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The prognostic significance of pulse pressure (PP) differs across HF phenotypes, but its relevance in HFmrEF remains uncertain. We evaluated associations between PP and clinical outcomes across HF phenotypes and assessed whether PP provides prognostic information beyond SBP. We performed a patient-level pooled analysis of 13 randomised HF trials including 35,550 patients with HFrEF, 6,484 with HFmrEF, and 19,173 with HFpEF. PP-outcome associations were assessed using Cox models for quartiles and Poisson regression with restricted cubic splines for continuous PP. Across HF phenotypes, patients with higher PP were older, more frequently female, and had higher LVEF and greater adiposity. In HFrEF, PP was inversely associated with first HF hospitalization or cardiovascular death, with the lowest event rate in the highest PP quartile (>56 mmHg; 13.3 per 100 person-years [95% CI, 12.8-13.8]) and the highest event rate in the lowest quartile (<40 mmHg; 18.2 [17.5-18.9]). In contrast, HFpEF demonstrated a J-shaped relationship, with the lowest event rate in the second quartile (48-56 mmHg; 6.8 [6.4-7.3]) and the highest in the fourth quartile (> 66 mmHg; 9.7 [9.1-10.3]). HFmrEF exhibited a similar J-shaped association, closely paralleling HFpEF. PP improved model fit beyond SBP, but the incremental improvement in discrimination was small and largely limited to HF hospitalization-related outcomes in HFpEF. PP has phenotype-specific prognostic implications in HF. Low PP identifies higher risk in HFrEF, whereas high PP identifies higher risk in HFpEF and HFmrEF. PP may support phenotype-specific risk stratification.

Exercise stress echocardiography is recommended as an alternative to invasive testing for diagnosing heart failure with preserved ejection fraction (HFpEF), but an evidence-based operational framework guiding its application is lacking. Patients with chronic unexplained dyspnoea underwent invasive haemodynamic exercise testing with simultaneous echocardiography to test the hypotheses that (i) the current diagnostic algorithms (H2FPEF, HFA-PEFF, and HFpEF-ABA scores) could be enhanced when combined with exercise echocardiography; and (ii) incorporating resting left atrial (LA) compliance (LA reservoir strain divided by E/e') could further improve diagnostic triage, using separate cut points optimizing sensitivity and specificity. Findings were then validated in an international multicentre cohort. Of 482 patients, HFpEF was present in 386 and non-cardiac dyspnoea in 96. Sensitivity to detect HFpEF was only 55%-60% and accuracy 61%-67% using individual diagnostic scores with currently recommended exercise echocardiography. Addition of abnormal resting LA compliance to exercise echocardiography increased sensitivity to 84%-85% but increased the false-positive rate to 31%-43%. Applying separate cut points that optimize specificity and sensitivity (either exercise E/e' ≥ 13.8 or resting LA compliance ≤1.6% to rule-in HFpEF; both exercise E/e' < 7.2 and resting LA compliance >4.4% to rule-out HFpEF, remaining patients indeterminate who require invasive testing) improved sensitivity to 95%-99% among definitively classified patients and reduced the number of patients that require invasive exercise testing from ∼60% to ∼30%. Findings were replicated in a multicentre, international validation cohort of patients undergoing rest-exercise echocardiography and invasive exercise testing. Currently used non-invasive approaches to HFpEF diagnosis have inadequate sensitivity, indicating that exercise echocardiography cannot supplant invasive testing. Addition of LA strain imaging with optimized rule-in or rule-out values improves diagnostic triage by expanding non-invasive rule-in/rule-out classifications while identifying patients who still require invasive testing in the evaluation of HFpEF.

Myeloperoxidase (MPO)-derived oxidants reduce nitric oxide bioavailability and promote coronary microvascular dysfunction, cardiomyocyte stiffening and interstitial fibrosis-mechanisms implicated in the pathogenesis of heart failure with preserved and mildly reduced ejection fraction. Here, in a multicenter, randomized, double-blind, placebo-controlled, three-arm, parallel-group phase 2b trial of patients with heart failure and an ejection fraction of >40%, we evaluated whether treatment with the MPO inhibitor mitiperstat versus placebo for 48 weeks improved symptoms and exercise function at 16 weeks (the co-primary endpoints were the Kansas City Cardiomyopathy Questionnaire Total Symptom Score (KCCQ-TSS) and 6-minute walk distance (6MWD)). Secondary endpoints included changes in natriuretic peptides and inflammatory markers (up to 48 weeks) and echocardiographic parameters (up to 24 weeks). In total, 711 patients (45% women) were randomized 1:1:1 to mitiperstat 2.5 mg, mitiperstat 5 mg or placebo. Mitiperstat (pooled doses) did not improve KCCQ-TSS (placebo-corrected difference in mean change from baseline, -1.4 points (95% confidence interval (CI) -3.9, 1.2; P = 0.29), 6MWD (3.8 m (95% CI -3.1, 10.8)); P = 0.28) or any secondary endpoint. Adverse and serious adverse events, including infections, were similar among groups except for maculopapular rash (mitiperstat, 3.6%; placebo, 0.4%). These results indicate that mitiperstat was safe and well tolerated but did not improve symptoms or exercise function in chronic heart failure with preserved or mildly reduced ejection fraction. ClinicalTrials.gov registration: NCT04986202 .

Heart failure (HF) affects more than 60 million people worldwide, with significant discrepancies in diagnosis and management. Moreover, HF is associated with elevated mortality and hospitalization rates, increasing in the last decades. The universal definition of HF included a staging system (Stages A-D) specifically focused on disease progression. Patients "at risk" for HF (but without current or prior symptoms or signs of HF and without structural cardiac changes or elevated biomarkers of heart disease) represent stage A. The "pre-heart failure" refers to stage B, in which the patients display at least one of the following conditions: the evidence of structural heart disease, impaired cardiac function, or elevated cardiac biomarkers -such as troponins or natriuretic peptides. The specific purpose of this classification is to improve the early detection, risk stratification, and prevention of disease progression, promoting specific actions focused on the early risk identification and the optimization of metabolic and cardiovascular factors that could potentially favour the HF onset and progression. In this review, an expert panel analysed both the risk and the promoting factors for HF progression to early identify patients with higher risk of progression. In addition, a score has been proposed, based on a comprehensive evaluation of the patients through the identification of the HF risk factors, the natriuretic peptide levels, and the echocardiographic measurement, to help clinicians in early HF diagnosis. Overall, the lifestyle modifications and the intensive treatment of HF risk factors using old (ACEis/ARBs) and new drugs (SGLT2is, GLP1 RAs and nsMRAs) could prevent HF progression from stage A to stage B improving HF prognosis.

It is uncertain whether the effect of vericiguat varies across levels of background guideline-directed medical therapy (GDMT) in heart failure with reduced ejection fraction (HFrEF). We conducted an exploratory analysis of VICTOR, which enrolled 6105 ambulatory patients with HFrEF without recent worsening. GDMT exposure was classified as basic adherence (on vs. off), indication-corrected adherence (accounting for eligibility and contraindications), and dose-corrected adherence (≥50% target dose). A GDMT intensity score was computed from class-specific dose levels. The primary endpoint was the composite of cardiovascular death or first HF hospitalization. Stratified Cox proportional hazards regression models estimated adjusted hazard ratios for vericiguat versus placebo within GDMT strata, with treatment-by-GDMT interaction test. Baseline contemporary GDMT use was high (any ARNI/ACE/ARB 93.9%, ARNI 56%, SGLT2i 59%, MRA 78%, beta-blocker 94%). Basic adherence: adjusted HRs for the primary endpoint were similar whether or not patients were on ACEi/ARB, ARNI, any RAS inhibitor, beta-blocker, or SGLT2i. Dose-corrected adherence: adjusted HRs favored vericiguat in ARNI target-dose users (0.73; 0.57-0.93) and in any RAS target-dose users (0.77; 0.64-0.93), with lower risk on vericiguat in patients not meeting MRA target dose (0.67; 0.48-0.95); interaction P-values were nominally significant. The GDMT intensity score showed no significant interaction with treatment. Patterns for cardiovascular death and all-cause death paralleled the primary endpoint. In ambulatory patients with HFrEF receiving contemporary GDMT, we did not find convincing evidence that the neutral effect of vericiguat on cardiovascular death or first HF hospitalization was modified by GDMT class, dose attainment, or overall intensity, in a cohort with very high background GDMT use and limited power for interaction testing. These exploratory, hypothesis-generating findings do not establish independent efficacy or pathway additivity for vericiguat and should not be used to guide clinical recommendations regarding GDMT sequencing.

Patients with established atherosclerotic cardiovascular disease (ASCVD) are at high risk of developing heart failure (HF). However, incident HF is not part of the risk assessment of current guideline-recommended models. The aim of this study was to develop and externally validate the SMART2-HF model for prediction of incident HF in patients with ASCVD. SMART2-HF was developed in 7698 individuals with established ASCVD (coronary, cerebrovascular, or peripheral artery disease, or abdominal aortic aneurysm) but without prior HF from the UCC-SMART cohort. Cox proportional hazards models including sex-predictor interactions and with age as the time scale were derived to estimate the 10-year and lifetime risk of incident HF (hospitalization for HF or HF-related death), accounting for competing non-HF mortality. Predictors, limited to routinely available clinical characteristics, were aligned with the SMART2 risk model for recurrent cardiovascular (CV) risk in the same population. External validation was performed in 240 741 patients with ASCVD from six data sources: the Clinical Practice Research Datalink, the HUNT3 study, the SWEDEHEART Registry, the ASCVD-Particles cohort, the Estonian Biobank and the international REACH Registry. During a median follow-up of 11.2 years (interquartile range 6.1-16.4 years), 1031 incident HF events (13%) occurred in the UCC-SMART cohort. In the external validation data sources, a total of 24 885 incident HF events (10%) occurred. The pooled C-statistic was .696 (95% confidence interval .674-.717), with consistent performance in subgroups by sex and type of ASCVD. Predicted risks matched observed incidence in external validation. The SMART2-HF model enables the prediction of incident HF in patients with ASCVD. Aligned with the guideline-recommended SMART2 model for recurrent CV risk, SMART2-HF can be used as a complementary tool in this population.

