thereby limiting systemic spillover of bacterial endotoxin (LPS) and other microbial metabolites. Multi-omics profiling supported this dual-compartment mechanism: proteomics revealed modulation of immune regulatory (CAPG, CORO1A, MCAM) and cardioprotective (clusterin, NPPA) proteins, while metabolomics demonstrated attenuation by ALY688 of post-IR elevations in pathogenic gut-derived metabolites (anthranilic acid, imidazole propionate, linoleic acid derivatives). This study establishes adiponectin receptor activation as a multi-organ immunometabolic intervention that simultaneously resolves cardiac inflammation while protecting intestinal barrier function. These findings provide mechanistic insight for therapeutic strategies that target the gut-heart axis to address a major remaining unmet clinical need in ischemic heart disease.

Acute myocardial infarction (AMI) is a leading cause of morbidity and mortality globally, with timely percutaneous coronary intervention (PCI) as the standard treatment. Early time reperfusion (ETR) shown to reduce arrhythmias and improved survival rates compared to late time reperfusion (LTR). However, cellular and molecular mechanisms underlying the protective effects of ETR effects relative to LTR on AMI remain poorly understood. This study aims to elucidate these mechanisms through an integrated multi-omics approach, focusing on cardiomyocyte energenesis and dedifferentiation, while also exploring the therapeutic potential of ERRβ/γ activation. AMI was induced in rats by ligating the left anterior descending coronary artery (LAD) for one hour (ETR) or six hours (LTR), followed by reperfusion. Sham-operated rats served as controls. Comprehensive analyses of the ischemic hearts were performed using bulk tissue transcriptomic sequencing, metabolomic profiling, and single-nucleus RNA sequencing. Additionally, the role of ERRβ and ERRγ was investigated in neonatal rat ventricular myocytes (NRVMs) subjected to hypoxia/reoxygenation (H/R). The ERRβ/γ agonist GSK4716 was administered in vivo before ETR to assess its potential to enhance the therapeutic effects of ETR on AMI injury, and its protective mechanism was compared to fenofibrate. Transcriptomic and metabolomic profiling revealed that the protective effect of ETR on AMI relative to LTR is primarily mediated by cardiomyocyte energenesis and dedifferentiation. Single-nucleus RNA sequencing identified four distinct cardiomyocyte subpopulations (CM1-CM4), with ETR preserving a larger proportion of sub-injured CM2 and immature-like CM4. Additionally, ERRβ/γ was found to regulate the expression of cardiomyocyte energenesis and dedifferentiation signature genes both in vivo and in vitro. Treatment with the ERRβ/γ agonist GSK4716 significantly enhanced ETR's protective effects on AMI relative to LTR by activating energenesis and dedifferentiation-associated genes. These findings indicate that ETR protects against AMI relative to LTR by preserving cardiomyocyte energenesis and dedifferentiation. The activation of ERRβ/γ significantly enhanced these protective effects, highlighting its therapeutic potential in mitigating AMI outcomes.