Heart failure (HF) presents a significant and growing public health challenge. The aim of this study was to develop and validate SCORE2-HF, a model for HF risk estimation in European adults aged over 40 years without previous cardiovascular disease. Using data from 25 prospective cohorts (14 countries, 611 778 individuals, 21 818 incident HF events), the sex-specific, competing risk-adjusted SCORE2-HF models were derived, including age, smoking status, systolic blood pressure, antihypertensive treatment, body mass index (BMI), estimated glomerular filtration rate, and type 2 diabetes mellitus (including age at diagnosis and glycated haemoglobin). Using Europe-wide statistics from the World Health Organization and linked health records from five countries (>36 million individuals, 515 466 incident HF events), models were recalibrated to contemporary 10-year and 30-year HF incidence in four European risk regions. SCORE2-HF was validated using data from three further cohorts (three countries; 1 336 824 participants; 36 841 incident HF events). In the three external validation cohorts, C-indices (95% confidence interval) were .827 (.824-.829), .839 (.827-.850), and .874 (.863-.884). SCORE2-HF risks varied importantly by individual's risk factors and risk region. For example, in the low-risk region, the average 10-year risk for 70-year-old individuals with zero vs four adverse risk factors (smoking, type 2 diabetes mellitus, hypertension, and BMI ≥ 30 kg/m2), was 8% vs 24% in men and 6% vs 20% in women. By contrast, in the very high-risk region, the average SCORE2-HF risk with four adverse risk factors was 59% in 70-year-old men or women. SCORE2-HF-a model derived, recalibrated, and validated to estimate 10-year and 30-year risk of incident HF across European countries-may enhance the identification of individuals at higher risk of developing HF.

Heart failure (HF) with preserved ejection fraction (HFpEF) constitutes a heterogeneous disease with varying prognosis. Given the rising incidence of HFpEF, accurate risk prediction for these patients is needed to identify high-risk individuals, who may benefit the most from preventive treatments. The LIFE-Preserved model was developed and validated for the prediction of individual short-term and lifetime risk for HF hospitalization or cardiovascular (CV) death in patients with HFpEF. LIFE-Preserved was derived in 20 332 patients aged 40-90 years with a left ventricular ejection fraction ≥ 50% from the Swedish HF Registry. Cause- and sex-specific Cox models were derived to predict the risk of HF hospitalization or CV death using 14 routinely available predictors. Use of age as the timescale allowed for predictions beyond the maximum follow-up duration in the derivation data, adjusted for competing risks. External validation was performed in two trials (EMPEROR-Preserved and TOPCAT-Americas) and three registries (NHS England Secure Data Environment, Veterans Affairs, and HF-Particles). Model performance was assessed by discrimination and calibration. During a median follow-up of 1.8 years (interquartile range .6-4.2, maximum 19 years), 9341 first HF hospitalizations or CV deaths (46%) were observed in Swedish HF Registry. External validation included data from 28 062 patients with HFpEF [9930 (35%) first HF hospitalizations or CV deaths]. Pooled C-statistics were .714 (95% confidence interval .652-.775) in trials and .658 (95% confidence interval .599-.717 in registries, with adequate calibration in all external validation sources. Performance was similar in men and women. An interactive calculator of the LIFE-Preserved model has been made available here. The LIFE-Preserved model enables prediction of short-term and lifetime risk of HF hospitalization or CV death in patients with HFpEF. The model could serve as a tool to identify high-risk HFpEF patients, guiding clinical management and shared decision-making.

Heart failure (HF) is a major global health burden, yet its true prevalence remains uncertain due to heterogeneous study designs and evolving diagnostic criteria. The Portuguese Heart Failure Prevalence Observational Study (PORTHOS) aimed to estimate the prevalence and phenotypic distribution of HF in community-dwelling adults aged ≥50 years in mainland Portugal. PORTHOS was a cross-sectional, population-based study with a two-stage design. Stage 1 randomly selected community-dwelling individuals aged ≥50 years via structured interviews and point-of-care N-terminal pro-B-type natriuretic peptide (NT-proBNP) testing. Individuals with NT-proBNP ≥125 pg/mL and/or a self-reported HF diagnosis, plus a random 5% of screen-negatives, proceeded to stage 2. This confirmatory stage included clinical assessment, electrocardiogram, and echocardiography. HF diagnosis required the presence of symptoms, NT-proBNP ≥125 pg/mL, and echocardiographic criteria. HF was defined as per the 2021 ESC and HFA-PEFF guidelines. Of 6189 participants, 2249 screened positive and 1136 were diagnosed with HF. The estimated HF prevalence was 16.54%, increasing with age (from 4.01% in 50-59 years old to 30.68% in those ≥70) and higher in females than males (21.00% vs 10.47%). Notably, 93.4% had HF with preserved ejection fraction (HFpEF), and 90% were previously undiagnosed. HFpEF was independently associated with older age, female sex, type 2 diabetes, atrial fibrillation, and dyslipidaemia. HF affects approximately one in six Portuguese adults aged ≥50 years, with HFpEF accounting for over 90% of cases, most previously undiagnosed. These findings support NT-proBNP-based screening combined with echocardiographic evaluation to improve early HF detection in ageing populations.

Respiratory sarcopenia, characterized by reduced respiratory muscle mass and function, can impair ventilatory reserve and physical capacity, potentially worsening outcomes. However, its prevalence and prognostic significance in older patients with heart failure remain unclear. This study aimed to investigate the clinical significance of respiratory sarcopenia in this population. This was a post hoc analysis of the compariSON of various methods In evaluatIon of sarCopenia in patients with Heart Failure (SONIC-HF) study, a multicentre prospective observational study. Among 435 patients hospitalized for heart failure [median age: 81 (interquartile range 74-85) years; 41.8% female], we defined respiratory sarcopenia as the presence of both low resting diaphragm thickness, assessed using ultrasonography, and reduced per cent predicted forced vital capacity (FVC), a surrogate for respiratory muscle strength. The primary outcome was 2 year all-cause mortality. Respiratory sarcopenia was observed in 47 patients (10.8%). During the 2 year follow-up, 78 patients (17.9%) died. All-cause mortality was significantly higher among patients with respiratory sarcopenia than those without (P < 0.001). In Cox proportional hazards analysis, respiratory sarcopenia was independently associated with increased mortality risk (hazard ratio, 2.51; 95% confidence interval, 1.40-4.50; P = 0.002), even after adjustment for conventional risk factors. Low diaphragm thickness or reduced per cent predicted FVC alone were not associated with mortality. In older patients with heart failure, respiratory sarcopenia was uncommon but associated with significantly higher mortality. Simultaneous assessment of respiratory muscle mass and function may aid in identifying high-risk individuals and enhance risk stratification beyond structural assessments alone.

The Global Leadership Initiative on Sarcopenia (GLIS) defines sarcopenia based on muscle mass, muscle strength, and muscle-specific strength, considering physical performance as an outcome rather than a diagnostic criterion. This study aimed to evaluate whether the GLIS model can effectively assess the prognostic value and impaired physical performance in older patients with heart failure. A post hoc analysis of the FRAGILE-HF study, a multicentre prospective observational cohort study, was conducted. The analysis included 891 patients [median age: 81 (interquartile range: 74-86) years; 41.9% women] hospitalized for heart failure. Sarcopenia and possible sarcopenia were assessed using the GLIS model. The primary outcome was 2-year all-cause mortality, and the secondary outcome was impaired physical performance, including 6-min walk distance. According to the GLIS model, sarcopenia and possible sarcopenia were observed in 186 (20.9%) and 539 (60.5%) patients, respectively. Sarcopenia was associated with significantly increased 2-year mortality [adjusted hazard ratio 3.38, 95% confidence interval (CI) 1.74-6.56, P < 0.001]. Sarcopenia and possible sarcopenia were significantly associated with impaired physical performance. The diagnosis of sarcopenia based on the GLIS model provided superior prognostic discrimination compared to the diagnosis based on the conventional Asian Working Group for Sarcopenia 2019 model (net reclassification improvement 0.269, 95% CI 0.141-0.397, P < 0.001). The diagnosis of sarcopenia based on the GLIS model was associated with prognosis and impaired physical performance in older patients with heart failure.

Trial registration NCT06684743, registered 9 November 2024 (https://clinicaltrials.gov/study/NCT06684743).

Galectin-3, a β-galactoside-binding lectin, is a driver and regulator of inflammation and fibrosis, and its levels are elevated in some heart and lung diseases. It also serves as a biomarker for the risk and severity of some forms of heart failure and, potentially, for various other pathological conditions. These observations make galectin-3 a promising potential therapeutic target. Both genetic and pharmacological inhibition of galectin-3 have been shown to ameliorate renal dysfunction and exert protective effects against liver fibrosis in animal models. Several galectin-3 inhibitors have been developed for therapeutic application in various pathological conditions. This review examines the progress of the development of 161 galectin-3 inhibitors, including monosaccharides, oligosaccharides, natural polysaccharides and their derivatives, carbohydrate polymers, antibody-drug conjugates, and non-carbohydrate compounds. Structure-activity relationships are emerging for these inhibitors, and the atypical binding pockets of galectin-3 have informed the development of a pharmacophore model that is expected to guide the design and discovery of potent, selective inhibitors for treatment of cancer, inflammation, and fibrosis.

Pathogenic immune-cardiac crosstalk underlies maladaptive remodeling in chronic heart failure, yet therapies directly targeting this axis are lacking. Glycoconjugates, which are crucial for signal transduction and extracellular matrix integrity, represent an underexploited therapeutic avenue. This study sought to define the role of glycoconjugate-metabolizing enzymes at the immune-cardiac interface and evaluate their translational potential. We performed integrative analyses of bulk and single-cell RNA sequencing data from failing human and mouse hearts. Employing mouse models of pressure overload (transverse aortic constriction) and ischemia-reperfusion, we used global and mast cell (MC)-specific gene deletion, bone-marrow chimeras, and pharmacological neutralization. Mechanistic insights were gained through multiomics profiling, including RNA-seq, ATAC-seq, CUT&Tag, and proteomics. The ganglioside GD3 synthase, St8sia1, was selectively induced in cardiac MCs during pathological remodeling in both mice and humans. MC-specific or hematopoietic deletion of St8sia1 preserved ventricular function, attenuated fibrosis, and markedly reduced neutrophil and Ly6C+ monocyte recruitment after transverse aortic constriction and ischemia-reperfusion. Therapeutic neutralization of GD3 with the clinical-grade monoclonal antibody R24 improved cardiac function and diminished scar formation after ischemia-reperfusion. Mechanistically, GD3 bound specific histone variants, such as H2A.Z and H3.3C, thereby reprogramming chromatin accessibility to activate proinflammatory and profibrotic transcriptional programs in MCs. Consequently, GD3 inhibition suppressed MC degranulation, disrupted pathogenic MC-cardiomyocyte/fibroblast crosstalk, and preserved reparative macrophage populations. The MC-restricted St8sia1-GD3 axis functions as a glyco-epigenetic checkpoint driving maladaptive cardiac remodeling. Targeting this axis represents a translatable immunomodulatory strategy to prevent the progression to chronic heart failure.

Nx3 (novex-3) is an exceptionally small isoform of the giant protein titin, whose structural and functional roles within the sarcomere remain poorly understood. We used a comprehensive, multimodal approach to define the key properties of Nx3 in healthy and failing hearts, including its abundance relative to FLT (full-length titin), sarcomeric localization, protein interactions, and functional relevance in mouse and human cardiomyocytes under physiological and pathological conditions. Using Western blotting, quantitative polymerase chain reaction, total RNA sequencing, and ribosome profiling, we show that Nx3 is constitutively expressed from fetal development through adulthood. In adult mouse and human myocardium, Nx3 accounts for ≈20% to 25% of total titin protein, despite representing only ≈8% to 14% at the transcript level. Immunoelectron microscopy and binding studies reveal that Nx3 adopts a nonlinear configuration within the sarcomere: its N terminus is anchored at the Z-disk, although the proximal portion of its unique region encoded by Ttn exon 48, enriched in coiled-coil motifs, engages laterally with adjacent titin or Nx3 molecules at the Z-disk/I-band interface. Its monomeric C terminus extends toward the A-band but remains confined to the Z-/I-band region. This architecture confers enhanced stability and flexibility to the Z-disk under mechanical load. Protein interaction studies, including yeast 2-hybrid screening and coimmunoprecipitation, identified Pin1 (peptidyl-prolyl cis-trans isomerase NIMA-interacting 1) and TBC1D4 (TBC1 domain family member 4) as binding partners of the Nx3 C terminal region, suggesting participation in signaling networks regulating cardiomyocyte metabolism. Genetic ablation of Nx3 in mouse hearts and human induced pluripotent stem cell-derived cardiomyocytes indicates that, although dispensable for sarcomere assembly, Nx3 is required for optimal Z-disk organization and mechanical performance. In end-stage dilated cardiomyopathy, human hearts exhibit dysregulated Nx3 expression, with reduced protein abundance relative to nonfailing controls and focal Z-disk disruption, likely contributing to impaired contractile function. Nx3 regulates Z-disk stability and modulates signaling pathways that optimize cardiac performance, and its dysregulation contributes to heart failure pathogenesis.

Stratification of stroke risk remains challenging, but metabolomic profiling offers the potential to detect new biomarkers and to improve early risk assessment of incident stroke. The objective of this study was to evaluate the association between circulating metabolites and the incidence of stroke in a case-cohort study conducted across several large population-based European cohorts. Following the case-cohort design, a subset of 10 299 individuals, including all individuals with incident stroke, was selected from the original cohort of >70 000 individuals. The case-cohort design used a random subsample of the selected population cohorts, supplemented with cases not sampled in this random subcohort. A total of 141 circulating metabolites were measured from serum samples of the selected individuals, and associations of these metabolites with risk of incident stroke were estimated and compared with those of classic risk factors (sex, age at examination, systolic blood pressure, total cholesterol, body mass index, diabetes, daily smoking status, and antihypertensive treatment). Associations with time to stroke were assessed using weighted Cox proportional hazards models adjusted for the classic risk factors. Hazard ratios (HRs) for the log-transformed metabolites were reported per 1 SD increase. Of the 70 195 individuals in the original cohort, 1516 (2.2%) experienced incident strokes during a median follow-up time of 8.9 years (interquartile range, 4.4-14.7). Median age was 56.8 years (interquartile range, 49.5-62.4), and 39.5% were female. Six of the 141 metabolites (2 diacyl-phosphatidylcholines, 2 lyso-phosphatidylcholines, 1 hydroxysphingomyelin, and glutamic acid) remained significantly associated with incident stroke after correction for multiple comparisons (adjusted HRs [95% CIs] per SD: lyso-phosphatidylcholines a C18:2 HR, 0.88 [95% CI, 0.82-0.93], lyso-phosphatidylcholines a C17:0 HR, 0.88 [95% CI, 0.83-0.94], hydroxysphingomyelin C14:1 HR, 0.90 [95% CI, 0.85-0.94], diacyl-phosphatidylcholines C34:1 HR, 1.10 [95% CI 1.05-1.16], diacyl-phosphatidylcholines C32:1 HR, 1.14 [95% CI, 1.08-1.21], glutamic acid HR, 1.23 [95% CI 1.11-1.37]). The strengths of these associations were similar to those for classic cardiovascular risk factors (C statistics for 10-year prediction ranging from 0.782 to 0.785 for metabolites compared with 0.781 to 0.792 for classic cardiovascular risk factors). Among 10 299 individuals from the general European population, we identified 6 metabolites from 4 different metabolite classes that were associated with future risk of stroke. The application of specific circulating metabolites may improve early stroke risk prediction before the onset of potentially irreversible cerebrovascular pathological processes.

Acute basilar artery occlusion causes devastating strokes. Despite the benefit of endovascular treatment, the optimal management remains controversial in specific subgroups, particularly patients with mild deficits, and would benefit from robust prognostic tools. Given the dense white matter networks within the posterior fossa, we tested whether quantifying disconnections from acute diffusion-weighted imaging could improve outcome prediction and identify responders to recanalization compared with conventional metrics. We conducted a secondary analysis of a prospective multicenter stroke registry in France, including consecutive patients (2017-2024) with basilar artery occlusion and admission magnetic resonance imaging. Ultra-high-resolution diffusion magnetic resonance imaging was acquired in 2 healthy participants to build normative tractograms with optimized posterior fossa quality. Patient infarcts delineated on diffusion-weighted imaging were projected onto these tractograms to estimate disconnected fiber volume. The primary outcome was 90-day modified Rankin Scale score (0-3 versus 4-6). Predictive performance of disconnected fiber volume was compared with baseline National Institutes of Health Stroke Scale (NIHSS), infarct volume, and posterior circulation Alberta Stroke Program Early Computed Tomography Score using logistic regressions and area under the receiver operating characteristic curves. Ordinal regressions tested associations between dichotomized disconnection status and the full modified Rankin Scale spectrum, stratified by recanalization status. Analyses were repeated in patients with an NIHSS score ≤10. Among 201 patients (median age, 70; NIHSS score, 10), 97 (48.3%) had a poor outcome. Despite a small median infarct volume (4.75 mL), disconnected fiber volume was substantial (median 25.15 mL). Disconnected fiber volume achieved an area under the receiver operating characteristic curves of 0.84, outperforming NIHSS score (0.67; P<0.0001), infarct volume (0.75; P=0.00059), and posterior circulation Alberta Stroke Program Early Computed Tomography Score (0.76; P=0.0127). Patients without significant disconnection had better outcomes across the full modified Rankin Scale spectrum (odds ratio, 0.12 [95% CI, 0.065-0.204]) and derived greater benefit from successful recanalization (odds ratio, 0.33 [95% CI, 0.15-0.70]). In patients with an NIHSS score ≤10 (n=102), disconnected fiber volume remained the strongest predictor (area under the receiver operating characteristic curves of 0.83). Disconnected fiber volume derived indirectly is a robust prognostic marker of basilar artery occlusion outcomes that outperforms conventional predictors and may support future treatment decisions after prospective validation. URL: https://clinicaltrials.gov; Unique identifier: NCT03776877.

Vessel wall magnetic resonance imaging (VW-MRI) is a promising tool for evaluating intracranial arteriopathies in pediatric non-neonatal arterial ischemic stroke, but its diagnostic and prognostic roles remain underexplored. This study assesses the utility of VW-MRI in identifying arteriopathy subtypes and predicting clinical and radiological outcomes in children. We conducted an ancillary retrospective study using the national KidClot cohort and the stroke database at Necker-Enfants Malades Hospital (Paris). Children with arterial ischemic stroke who underwent VW-MRI within 3 months of onset and follow-up MRI at least 18 months later were included. Stroke causes were assessed according to the Childhood Arterial Ischemic Stroke Standardized Classification and Diagnostic Evaluation, and intracranial arterial vessel wall enhancement (VWE) was evaluated. Analyses focused on the focal cerebral arteriopathy (FCA) subgroup, comparing VWE-positive and VWE-negative patients and assessing correlations with clinical factors, imaging metrics, and outcomes. Categorical variables were compared using the χ2/Fisher exact test, qualitative/ordinal variables using the Mann-Whitney U test, and correlations were assessed using the Spearman rank correlation coefficient (ρ). From 193 children, 67 were included (median age, 4.1 years, interquartile range, 2.0-9.8; 61.1% male). Causes were FCA (42%, 28/67), bilateral cerebral arteriopathy (5%, 3/67), aortic/cervical arteriopathy (12%, 8/67), cardioembolic (7%, 5/67), other (22%, 15/67), and multifactorial (12%, 8/67). In FCA, 75% (21/28) showed concentric VWE, correlating with stenosis severity (ρ=0.31; P=0.001). VWE-positive patients with FCA had a higher initial focal cerebral arteriopathy severity score (median 5 versus 3; P=0.046) than VWE-negative patients, but no statistically significant differences were found in other evaluated factors, including initial Pediatric National Institutes of Health Stroke Scale (median 8.5 versus 8; P=0.5) and 12-month Pediatric Stroke Outcome Measure (median 0.5 versus 1; P=0.8). VW-MRI detects inflammatory arterial changes in pediatric FCA. However, its prognostic value is limited, suggesting enhancement reflects acute inflammation rather than long-term trajectory.