Multiple germline gene variants promote familial and idiopathic pulmonary arterial hypertension (PAH); however, none are consistently identified in associated PAH with connective tissue disease (APAH-CTD). Moreover, the role of somatic variants in genes mediating clonal haematopoiesis of indeterminate potential (CHIP) in PAH is unknown. Here, somatic and germline DNMT3A variants and CHIP gene variants in PAH were evaluated. Exome sequencing (ES) was compared between PAH Biobank participants (n = 1832 European ancestry/2572 total), vs. gnomAD controls (7509 European ancestry/141 456 total). Subsequently, targeted panel sequencing (TPS) of 22 CHIP genes, including DNMT3A, was performed in PAH (n = 1659) vs. controls (n = 3644). Somatic CHIP variants in the UK Biobank using ES (controls = 448 239; PAH = 2559) were also assessed. DNMT3A mRNA expression was measured in peripheral blood mononuclear cells (PBMCs) of patients with scleroderma APAH-CTD (n = 50), idiopathic PAH (n = 30), scleroderma without PAH (n = 19), and healthy controls (n = 41). Hemodynamic were evaluated in haematopoietic Dnmt3a-knockout mice. Predicted deleterious germline DNMT3A variants were increased in subjects of European ancestry (6/1832) vs. controls (6/7509) (relative risk [RR] = 4.1, P = .018). In the entire PAH Biobank cohort (n = 2572), DNMT3A germline and somatic variants were further enriched (PAH: 1.28% vs. controls: .43%, P = 1.65 × 10-10). Eight DNMT3A mutations (.39%) were likely germline (female/male: 7/1) and 25 (.82%) likely somatic (female/male: 21/4), including 13/33 APAH-CTD participants. TPS identified CHIP in 242 PAH subjects (48% DNMT3A). DNMT3A- and all-CHIP variants were associated with PAH after correcting for age, sex, and age-CHIP interactions (odds ratio [OR]: 25.44, P = 4.50 × 10-5; OR: 23.35, P = 2.87 × 10-8, respectively). In the UK Biobank, CHIP mutations were increased in PAH (PAH = 5.35% vs. Control = 3.45%, P ≤ .0001). DNMT3A was reduced in PAH-PBMCs (area under curve [AUC] = .82) (P < .0001). Haematopoietic Dnmt3a-knockout in mice caused inflammatory PAH, which was attenuated by IL-1β antibody therapy. Germline DNMT3A variants and somatic variants of DNMT3A and CHIP genes increase the risk of PAH, including APAH-CTD, promote inflammation, and constitute potential biomarkers and therapeutic targets.

Idiopathic intracranial hypertension (IIH) is characterized by elevated intracranial pressure and dural venous sinus stenoses, which can be relieved by venous stenting. Here we investigated whether venous blood flow may play a role in controlling brain pressure. Using magnetic resonance imaging in patients with IIH and healthy controls, we identified that dural venous stenoses in IIH were associated with alterations of the perivenous fluid pattern and brain edema. We developed a mouse model of jugular vein ligation (JVL), which developed transient intracerebral hypertension, brain edema and impaired brain clearance, along with defective meningeal lymphatic vessels (MLVs). MLV depletion increased intracerebral pressure in control and JVL mice, but only MLV-deficient ligated mice failed to restore brain fluid clearance. These findings implicate MLVs in the control of intracerebral pressure and establish the dural venous sinuses as critical platforms where venous flow directs MLVs to ensure brain fluid clearance.

Accurate vascular structural alignment between 3D computed tomography angiography (CTA) images and 2D digital subtraction angiography (DSA) can significantly enhance visualization during percutaneous coronary intervention (PCI), thereby improving procedural success and reducing surgical risks. Existing methods typically rely on 2D/3D rigid, deformable, or hybrid registration driven by handcrafted features and manually designed matching strategies, which are inefficient and often fail in the challenging clinical scenarios involving vessel overlaps, missing branches, and complex deformations. Although deep learning has demonstrated superior performance in registration, its adoption in this domain is constrained by the lack of algorithms tailored to the unique vascular topology and the scarcity of high-quality paired training data. To address current limitations, we propose a two-stage deep learning registration framework with rigid and deformable stages for robust, efficient vascular structural alignment between 3D CTA and 2D DSA. In the rigid stage, we develop a vascular topology-aware matching network that uses hybrid attention and branch missing prediction to establish correspondences, leveraging a specialized tree attention for robustness in overlapping regions. In the deformable stage, we estimate complex deformations in a coarse-to-fine manner using a pyramid-based hierarchical module, guided by soft correspondence scores from the rigid stage to preserve anatomical consistency. To train and evaluate the framework, we collect 4983 CTA scans and 783 DSA sequences, and further generate 1,050,000 synthetic CTA-DSA pairs via simulations with controlled geometric transformations, anatomical variations such as branch trimming, and diverse imaging artifacts, thereby laying the groundwork for the deep learning-based method in this domain. Extensive experiments on real and simulated datasets demonstrate the effectiveness of our method and highlight its potential to enhance intraoperative PCI visualization. A public repository has been created at Link. The simulation pipeline, pretrained inference weights, and evaluation scripts are being organized for public release to support reproducible testing.