Intravenous thrombolysis remains the standard treatment for distal and medium vessel occlusion (DMVO) strokes. However, unlike large vessel occlusions, whether tenecteplase achieves higher early successful recanalization rates than alteplase in DMVO strokes remains uncertain. This single-center observational cohort study included consecutive patients with magnetic resonance imaging (MRI)-confirmed DMVO stroke treated at Centre Hospitalier Sud-Francilien, France, according to an institutional thrombolysis protocol specifying alteplase (0.9 mg/kg, 2016-2018) or tenecteplase (0.25 mg/kg, 2018-2023), with follow-up MRI 1 to 2 hours after intravenous thrombolysis. Patients intended for endovascular thrombectomy or without diagnostic-quality follow-up MRI were excluded. Recanalization was blindly assessed using a modified Arterial Occlusion Lesion scale designed for MRI and DMVO. Early successful recanalization was defined as ≥50% recanalization on early follow-up MRI (grade ≥2b), and substantial early infarct growth, assessed using a semiautomatic segmentation technique, was defined as a ≥0.5 mL and ≥20% increase in lesion volume. Propensity-score weighting accounted for baseline imbalances, including age, sex, vascular risk factors, baseline National Institutes of Health Stroke Scale score, occlusion site, and time period (2020-2023 versus 2016-2019). Of the 319 included patients, 159 were treated with tenecteplase and 160 with alteplase. Median baseline National Institutes of Health Stroke Scale was 3 (1-7) in the tenecteplase group versus 4 (1-7.5) in the alteplase group, while M2 occlusions accounted for 54.1% versus 43.8% of cases. Early successful recanalization, assessed at a median postintravenous thrombolysis time of 80 (70-94) minutes, occurred in 72 (45.3%) and 53 (33.1%) patients treated with tenecteplase and alteplase, respectively (propensity-score weighting-odds ratio, 1.59 [95% CI, 1.15-2.20]; P=0.005). Substantial early infarct growth was observed in 42 (26.8%) and 64 (40.5%) patients, respectively (propensity-score weighting-odds ratio, 0.49 [95% CI, 0.35-0.69]; P<0.0001). Compared with alteplase, tenecteplase-treated patients with DMVO had higher early successful recanalization and a lower risk of substantial early infarct growth, supporting its preferential use in this setting. URL: https://www.clinicaltrials.gov; Unique identifier: NCT05635786.

Acute ischemic stroke (AIS) survivors are at high risk of major adverse cardiovascular events (MACE), highlighting the need to identify modifiable secondary prevention targets. We assessed whether postacute discharge destination is associated with 1-year MACE risk among AIS survivors. In this retrospective cohort study, adult AIS survivors were identified from the state inpatient and emergency department databases of 5 US states (2016-2019) and categorized by discharge destination: home, inpatient rehabilitation facility (IRF), or skilled nursing facility (SNF). Other destinations were excluded. The primary outcome was 1-year MACE, defined as recurrent stroke, acute myocardial infarction, systemic embolism, or vascular death. Multivariable Cox models, adjusted for demographic and clinical factors, were used to evaluate the association between discharge disposition and MACE risk. Fine-Gray models were used for nonfatal secondary outcomes, and restricted mean survival time analyses were used to estimate absolute risk. Effect modification by age (<65 versus ≥65 years) was examined. Confounder-adjusted number-needed-to-be-exposed was estimated by marginal standardization. Among 213 511 AIS survivors (median age, 71 years), 16 237 (7.6%) experienced MACE within 1-year. MACE incidence was lowest after IRF discharge (6.6%) versus home (7.6%) or SNF (8.3%). In adjusted analyses, IRF discharge was associated with lower MACE risk versus home (adjusted hazard ratio, 0.88 [95% CI, 0.83-0.93]) and SNF (0.84 [95% CI, 0.79-0.89]). The association persisted across age strata but was more pronounced in patients <65 years (Pinteraction=0.014). Restricted mean survival time analyses indicated that IRF discharge was associated with 3.47 and 3.87 additional MACE-free days versus home and SNF discharge, respectively (both P<0.001). Adjusted number-needed-to-be-exposed were 115 (95% CI, 80-207) for IRF versus home and 87 (95% CI, 64-136) for IRF versus SNF. Postacute IRF discharge is associated with a lower 1-year MACE risk after AIS, highlighting the postacute care setting as a potentially modifiable system-level target for secondary prevention of long-term vascular outcomes.

Carotid artery disease remains a major cause of acute ischemic neurologic syndromes. Contemporary care has evolved into a multi-disciplinary model, involving vascular medicine, neurology, vascular surgery, interventional radiology, interventional cardiology and others. An integrated approach that combines plaque characteristics, symptom timing, cerebral vulnerability, vascular anatomy, patient age and comorbidities is employed to identify optimal treatment strategies. This review focuses on mechanisms of carotid-related stroke, imaging, medical therapy, revascularization of symptomatic and asymptomatic patients and procedural planning. Emphasis is placed on vascular anatomy-driven procedural selection, embolic-risk mitigation, and the complementary roles of carotid endarterectomy, carotid artery stenting, and transcarotid artery revascularization. Optimal outcomes depend less on applying a single preferred revascularization procedure and more on selecting the strategy that most effectively reduces embolic risk and minimizes patient-specific hazards.

White matter preservation is a rate-limiting factor in neurological recovery after ischemic stroke and depends on efficient clearance of myelin debris by microglia/macrophages. Our prior work demonstrated that microglia/macrophage-specific SIK3 (salt-inducible kinase) knockout (SIK3-mKO) promotes an anti-inflammatory subset, enhances myelin phagocytosis, and limits white matter injury, yet the downstream molecular mechanisms remain undefined. Here, we elucidate a previously unrecognized signaling axis underlying these protective effects. SIK3-mKO mice (SIK3Flox+/+;CX3CR1CreER) were generated via tamoxifen-induced Cre recombination. Transient focal cerebral ischemia was induced by 60-minute transient middle cerebral artery occlusion. Neurological outcomes were assessed via Garcia, rotarod, foot-fault, and adhesive-removal tests. Immunofluorescence, flow cytometry, single-cell RNA sequencing, real-time quantitative polymerase chain reaction, ex vivo myelin phagocytosis assay, magnetic resonance imaging, and compound action potential recordings were used to characterize microglia/macrophage polarization, myelin phagocytic capacity, white matter integrity, and nerve conduction function. In the acute phase poststroke, SIK3-mKO selectively upregulated CD11c and its upstream complement initiator component 1q in anti-inflammatory microglia/macrophage subsets. Within the 400 to 800 µm peri-infarct zone, SIK3-mKO elevated the proportion of CD11c+ microglia/macrophage by 15.1% and C1q+ microglia/macrophage by 15.8% relative to wild-type controls. This CD11c-component 1q axis enhanced myelin debris clearance by 19.0% while constraining pathological engulfment of intact myelin, representing a balanced functional switch that mitigates severe demyelination. Conversely, myeloid-CD11c silencing using AAV-Itgax shRNA partially reversed SIK3-mKO-conferred protection. CD11c knockdown reduced anti-inflammatory microglia/macrophage proportions by 9.7%, attenuated physiological phagocytosis and lowered debris clearance efficiency by 7.5%, reduced MBP (myelin basic protein)-positive myelin preservation by 10.0%, and ultimately impaired white matter preservation and neurological recovery. We identify the SIK3-CD11c-component 1q axis as a novel pathway that orchestrates microglia/macrophage phagocytic homeostasis and preserves white matter integrity after ischemic stroke. These findings clarify SIK3 signaling in microglia/macrophage and highlight the CD11c-centered complement cascade as a promising therapeutic target for restoring white matter integrity in poststroke neurorepair.

Intracerebral hemorrhage (ICH) is among the most severe stroke subtypes, especially the secondary brain injury synergistically driven by oxidative stress and neuroinflammation, which leads to severe progressive tissue damage and neurological deterioration. Currently, there are no effective and long-lasting targeted treatments for secondary brain injury caused by ICH. Here, we report an in situ biomimetic self-assembly strategy based on a fibrillar, transformable peptide (NKF) that coordinately suppresses oxidative stress and neuroinflammation. In aqueous solution, NKF self-assembles into nanoparticles; upon binding to KEAP1 in microglia, however, it undergoes an in situ transformation into nanofibrils, thereby enhancing intracellular retention and sustaining KEAP1 sequestration. In cellular and rat ICH models, NKF promotes sustained Nrf2 nuclear translocation and ARE-dependent transcription, resulting in enhanced antioxidant defense, attenuated pro-inflammatory signaling, and a shift in microglial phenotype towards a neuroprotective anti-inflammatory state. This physical conformation transformation strategy based on lesion-responsive peptide biomimetic assembly establishes a generalizable nanoplatform for durable activation of an endogenous neuroprotective pathway.

Stroke induces complex pathophysiological responses that extend beyond the brain, yet the mechanisms through which peripheral signals influence stroke recovery remain largely unclear. Here, we identify a novel gut-brain neural circuit that promotes stroke recovery via kynurenic acid (KYNA) signalling. In a training cohort (30 patients with acute ischaemic stroke (AIS) and 30 controls), untargeted metabolomics profiled intestinal metabolites and the key metabolite KYNA was validated in an independent cohort (100 patients with AIS and 100 controls) using targeted metabolomics and assessed for its 3-month prognostic value. In stroke mouse models, KYNA was administered to evaluate therapeutic effects. Mechanistic studies combined neuronal calcium imaging, enteric neuron receptor manipulation, vagotomy, neuronal tracing, electrophysiology and immunofluorescence to delineate the KYNA-mediated gut-brain neural circuit regulating stroke recovery. Our study demonstrates a significant reduction of intestinal KYNA in patients with AIS and validates its prognostic value for neurological recovery at 3 months poststroke in both the training and validation cohorts. Oral KYNA supplementation markedly improves poststroke cerebral injury by activating G protein-coupled receptor 35 (GPR35) on enteric neurons, initiating vagal nerve signalling. Mechanistically, KYNA-GPR35 interaction activates vagal afferents, transmitting signals through the nucleus tractus solitarius to hippocampal and hypothalamic regions. This GPR35-vagus nerve signalling pathway, further validated with the selective GPR35 agonist Zaprinast, confers neuroprotection by shifting microglial polarisation towards the anti-inflammatory M2 phenotype and enhancing neuronal α7 nicotinic acetylcholine receptor activity. KYNA acts through an intestinal GPR35-vagus neural pathway to influence stroke recovery, highlighting this gut-brain signalling axis as a promising therapeutic avenue.

Evidence on the associations between tropical cyclone (TC) exposure and acute coronary syndrome (ACS) remains limited, particularly in developing countries. Therefore, this study aimed to investigate the short-term association between TC exposure and ACS incidence and explore potential effect modifiers. This time-stratified case-crossover study included ACS patients from a nationwide registry in mainland China between 2015 and 2022. The Willoughby wind field model was chosen to estimate TC-associated wind speeds, with TC exposure defined as the occurrence of daily maximum sustained wind speeds ≥17.5 m/s. The outcomes included ACS and its subtypes, namely, ST-elevation myocardial infarction, non-ST-elevation myocardial infarction, and unstable angina. Conditional quasi-Poisson models with distributed lag non-linear models were applied to assess TC-ACS associations and lag structures. Subgroup analyses were conducted to identify potential effect modifiers. A total of 2 563 780 individuals (64.0 ± 12.4 years; 68% males) were included. Compared with non-TC days, TC days were associated with longer delays in self-referral to the hospital (5.8 vs 5.3 h) and longer admission-to-catheterization times (1.0 vs 0.9 h). Over the 0-3-day period following TC exposure, the risk of developing ACS increased by 14% (95% confidence interval: 2% to 27%). Stronger associations were observed among males, individuals with lower education levels, and those with more ACS risk factors. TC exposure may increase the ACS burden by simultaneously increasing the risk of incidence and delaying treatment. The government, the public, and healthcare institutions must collaborate proactively to alleviate the burden of TC-associated ACS.

We aimed to (i) investigate associations between leisure time physical activity level cumulated over 20 years and multiple plasma proteins and (ii) explore if proteins significantly associated with physical activity are also associated with risk of imminent myocardial infarction (MI), long-term MI, and mortality. In the cohort Uppsala Longitudinal Study of Adult Men, leisure time physical activity was self-reported at Ages 50, 60, and 70. At Age 70, 720 plasma proteins were analysed in 782 participants with up to 19.3 years of follow-up for MI and 26.3 years follow-up for mortality. In the nested case-cohort study Markers of Imminent Myocardial Infarction, plasma proteins were measured in disease-free individuals from six European cohorts. Cases (n = 420) were those with acute MI within 6 months of a blood draw, with up to four cohort representatives per case (n = 1598). A higher level of leisure time physical activity level was inversely associated with 12 plasma proteins after adjusting for age, education, smoking, and established cardiovascular risk factors (Bonferroni-corrected P < 0.000069). Of these 12 proteins, interleukin-6 was associated with increased incidence of imminent MI [hazard ratio, HR 1.22; 95% confidence interval, CI (1.09-1.37)], tumour necrosis factor receptor superfamily member 11A was associated with increased long-term MI incidence [HR 1.22 (1.01-1.48)] and 11 proteins were associated with increased mortality [HR 1.14-1.30 (1.01-1.42)]. These findings confirm and extend our understanding of how physical activity could assert its beneficial effect on cardiovascular health through proteins involved with modulating inflammatory, immune, and metabolic pathways. Further research is needed to explore the causal mechanisms behind these associations. In this study, we aimed to investigate (i) whether leisure time physical activity level cumulated over 20 years is associated with 720 plasma proteins and (ii) if proteins that are significantly associated with leisure time physical activity level across 20 years in Part 1 are also associated with imminent and long-term risk of myocardial infarction (MI) and mortality.Higher physical activity level over 20 years was inversely associated with 12 plasma proteins involved in inflammatory, immune, and metabolic processes. Several plasma proteins were in turn associated with MI and mortality.Findings confirm and extend our understanding how physical activity could assert its beneficial effect on cardiovascular health via the circulating plasma proteins.

Many observational studies have reported associations between low serum 25-hydroxyvitamin D [25(OH)D] levels and adverse cardiovascular (CV) outcomes. However, randomized trials have not demonstrated a reduction in CV events with vitamin D supplementation, potentially due to fixed or non-targeted dosing strategies. The aim of this study was to determine if targeted vitamin D management among myocardial infarction (MI) patients reduces CV events. TARGET-D is a pragmatic randomized trial, where subjects were randomized to usual care or targeted vitamin D management between April 2017 and May 2023 (average follow-up 4.2 ± 2.0 years). The treatment arm received vitamin D3 supplementation and ongoing titration based on a dosing algorithm to reach and maintain a target 25(OH)D level of >40-80 ng/mL. TARGET-D concluded follow-up on 17 March 2025, when ≥104 primary outcome events (major adverse CV events: composite of death, MI, heart failure hospitalization, and stroke) occurred. Participants (n = 630) had a median age of 63 (interquartile range: 55-70) years and 78.1% were men. Baseline 25(OH)D levels were 25 (interquartile range: 18-33) ng/mL, with 87.0% ≤ 40 ng/mL, and 52.4% began vitamin D3 dosing at 5000 IU. Major adverse CV events did not achieve significance [vitamin D: 15.7% vs usual care: 18.4%; hazard ratio (HR) .85, 95% confidence interval .58-1.24, P = .40]. Among secondary endpoints, outcomes for vitamin D vs usual care were 8.9% vs 9.2% for death (HR .98, P = .95), 3.8% vs 7.9% for MI (HR .48, P = .03), 4.2% vs 3.5% for heart failure hospitalization (HR 1.21, P = .65), and 1.6% vs .9% for stroke (HR 1.69, P = .47). Prevalence of 25(OH)D insufficiency was high among MI patients. Targeted vitamin D supplementation and ongoing titration did not significantly reduce major adverse CV events.

Ischemic heart disease remains a leading cause of global mortality, primarily driven by myocardial infarction and subsequent ischemia-reperfusion injury (MI/RI) following coronary artery occlusion. This highlights a critical unmet clinical need for integrated strategies that enable both timely intervention during the acute phase and precise postinjury assessment of myocardial damage. Here, we report a theranostic platform based on a dual-modality near-infrared II fluorescence and photoacoustic imaging probe targeting the angiotensin II type 1 receptor (AT1R). The system is coloaded with losartan and exosomes derived from induced pluripotent stem cell-derived cardiomyocytes (iCMs), enabling noninvasive, high-resolution visualization and evaluation of myocardial injury. Under imaging guidance, this platform allows spatially precise delivery of therapeutics, thereby integrating the antifibrotic and anti-inflammatory effects of AT1R blockade with the regenerative paracrine signaling mediated by iCM-derived exosomes. The synergistic therapeutic efficacy of this system was systematically validated in established mouse and rat models of MI/RI, demonstrating enhanced angiogenesis, attenuation of fibrosis, and improved cardiac functional recovery. Collectively, this study establishes a multifunctional platform that integrates diagnosis and therapy, providing a promising strategy for the precise management of MI/RI.

Postmenopausal women have higher risks of myocardial infarction (MI) and subsequent cardiac dysfunction. Exercise is widely recognized to protect the cardiovascular system, but its molecular mechanisms in postmenopausal MI are not fully understood. This study explored the effects and mechanisms of swim exercise against cardiac dysfunction in ovariectomized (OVX) mice post MI. OVX mice were subjected to a 3-week swim training before MI induction via permanent ligation of the left anterior descending artery. Cardiac systolic function was evaluated by echocardiography. Masson, hematoxylin-eosin (HE), wheat germ agglutinin (WGA) staining, reverse transcription quantitative polymerase chain reaction (RT-qPCR), and western blotting were combined to detect the extent of cardiomyocyte hypertrophy, myocardial fibrosis, and apoptosis. To explore the key exercise-effectors, we detected microRNAs (miR-21, miR-146a, and miR-155) in serum samples of elderly post-MI women performed exercise rehabilitation training. miR-21 expression was further investigated in heart samples of OVX plus MI mice. The role of miR-21 in vivo was elucidated through an miR-21 knockout mice model and an adeno-associated virus serotype 9 (AAV9)-mediated miR-21 overexpression mice model combined with ovariectomy treatment. The function of miR-21 in vitro was evaluated in cardiac fibroblasts isolated from OVX mice and treated with transforming growth factor-beta (TGF-β) to induce its activation. Target genes of miR-21 were identified by RNA-sequencing (RNA-seq) and validated using luciferase reporter assays and functional rescue experiments. Swim training significantly improved cardiac function in OVX mice post MI, alleviated cardiomyocyte hypertrophy, reduced myocardial fibrosis, and inhibited apoptosis. miR-21 expression was downregulated by exercise training in the hearts of OVX mice post MI and in the serum of elderly women after MI. miR-21 knockout mice recapitulated the cardioprotective effects of swim training in OVX mice post MI, whereas miR-21 overexpression eliminated these effects. The overexpression of miR-21 promoted the TGF-β-induced differentiation of cardiac fibroblasts into myofibroblasts and their proliferation, whereas its inhibition blocked TGF-β's pro-fibrotic role. RNA-seq and luciferase reporter assays identified SRY-box transcription factor 7 (Sox7) as a direct miR-21 target. Furthermore, Sox7 knockdown reversed anti-fibrotic effects conferred by miR-21 inhibition. Swim training protects against post-MI cardiac dysfunction in OVX mice by downregulating myocardial miR-21, thereby upregulating its target gene Sox7 and inhibiting cardiac fibroblast activation. miR-21 and its downstream target Sox7 contribute to the cardioprotective effects of swim training, offering a potential target for postmenopausal MI treatment.

Myocardial infarction (MI) initiates a wound-healing response where immune cells shape inflammation, tissue repair, and long-term remodeling. Although CD4+ T cells are increasingly recognized as contributors to post-MI healing, the transcriptional reprogramming defining their early pro-reparative functions remains incompletely resolved. Here, RNA sequencing of cardiac CD4+ T cells isolated 1 week after MI found that a substantial post-MI transcriptional fraction lay outside canonical cytokine-induced T helper subset polarization, including type 1 T helper cell (Th1), Th2, Th17, nature-occurring CD4+ regulatory T cell (nTreg), and peripherally induced Treg (iTreg) reference transcriptomic programs. Instead, this response was organized into a distinct CD4+ Th tissue injury-polarized (CD4+/TIP) transcriptomic module enriched for extracellular matrix organization, adhesion, vascular, and developmental programs, with a coordinated downregulated arm involving RNA metabolism, chromatin regulation, and protein catabolic processes. Within the CD4+/TIP population, MI induced and polarized at least 10 transcriptionally distinct CD4+ Th subsets at 1 week post-MI. Integration with curated transcription factors, epigenetic, reduction-oxidation (redox), and unfolded protein response (UPR) datasets identified a stress-adaptive architecture, in which regulatory subsets and the CD4+/TIP population shared redox attenuation features, while the CD4+/TIP state showed the strongest coupling to reparative tissue interaction programs, predominant Activating Transcription Factor 6 (ATF6)-aligned UPR structure, restrained proteostasis related outputs, and an innate-adjacent immune and secretome signature enriched for complement-associated, inflammatory recruitment, and extracellular communication genes. These findings identify a specific MI-associated CD4+ T-cell transcriptomic state during early MI inflammation and tissue repair. They establish a coordinated framework in which redox control, UPR, and tissue-injury-polarized CD4+ T-cell immune programs converge outside traditional Th and Treg lineages, offering new targets for CD4+ T-cell-mediated tissue repair after MI.