Cardiovascular disease (CVD) remains the leading cause of morbidity and mortality worldwide, and its progression is closely linked to mitochondrial dysfunction in cardiomyocytes. Given the high energy demands of the heart, precise regulation of mitochondrial homeostasis, including oxidative phosphorylation, reactive oxygen species balance, calcium handling, and mitophagy, is essential for maintaining cardiac function. Emerging evidence has identified mitochondrial-associated long non-coding RNAs (mito-lncRNAs) as important regulators of these processes. Mito-lncRNAs comprise both nuclear-encoded transcripts that translocate to mitochondria and mitochondrial genome-encoded lncRNAs that function within the organelle. These molecules modulate mitochondrial gene expression, respiratory chain stability, metabolic flux, and stress responses, thereby influencing the pathogenesis of acute myocardial infarction, heart failure, diabetic cardiomyopathy, pulmonary hypertension, and cardiac remodeling. In this review, we categorize mito-lncRNAs based on their genomic origin and mitochondrial localization and summarize their mechanistic roles in cardiovascular physiology and disease. Moreover, the review highlights context-dependent effects of key transcripts such as LIPCAR, MALAT1, RMRP, H19, and lncND5. We further discuss the emerging value of mito-lncRNAs as circulating biomarkers and examine the major challenges that currently limit therapeutic translation, including cardiac- and mitochondrial-specific delivery, mechanistic ambiguity, species conservation, and technical limitations in detection. A deeper understanding of mito-lncRNA biology may provide new insights into mitochondrial regulation in the heart and inform the development of novel diagnostic and therapeutic strategies for CVDs.

With the acceleration of global population aging, the progressive deterioration of cardiac structure and function has become a critical determinant of cardiovascular health, presenting a significant public health challenge. Checkpoint kinase 1 (CHK1), a key cell cycle checkpoint protein, plays an essential role in various biological processes by mediating signaling cascades. While CHK1 has been shown to be important for heart regeneration, its role in the aging process of the heart remains unclear. In this study, we investigated the alterations in CHK1 expression in aging hearts and elucidated the underlying regulatory mechanisms. In both in vivo and in vitro models, CHK1 expression was significantly downregulated during aging. To assess its functional role, we generated cardiomyocyte-specific CHK1 overexpression and knockout mice and compared their cardiac performance. We found that CHK1 overexpression alleviated age-associated cardiac dysfunction, while CHK1 knockout worsened cardiac function in aged mice. Furthermore, CHK1 overexpression significantly attenuated doxorubicin (DOX)-induced acutely senescence in adult mouse cardiomyocytes (AMCMs) and human induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Mechanistic studies revealed that CHK1 overexpression delayed cardiac aging by activating heat shock protein 90 (HSP90)-mediated mitophagy. Immunoprecipitation and mass spectrometry (IP-MS) analyses demonstrated that CHK1 directly interacts with the activator of HSP90 ATPase homolog 1 (AHSA1), thereby suppressing TRIM8-mediated ubiquitination and degradation, facilitating AHSA1-HSP90 complex formation, and enhancing HSP90 ATPase activity. Overall, our results suggest that CHK1 overexpression activates mitophagy via the AHSA1-HSP90 pathway to mitigate cardiac aging. This study highlights the critical role of CHK1 in cardiac aging and proposes a potential therapeutic strategy for aging-associated cardiomyopathy and heart failure.

Adiposity exerts multisystem insults that influence multiple organs and physiological pathways. This underscores the need for a systems-level framework integrating key organ fat measurements to disentangle the heterogeneous pathways through which adiposity shapes differential cardiometabolic risk profiles. Such an approach could advance mechanistic understanding and enable more precise risk stratification. In the UK Biobank, 24 935 participants without overt cardiac disease were studied. Six adiposity phenotypic groups were identified using unsupervised clustering of magnetic resonance imaging-derived adiposity measures (subcutaneous, visceral, pericardial, liver, pancreatic, and muscle fat). These phenotypes were characterised in terms of body composition, cardiac remodelling, and the development of major cardiometabolic diseases. Each phenotype showed distinct organ-dominant fat accumulation and body composition pattern. A pancreatic fat dominant phenotype, marked by visceral adiposity and sarcopenic features, showed a cardiorenal-metabolic risk profile. A muscle fat dominant phenotype, characterised by subcutaneous adiposity and sarcopenic features, was associated with increased heart failure risk. While pericardial fat dominant and liver fat dominant phenotypes did not associate with cardiac disease risk, they exhibited distinctive cardiac remodelling patterns, revealing phenotypespecific metabolic-cardiac interactions. Lastly, normal-weight individuals with mild multi-organ fat showed elevated chronic ischaemic heart disease risk, highlighting the value of phenotype-based risk assessment beyond general weight measures. Distinct patterns of multi-organ fat accumulation were associated with differential body composition, cardiac remodelling, and cardiometabolic disease risk profiles. The identified adiposity phenotypic groups capture clinically meaningful heterogeneity across the cardiorenal-metabolic spectrum and may inform future personalised, multisystem approaches to prevention and management.