Direct reprogramming of cardiac fibroblasts (CFs) into induced cardiomyocytes (iCMs) holds promise as a therapeutic strategy for heart regeneration. After myocardial infarction (MI), resident quiescent CFs (QCFs) activate and differentiate into myofibroblasts (MFs) in the infarcted region that drive pathological cardiac fibrosis. Converting these injury-activated MFs into iCMs could simultaneously alleviate fibrosis and replenish lost cardiomyocytes. However, whether the marked heterogeneity of CFs in the infarcted heart, and in particular the activation of QCFs into MFs, creates an intrinsic barrier that limits the reprogramming of these injury-activated MFs remains unknown. To define the molecular basis of this heterogeneity, we purified PDGFRα+ CFs and used Postn lineage tracing to distinguish injury-activated MFs from quiescent CFs, enabling matched comparison of their reprogramming competence and single-cell RNA sequencing (scRNA-seq) profiling of post-MI CF subpopulations. A targeted in vitro shRNA screen was conducted against 9 MF-enriched TFs as candidate molecular barriers for cardiac reprogramming. The lead candidate was validated in mouse MFs, human iPSC-derived MFs, primary human MFs, and in vivo using dual-recombinase-mediated lineage tracing. Mechanistic insights were gained through integrated bulk RNA-seq, scRNA-seq and Cleavage Under Targets and Tagmentation (CUT&Tag), together with functional assays including DNA-binding-deficient and domain-swap MEOX1 mutants. We identified the upregulated transcription factor MEOX1, a known fibrosis determinant downstream of the key post-MI cytokines transforming growth factor-beta 1 and interleukin-1 beta, as the principal molecular barrier responsible for the profound reprogramming resistance of MFs. MEOX1 knockdown markedly enhanced reprogramming efficiency in both mouse and human MFs and enabled GATA4-free reprogramming combinations. This inhibition depended on the transcriptional activation activity of MEOX1, as disrupting its DNA-binding domain or fusing it to a repressor domain rescued reprogramming. Integrated scRNA-seq and CUT&Tag analyses revealed that MEOX1 binds and stabilizes a fibrotic, MF-defining transcriptional program that antagonizes the cardiogenic program while also modulating the inflammatory response; its knockdown disrupted this fibrotic network to favor iCM fate acquisition. Using stringent dual-recombinase lineage tracing, we demonstrated that MEOX1 knockdown enables highly efficient in vivo MF-to-iCM conversion, leading to significant reductions in cardiac fibrosis and substantial improvement in cardiac function after MI. Our study identifies pathological MEOX1 upregulation as a key mechanism underlying the reprogramming resistance of post-MI mouse MFs and activated human MFs. Overcoming this barrier achieves unprecedented, lineage-confirmed in vivo reprogramming efficiency, thereby addressing a significant obstacle for the clinical translation of in situ reprogramming therapies.

Evidence of the diverse genetic architecture of dilated cardiomyopathy (DCM) continues to emerge and requires reassessment of the clinical relevance of implicated disease genes. Building on the 2019-2020 Clinical Genome Resource evaluation, the DCM gene curation expert panel reconvened in 2024-2025 to conduct a reassessment of genes in DCM. The Clinical Genome Resource semiquantitative clinical validity classification framework was applied with specifications to DCM to classify genes into categories on the basis of strength of published evidence for a DCM phenotype. Previously curated genes were reassessed, and newly reported gene-disease-mode of inheritance (MOI) relationships, termed "curations," were evaluated. Sixty-eight genes were evaluated, inclusive of 72 unique gene-disease-MOI relationships across 51 previously evaluated and 17 newly assessed genes. Thirty-five curations were classified as high evidence (16 Definitive, 10 Strong, 9 Moderate), increasing by 16 from the prior assessment. Nine newly assessed genes were classified as high evidence: BAG5, FLII, LMOD2, MYLK3, MYZAP, NRAP, PPA2, PPP1R13L, and RPL3L. Twelve genes (11 newly appraised) were rated as high evidence with an autosomal recessive (AR) MOI. Five reevaluated genes from 2019-2020 had clinically significant changes in classification. Except for JPH2, for which curation was modified to separate autosomal dominant and AR MOI curations, clinically significant changes involved upgrades from low- to high-evidence categories (PLEKHM2, PRDM16, TBX20, TNNI3K), demonstrating the robustness of the Clinical Genome Resource gene curation process over time. An additional 29 gene-disease-MOI curations were classified as Limited, including 6 newly evaluated genes and 1 new MOI for a previously evaluated gene, MYBPC3-AR; 4 were classified as No Known Disease Relationship, and remained Disputed. Four previously evaluated genes were curated for both AD and AR MOIs: JPH2 (AD-Strong, AR-Limited), LDB3 (AD-Limited, AR-Strong), MYBPC3 (AD-Limited, AR-Limited), and TNNI3 (AD- and AR- Strong). With substantial new evidence, the genetic architecture of DCM has rapidly expanded. This updated assessment of genes reported in DCM yielded 35 high-evidence curations, an increase from 19 only 5 years ago. The results of this evidence-based evaluation process inform clinical interpretation of genetic information in the care of DCM patients and families.

Chagas disease (ChD), a neglected cardiovascular condition, affects 7.5 to 10.5 million people worldwide. Opportunistic screening during routine electrocardiography may allow earlier detection of unrecognized infections, enabling timely antiparasitic therapy or optimized cardiac care. This study prospectively evaluated the feasibility and diagnostic accuracy of an artificial intelligence (AI)-enabled ECG model enriched with 3 epidemiological questions (AI-ECG-EPI model) as an opportunistic screening for ChD in endemic regions of Brazil. We conducted a prospective study embedded in the Telehealth Network of Minas Gerais, Brazil, across 107 municipalities in hyperendemic and endemic regions. From October 2023 to September 2024, adults undergoing routine tele-ECGs were eligible. The primary exposure was the output of the AI-ECG-EPI model: all positive individuals and a 3:1 sample of negative individuals were invited for serology (index test-dependent sampling), the reference standard. Weighted analyses (inverse probability) accounted for this sampling design. Diagnostic metrics included sensitivity, specificity, predictive values, likelihood ratios, area under the receiver operating characteristics curve, and area under the precision recall curve. The AI-ECG-EPI model was compared with both an epidemiological questions model and an AI ECG-only model. Among 75 779 eligible ECGs, the AI-ECG-EPI model was available for 59 154 individuals; 6812 (11.5%) screened positive. A total of 7804 selected were invited for serology, and 3509 completed testing (2517 positive; 992 negative). ChD was confirmed in 36.8% of positive and 9.3% of negative individuals. The weighted prevalence of ChD was 12.2%. Sensitivity was 34.3%, specificity 91.6%, harmonic mean of precision and recall score 0.52, and diagnostic odds ratio 5.69. The AI-ECG-EPI model showed higher discrimination than both the epidemiological questions model and AI ECG-only model (area under the receiver operating characteristics curve, 77.6% versus 70.0% and 64.5%, respectively; P<0.001). Precision recall curves showed higher precision across most recall levels. Exploratory analysis suggested improved risk reclassification (net reclassification improvement, 0.503). Performance was higher in women and in individuals with Chagas cardiomyopathy. In this community-based study, an AI-ECG-EPI model integrated into a public telecardiology network enabled feasible opportunistic screening for ChD in primary care. It showed acceptable diagnostic accuracy, with higher discrimination than epidemiological questions and AI ECG-only models, and identified many previously undiagnosed patients in endemic regions, supporting its potential role in scalable screening strategies. URL: https://www.clinicaltrials.gov; Unique identifier: NCT02646943.

Pathological fibrosis is a major finding in cardiovascular diseases and can result in arrhythmia and heart failure. Desmosome gene mutations can lead to arrhythmogenic cardiomyopathy. Among arrhythmogenic cardiomyopathies, pathogenic DSP (desmoplakin) variants cause a distinctive cardiomyopathy with excessive cardiac fibrosis that could precede ventricular dysfunction. DSP variants are also linked to other fibrotic diseases. Whether DSP plays any role in pathological fibrosis remains unknown. Mesenchymal stromal cells (MSCs) are resident fibroblast-like cells that are responsible for fibrogenesis in most organs, including the heart. We first used RNA-seq genome-wide analyses to generate cardiac fibroblast-like, induced pluripotent stem cell-derived MSCs from normal donors and patients with arrhythmogenic cardiomyopathy and DSP mutations. We then studied the fibrogenic responses of cardiac MSCs to TGFβ1 (transforming growth factor β1) using Western/Co-IP, autophagy assays, gene knockdowns/over-expressions, genomic analyses, mouse DSP knockdown models, immunostaining, and qPCR. TGFβ1 induced excessive accumulation of VIM (vimentin)/fibrillar collagens and over-activated fibrotic genes in DSP-mutant MSCs when compared with normal MSCs. In normal MSCs, VIMs bind to wild-type DSP during normal fibrogenesis after TGFβ1. DSP-mutant MSCs exhibited a haplo-insufficient phenotype with increased DSP-unbound VIMs that sequestered BECN1 (beclin-1) from activating autophagy and CAV1 (caveolin-1)-mediated endocytosis. Decreased autophagy caused collagen accumulation, and diminished CAV1 endocytosis resulted in abnormal CAV1 plaque formation that over-activated fibrotic genes (COL1A1, COL3A1, and fibronectin [FN]) via heightened p38 activity after TGFβ1. Genome-wide analysis and DSP knockdown in mouse fibroblasts confirmed this novel role of DSP mutations in pathological fibrosis. Overexpression of VIM-binding domains of DSP could suppress pathological fibrosis by increasing collagen autophagic degradation and decreasing fibrotic gene expression. Our data reveal that DSP deficiency in MSCs/fibroblasts leads to exaggerated fibrogenesis in DSP-cardiomyopathy by decreasing BECN1 availability for autophagy and CAV1-endocytosis. Overexpression of VIM binding domains of DSP could be a new strategy to treat pathological fibrosis.

In this study, we unexpectedly found that the immunoglobulin kappa light chain (Igκ) was expressed in normal cardiomyocytes of mice and humans, especially in intercalated discs (ICDs). Cardiomyocyte-specific knockout of Igκ in mice results in reduced myocardial contraction, atrioventricular block (AV block), and even sudden death. Histological analysis revealed that Igκ knockout in cardiomyocytes leads to structural disorder of ICDs, dissemination of the cytoskeleton proteins desmin and F-actin, as well as the loss of desmoplakin (DSP), N-cadherin, and connexin 43 (Cx43) on ICDs. Mechanistically, Igκ can bind to and stabilize plectin, a cytoskeleton-cross-linking protein that facilitates the assembly of desmin‒actin networks that maintain normal cytoskeletal architecture. Igκ can also anchor desmin to the DSP through plectin, thereby stabilizing the integrity of the ICDs. This molecular interplay critically reinforces cardiomyocyte cohesion and maintains structural and functional homeostasises. Our findings are the first to identify cardiomyocyte-expressed Igκ as a novel ICD-related molecule that participates in cardiomyocyte contraction and conduction by stabilizing plectins. Importantly, this work extends current arrhythmogenic cardiomyopathy (ACM) pathogenic models by revealing that ablation of the non-desmosomal gene Igκ disrupts ICD integrity, uncovering a new mechanism for non-desmosomal gene-related ACM and highlighting Igκ as a potential target for therapeutic investigations.

To examine the dose-response associations of step count and stepping intensity with risk of cardiovascular mortality and incidence of heart failure (HF), myocardial infarction (MI), and stroke (major adverse cardiovascular events, MACE) in people with hypertension. Data were obtained from participants with established hypertension from the UK Biobank accelerometry sub-study. Participants wore a wrist-worn accelerometer for seven consecutive days. Dose-response associations of daily step count and peak 30-min cadence were examined with risk of MACE. Hazard ratios (HR) and 95% confidence intervals (CI) associated with 1000-step increases in daily step count were calculated. In 36 192 participants [mean (SD) age 64 (7) years, 48% male, follow-up period 7.8 years], non-linear inverse dose-response associations with risk of MACE were observed for daily step count and peak 30-min cadence. Every 1000-step increase in daily step count led to an average lower risk of MACE, HF, MI, and stroke of 17.1% (95% CI: 10.2-23.2), 22.4% (95% CI: 11.0-31.7), 9.3% (95% CI: -2.8 to 19.6), and 24.5% (95% CI: 5.3-39.0), respectively. The magnitude of associations with increasing step count and stepping intensity was comparable between people with and without hypertension for risk of overall MACE, HF, and stroke, but of lower magnitude for MI. Incremental 1000-step increases in daily step count, up to 10 000 steps/day, were associated with substantially lower MACE risk in adults with hypertension, particularly when accrued at a higher stepping intensity.

Self-powered sensors that directly convert mechanical stimuli into electrical signals hold promise for next-generation bio-integrated electronics, but their practical translation is hindered by low electrical output and poor mechanical properties. Herein, we present an engineered copolymer ionogel featuring piezoionic amplification and enhanced mechanical properties through optimization of the hydrogen bond network by inserting polyurea chains into poly(vinyl alcohol) (PVA). The optimized copolymer ionogel achieves a voltage output of 20 millivolts, which is 10 folds higher than conventional PVA ionogels. Exceptional stretchability (1510%), toughness (23.1 megajoules per cubic meter), and durability are also achieved. Integrated into a wearable epidermal sensor with a machine learning algorithm, the copolymer ionogel enables cuffless, noninvasive, and continuous blood pressure monitoring, achieving mean absolute errors of 5.9 millimeters of mmHg (mmHg; systolic) and 3.6 mmHg (diastolic), thereby satisfying the stringent grade A of British Hypertension Society standard. This hydrogen-bond optimization strategy provides an avenue for piezoionic amplification and demonstrates the practicality of high-performance ionogels for wearable health-monitoring devices, thereby advancing the development of next-generation wearable biomedical systems.

Salt-sensitivity of blood pressure is an independent risk factor for cardiovascular diseases, yet the molecular pathways linking dietary sodium to immune activation and hypertension remain poorly defined. We previously demonstrated that sodium entry into antigen-presenting cells via the ENaC (epithelial sodium channel) promotes inflammation and salt-sensitivity of blood pressure. AP-1 (activator protein-1; c-FOS, FOSB, c-JUN, JUNB, JUND) regulates inflammatory signaling, but its role in salt-sensitivity of blood pressure has not been elucidated. We hypothesized that high salt drives AP-1-mediated inflammatory activation in antigen-presenting cells, contributing to immune dysfunction and hypertension. Using SV129 salt-sensitive mice, we assessed blood pressure responses and profiled immune cell phenotypes under normal- and high-salt conditions by flow cytometry. RNA-seq was performed on human monocytes exposed to high salt in vitro. In a clinical study, we enrolled prehypertensive subjects and performed an inpatient salt-loading/depletion protocol to characterize AP-1 gene expression signatures in salt-sensitive versus salt-resistant individuals. To test causality, we adoptively transferred PBMCs from salt-sensitive, salt-resistant, and salt-sensitive individuals pretreated with T5224 (a selective AP-1 inhibitor) into immunodeficient NSG-(KbDb)null (IA)null humanized mice, followed by assessment of blood pressure, vascular reactivity, kidney function, and immune infiltration. High salt robustly induced AP-1 gene expression in murine monocytes. In humans, salt-sensitive but not salt-resistant subjects exhibited concordant increases in AP-1 gene expression and blood pressure during salt loading. PBMCs from salt-sensitive individuals promoted greater tissue infiltration, AP-1 activation, and immune-mediated renal and vascular dysfunction in humanized mice compared with PBMCs from salt-resistant individuals. Strikingly, pretreatment of salt-sensitive PBMCs with T5224 abrogated these effects, preserving normal renal and vascular function despite high-salt exposure. These findings identify AP-1 as a key transcriptional driver linking dietary sodium, immune activation, and salt-sensitivity of blood pressure. Targeting AP-1 signaling mitigates immune-mediated renal and vascular injury, highlighting a novel mechanistic pathway and a therapeutic target for salt-sensitive hypertension.

Despite advances in managing traditional risk factors, coronary artery disease (CAD) remains the leading cause of mortality. Circulating hematopoietic cells influence risk for CAD separately from traditional risk factors, but the role of a key regulating organ, the spleen, is unknown. The understudied spleen is a representation of the hematopoietic system optimally suited for unbiased radiologic investigations toward mechanistic insights. Here, we leveraged deep learning to extract 107 splenic radiomic features from abdominal magnetic resonance imaging (MRI) scans of 42,059 UK Biobank participants and of 2745 Mass General Brigham Biobank (MGBB) participants. Of these, 10 features from UK Biobank were associated with CAD. Genome-wide association analysis of CAD-associated features identified 219 loci, including 9p21. Variants at 9p21, the strongest yet mechanistically elusive CAD locus, were associated with splenic features such as run-length nonuniformity, reflecting heterogeneity of continuous texture regions. Research MRI findings were consistent internally, but external clinical validation highlighted challenges in translating analyses of abdominal MRI scans to routine clinical practice because of variability in imaging protocols and greater clinical heterogeneity among patients. Our study, combining deep learning with genomics, presents a framework to uncover potential splenic involvement in CAD and emphasizes translational gaps between research and clinical radiomics.

Sedentary time (ST) can be reduced in patients with coronary artery disease (CAD) during cardiac rehabilitation (CR), but most patients relapse to sedentarism within months. We examined the effectiveness of a 3-week remote booster intervention on ST changes in CAD patients. Coronary artery disease patients who previously [2.0 (1.9-2.2) years] completed CR were included in this randomized controlled trial (1:1, stratified for gender). All participants received usual care, whereas booster participants additionally received a 3-week remote behavioural change intervention. The primary outcome was the change in accelerometer-derived ST from baseline to post-intervention and secondary outcomes included changes in sedentary behaviour and physical activity (PA) characteristics. A baseline constrained linear mixed model on an intention-to-treat basis was used. Participants (19% female, booster: n = 21, control: n = 21) were 69 [63-75] years old. Greater decreases in ST {-1.3 [95% confidence interval (CI): -2.0; -0.6] vs. -0.1 (95% CI: -0.8; 0.6) h/day, p-interaction = 0.012} and number of prolonged sedentary bouts [-1.1 (95% CI: -1.6; -0.6) vs. 0.2 (95% CI: -0.3; 0.7) bouts/day, p-interaction < 0.001] in combination with larger increases in light PA [+1.1 (95% CI: + 0.5; + 1.8) vs. +0.2 (95% CI: -0.4; + 0.8) h/day, p-interaction = 0.030] were found for the booster vs. control group. Changes in moderate-to-vigorous PA (p-interaction = 0.13) and step count (p-interaction = 0.18) did not differ between groups. The remote booster program effectively reduced ST and increased light PA in CAD patients. These findings highlight the potential to change physical (in)activity behaviour of patients beyond completion of traditional CR programs. NCT06038188 (ClinicalTrials.gov).

With obesity as a risk factor for atherosclerotic disease, recent research suggests that adipose tissue in obese animal models and humans can generate endocrine-like molecules that affect arterial health. Previous studies showed that microRNA-30e (miR-30e) levels are elevated in atherosclerosis and solute carrier family 7 member 11 (SLC7A11), a cystine/glutamate transporter, is involved in atherogenesis. However, whether an endocrine-like link between the adipose-derived miR-30e-5p and SLC7A11 in the vascular endothelium can lead to obesity-caused atherosclerosis is unknown. miRNA data mining and reverse transcription-polymerase chain reaction validations were used to demonstrate the positive association among serum levels of miR-30e-5p, obesity, and coronary arterial disease in human patients. Transcriptomics (bulk RNA sequencing and single-nucleus RNA sequencing), metabolomics, and in silico analysis were used to establish a miR-30e-5p-SLC7A11 regulation of central carbon metabolism, mitochondrial and endothelial cell (EC) function. Mouse models with EC-specific Slc7a11 knockout (EC-Slc7a11-/-) and gain- or loss-of- function of miR-30e-5p were used to elucidate the detrimental role of this endocrine-like axis in obesity-related atherosclerosis. The level of adipocyte-derived miR-30e-5p was significantly upregulated in obese human patients with coronary artery disease and in obese and atherosclerotic mice. Mediated through serum exosomes, the adipocyte-generated miR-30e-5p targeted SLC7A11 mRNA in vascular ECs. SLC7A11 deficiency due to miR-30e-5p targeting dysregulated glutamate/cystine metabolism, increased glycolysis, reduced oxidative phosphorylation, and impaired mitochondrial function. The EC dysfunction could be rectified by SLC7A11 overexpression or miR-30e-5p antagonism. Administration of exogenous miR-30e-5p or white adipose tissue-derived exosomes phenocopied the increased atherosclerosis in EC-Slc7a11-/- mice. In contrast, miR-30e-5p antagomir or GW4869 treatment reduced atherosclerosis in Apoe-/- and ob/ob mice. Our multiomics approaches demonstrate that the adipose-derived miR-30e-5p downregulated SLC7A11 mRNA in ECs via tissue crosstalk. The resulting EC dysfunction led to obesity-related atherosclerosis in mice. These findings underscore a causality between obesity and atherosclerosis in the context of cardiovascular-kidney-metabolic syndrome.