Low-density lipoprotein cholesterol (LDL-C) targets remain unmet in many high-risk atherosclerotic cardiovascular disease (ASCVD) patients on statins (± ezetimibe). VICTORION-Challenge compared inclisiran with bempedoic acid (BPA) for LDL-C lowering and target attainment in these patients, directly. In this phase 4, open-label study, ASCVD patients with LDL-C ≥70 mg/dL on statins (± ezetimibe) were randomized to inclisiran or BPA. The primary endpoint was percentage change in LDL-C at Day 150; key secondary endpoints at Day 150 included percentage LDL-C change stratified by ezetimibe use. Secondary endpoints included LDL-C goal attainment and absolute change; treatment-emergent adverse events (TEAEs) were evaluated. Among 402 randomized patients (mean±standard deviation age, 63.1±10.7 years; 64.2% men; baseline LDL-C 94.4±28.3 mg/dL), LDL-C reduction at Day 150 was superior with inclisiran vs BPA (least squares mean -56.3% vs -15.4%; between-group difference -41.0%, 95% confidence interval [CI] -45.7 to -36.2; p<0.0001). Inclisiran achieved greater absolute LDL-C reduction at Day 150 (-53.4 vs -17.5 mg/dL) regardless of ezetimibe use, with higher LDL-C goal attainment (78.2% vs 20.3%; adjusted odds ratio 16.36, 95% CI 9.72 to 27.54; descriptive p<0.0001). Inclisiran showed a favourable safety profile vs BPA, with comparable rates of TEAEs (63.1% vs 59.8%) and serious TEAEs (5.9% vs 7.5%). Most common TEAEs (inclisiran vs BPA) included nasopharyngitis (10.3% vs 7.5%), hypertension (4.9% vs 4.5%), and myalgia (3.4% vs 5.5%). One non-treatment-related death (inclisiran) was reported. Inclisiran provided superior LDL-C reduction versus BPA with favourable safety, supporting its use in high-risk patients not achieving guideline-recommended goals.

Hypertension is a common attributable cause of chronic kidney disease (CKD). Mineralocorticoid receptor overactivation can lead to hypertension and contributes to CKD progression. In FIND-CKD, finerenone reduced kidney function decline in participants with CKD without diabetes. This prespecified FIND-CKD analysis assessed finerenone efficacy and safety in participants with hypertensive nephropathy. Adults with estimated glomerular filtration rate (eGFR) 25-<90 mL/min/1.73 m2 and urinary albumin-to-creatinine ratio (UACR) 200-3500 mg/g were randomized 1:1 to once-daily finerenone or placebo. Hypertensive nephropathy was investigator-reported. Total eGFR slope from baseline to Month 32 was assessed, along with a kidney-cardiovascular composite of sustained ≥57% eGFR decline, kidney failure, hospitalization for heart failure, or cardiovascular death. Of 1584 randomized participants, 459 (29.0%) had hypertensive nephropathy. Mean blood pressure (± SD) was 134/80 ± 14/10 mmHg, mean eGFR was 44 ± 15 mL/min/1.73 m2, median UACR was 797 mg/g (Q1, Q3: 566, 1247). In participants with hypertensive nephropathy, finerenone slowed total eGFR decline versus placebo by 0.65 mL/min/1.73 m2/year (95% CI: 0.02, 1.29; P = .044) and was associated with a reduction in composite kidney-cardiovascular outcome events (HR: 0.61; 95% CI: 0.38, 0.99; P = .045). These effects were consistent irrespective of baseline systolic blood pressure (SBP) (P-interaction: eGFR slope, 0.96; composite outcome, 0.91). Finerenone reduced SBP by -3.5 mmHg and UACR by 33% at Month 6 vs placebo. Hyperkalaemia occurred more frequently with finerenone (17.1%) than placebo (9.8%); related discontinuation was uncommon (1.3% vs 0.0%, respectively). Finerenone slowed eGFR decline and reduced kidney-cardiovascular outcome risk in participants with hypertensive nephropathy, supporting its use in this population. ClinicalTrials.gov registration: NCT05047263.

Rising end-diastolic pressure in patients with a Fontan circulation has led to the hypothesis that circulatory failure is driven by progressive ventricular stiffening. However, end-diastolic pressure is influenced by loading conditions and extracardiac constraint and may not accurately reflect chamber stiffness. We aimed to characterize ventricular chamber stiffness using the end-diastolic pressure-volume relationship and examine its clinical and prognostic significance in patients with a Fontan circulation. In the FORCE registry (Fontan Outcomes Registry Using Clinical Examinations), chamber stiffness was quantified with the exponential coefficient β derived from single-beat end-diastolic pressure-volume relationship reconstruction using paired catheterization and cardiovascular magnetic resonance data. The β values were standardized as body surface area- and sex-based Z scores and related to clinical characteristics, ventricular remodeling, and a composite adverse outcome (death, transplantation listing, sustained atrial or ventricular arrhythmias, protein-losing enteropathy, or plastic bronchitis). Among 814 patients (median age, 14.7 years), median β was 0.034 mL-1 (0.025-0.046). Lower β Z score was associated with dominant right ventricle, eccentric remodeling with reduced ejection fraction, increased collateral flow and intracardiac recirculation, greater symptom burden, and higher arrhythmia prevalence, despite similar filling pressures. Over a median follow-up of 2.7 years (0.9-6.1 years), lower β Z score independently predicted adverse outcomes (adjusted hazard ratio, 1.30 per 1-SD decrease [95% CI 1.04-1.61]). A β Z score <-0.71, β<0.025 mL-1, or body surface area-indexed end-diastolic volume >103 mL/m2 showed similarly modest discrimination for adverse outcomes overall (area under the curve, 0.59), with greater discrimination in dominant right ventricles. Contrary to prevailing assumptions, lower rather than higher chamber stiffness was associated with adverse Fontan outcomes, identifying a high-compliance phenotype characterized by ventricular dilation and eccentric remodeling. These findings suggest that, in the contemporary FORCE cohort, Fontan failure might be more closely associated with this remodeling phenotype than with progressive stiffening.

Sodium-glucose cotransporter 2 (SGLT2) inhibitors improve outcomes in heart failure (HF) across the left ventricular ejection fraction (LVEF) spectrum, but patients with severe valvular heart disease have been excluded from pivotal trials. We investigated the efficacy and safety of dapagliflozin across the full range of baseline LVEF in elderly patients undergoing transcatheter aortic valve implantation (TAVI). DapaTAVI was a pragmatic, multicentre, randomized, open-label trial with blinded endpoint adjudication conducted at 39 Spanish centres. Patients with severe aortic stenosis undergoing TAVI were randomized after the procedure to dapagliflozin 10 mg once daily or standard of care. The primary endpoint was a composite of all-cause death or worsening HF. Among 1223 patients with available baseline LVEF, 213 (17.4%) had LVEF ≤40% and 1010 (82.6%) had LVEF >40%. During 1-year follow-up, the primary endpoint occurred in 20.2% of patients with LVEF ≤40% and 17.0% of those with LVEF >40% (adjusted HR 1.28, 95% CI 0.91-1.80; P = .15). Dapagliflozin reduced the risk of the primary endpoint consistently across LVEF subgroups, with no significant interaction between treatment effect and baseline LVEF (P for interaction = .41). Analyses modelling LVEF as a continuous variable confirmed a homogeneous treatment effect across the entire LVEF spectrum. Dapagliflozin was well tolerated, with a safety profile comparable to control across all LVEF categories, although genitourinary infections were more frequent with dapagliflozin. In elderly patients undergoing TAVI, dapagliflozin reduced the risk of all-cause death or worsening HF irrespective of baseline LVEF and was safe across the full LVEF spectrum. These findings extend the benefits of SGLT2 inhibition to patients with severe aortic stenosis treated with TAVI, independent of systolic function.