Nighttime light exposure has emerged as a potential risk factor for cardiovascular disease (CVD). However, its impact on cardiac structure and function remains unknown. This population-based cohort study included 11 071 UK Biobank participants who wore a wrist-worn accelerometer with an integrated light sensor for 7 days between 2013 and 2015 (baseline) and had subsequent cardiovascular magnetic resonance (CMR) imaging 3 years later. Nighttime light exposure >3 lux was estimated, and its dose-response relationships with CMR phenotypes were examined using generalized linear regression models. Associations of nighttime light exposure with incident CVD outcomes and mortality were examined using Cox models (n = 73 286). After multivariable adjustment, high (vs none) nighttime light exposure >3 lux was associated with left ventricular (LV) concentric hypertrophy and subclinical functional decline, including 2.4% (95% confidence interval 1.6%, 3.1%) greater LV mass indexed to height1.7, 1.5% (1.0%, 2.0%) greater mean wall thickness, and 1.9% (1.1%, 2.7%) lower myocardial contraction fraction. Nighttime light exposure was also associated with impaired myocardial deformation, including lower absolute global LV circumferential [-2.7% (-3.7%, -1.7%)], radial [-2.9% (-3.9%, -1.8%)], and longitudinal strain [-2.8% (-3.9%, -1.7%)] indices. Adverse associations were also observed for the right ventricle, including 0.9% (0.1%, 1.8%) greater end-diastolic and 1.6% (0.5%, 2.8%) greater end-systolic volumes indexed, and for the left atrium, including 2.3% (0.7%, 3.9%) greater maximum volume indexed and 1.1% (0.3%, 1.9%) lower ejection fraction. All associations exhibited linear dose-response relationships, with most partly mediated by shorter sleep duration (proportion mediated: 24%-49%). During 8-10 years of follow-up, participants with high (vs none) nighttime light exposure had 29% (12%, 49%) higher risk of heart failure, 15% (4%, 27%) higher risk of atrial fibrillation, 24% (7%, 44%) higher risk of myocardial infarction, 33% (11%, 59%) higher risk of stroke, and 26% (5%, 52%) higher risk of CVD mortality. Greater nighttime light exposure was associated with adverse cardiac remodelling and subclinical functional decline across multiple chambers, statistically mediated by shorter sleep duration. These findings provide potential mechanistic insights into how nighttime light exposure may elevate CVD risk and highlight dark nights and adequate sleep for cardiovascular health.

The study investigated the association between self-reported physical fitness (SRPF) and mortality in 3248 participants of the Ludwigshafen Risk and Cardiovascular Health (LURIC) study with a mean follow-up of 9.9 years. Self-reported physical fitness was inquired using an 11-point Likert scale on a paper-pencil questionnaire at enrolment, and we defined five distinct classes. Kaplan-Meier survival analysis and Cox regression models were used to investigate the association with mortality. Participants with higher baseline SRPF had a significantly lower risk of all-cause and cardiovascular mortality. Regarding cardiovascular mortality, participants in the highest SRPF class had the lowest risk with a hazard ratio of 0.14 (95% CI 0.08-0.24) compared with the lowest SRPF class. These associations remained statistically significant after adjustment for age, sex, hypertension, diabetes mellitus, low-density lipoprotein cholesterol, glycated haemoglobin A1c (HbA1c), smoking, and other confounders, including comorbidities. Similar results were seen in both participants with angiographically documented coronary artery disease (CAD, n = 2583, 78%) and those without CAD (n = 733; 22%). Higher SRPF was associated with significantly lower systolic blood pressure and resting heart rate as well as lower HbA1c, fasting glucose, serum uric acid, and lower inflammatory markers such as high-sensitive-C-reactive protein, interleukin-6, and serum amyloid A. Conversely, a higher SRPF was associated with higher apolipoprotein A-2 and high-density lipoprotein cholesterol concentrations (P < 0.001). Our research shows that SRPF is a strong predictor of overall and cardiovascular mortality for individuals with and without CAD. This suggests that SRPF should be part of routine medical check-ups, highlighting the importance of promoting physical activity for cardiovascular health. This study shows that self-reported physical fitness (SRPF) is a strong predictor of mortality, with higher self-rated fitness linked to lower risks of both all-cause and cardiovascular mortality, independent of other risk factors.Low SRPF is significantly associated with increased risk of all-cause and cardiovascular mortality, suggesting it may be an important indicator for health outcomes.High SRPF shows a protective association, highlighting its potential as an accessible, low-cost tool for promoting cardiovascular health in routine medical assessments.

Quantifying the multidimensional risk that subclinical liver disease imposes on cardiovascular health remains a critical unmet need. This study aimed to investigate the independent and synergistic associations of hepatic steatosis, fibrosis, and functional decline with incident cardiovascular disease (CVD). In this prospective cohort study of 318 308 participants free of clinical liver and CVD at baseline, this study evaluated the association of three non-invasive liver biomarkers-fatty liver index (FLI) for steatosis, fibrosis-4 index (FIB-4) for fibrosis, and albumin-bilirubin (ALBI) score for functional reserve-with major incident CVD events, including myocardial infarction, heart failure, atrial fibrillation, ischaemic stroke, and cardiovascular death. Over a median follow-up of 14.0 years, 32 637 incident CVD events (10.3%) occurred. Each biomarker independently predicted CVD risk after multivariable adjustment: the highest quartile (Q4) of FLI (adjusted hazard ratio [aHR] 1.46, 95% confidence interval [CI] 1.40-1.52), FIB-4 (aHR 1.66, 95% CI 1.60-1.73), and ALBI (aHR 1.42, 95% CI 1.37-1.47) showed significantly elevated risks compared to Q1. Critically, participants with all three biomarkers in Q4 exhibited a substantially elevated synergistic risk (aHR 2.53, 95% CI 2.38-2.70). Sex-specific analyses revealed FLI was more strongly associated with CVD in women, whereas FIB-4 and ALBI showed greater risk in men. Results were consistent across sensitivity analyses and specific CVD endpoints. These findings establish subclinical liver disease-through steatosis, fibrosis, and functional impairment-as an independent and synergistic determinant of CVD risk. Incorporation of these non-invasive biomarkers could refine CVD risk stratification and enable targeted prevention strategies.

Smoking has been associated with lower risks of Parkinson disease (PD) in epidemiological studies, but the underlying mechanisms remain poorly elucidated. To investigate the association of exhaled carbon monoxide (CO) with risk of PD. This nationwide prospective cohort study leveraged data from the China Kadoorie Biobank across 10 geographically diverse areas in China. A total of 512 724 adults aged 30 to 79 years were recruited between June 2004 and July 2008. Prospective analyses were restricted to first events occurring between ages 40 and 94 years and before January 1, 2019. Data were analyzed from May 2025 to March 2026. Self-reported smoking status and measured exhaled CO. During approximately 12 years' follow-up, 1131 individuals with PD and 2949 with other neurodegenerative diseases were recorded through linkage to national death and disease registries and the health insurance system. Cox regression was used to estimate adjusted hazard ratios (HRs) for associations of smoking and, among individuals who never smoked, exhaled CO levels with PD, other neurodegenerative diseases, and several known smoking-related diseases. Covariates included sociodemographic characteristics, lifestyle factors, and other confounders (ie, solid fuel use and passive exposure to smoking). Among the 512 701 participants included in the main analyses, the mean (SD) age was 52 (11) years and 302 041 (58.9%) were female. Overall, 156 650 male individuals (74.5%) and 9944 female individuals (3.3%) ever smoked regularly, with mean exhaled CO levels higher among those who regularly smoked (11.1 ppm) than those who never smoked (3.5 ppm), those who occasionally smoked (3.8 ppm), and those who formerly smoked regularly (3.7 ppm). Regular smoking was significantly associated with elevated risks of lung cancer, ischemic heart disease, stroke, and all-cause mortality but with lower risk of PD (adjusted HR, 0.70; 95% CI, 0.62-0.79). In individuals who never smoked, higher exhaled CO levels were associated with lower HRs of PD (n = 675) in a broadly dose-dependent manner (exhaled CO <2.0 ppm: 1.00 [95% CI, 0.85-1.18]; 2.0 to <3.0: 0.85 [95% CI, 0.73-0.99]; 3.0 to <5.0: 0.62 [95% CI, 0.53-0.73]; 5.0 to <11.5: 0.68 [95% CI, 0.56-0.83]; ≥11.5: 0.65 [95% CI, 0.45-0.92]; P for trend < .001) but were not associated with risks of smoking-related diseases or other neurodegenerative diseases. The associations with PD were more pronounced in female individuals who never smoked. Similar exhaled CO-PD associations were found in those who regularly smoked. Among individuals who never smoked, higher exhaled CO levels were associated with lower PD risk. These findings demonstrate a potentially protective role of CO in PD etiology, which help explain the association between smoking and PD observed in this and other epidemiological studies and support ongoing clinical trials of CO in the treatment of PD.

Cardiac troponin is increasingly used for cardiovascular risk prediction. While abnormal values often reflect subclinical cardiovascular disease, they can be raised due to interference, where antibodies influence the assay or clearance of troponin from the circulation by forming macrotroponin complexes. The frequency of macrotroponins and its association with future risk are unknown. In a general population cohort, participants with both cardiac troponin I and T measurements available (n=19 499, median 49 [25th-75th percentile, 36-58] years of age, 58.3% women) were categorized into 3 groups: no myocardial injury (neither cardiac troponin I or T was elevated), suspected macrotroponin (either cardiac troponin was elevated and discordant with a >3-fold difference in concentration), and myocardial injury (either cardiac troponin was elevated without discordance). Macrotroponin complex formation was verified in a subset of samples (n=203) using immunoglobulin depletion and ultracentrifugation. Associations with future myocardial infarction, ischemic stroke, or cardiovascular death were evaluated using Cox proportional hazards models adjusted for known cardiovascular risk factors. The generalizability of our findings was determined through replication in a second general population cohort study. Elevated cardiac troponin I was present in 1% (193 of 19 499) of participants and elevated cardiac troponin T in 6% (1159 of 19 499). Among those, 48% and 57% were discordant, respectively. Biochemical testing attributed 92.5% of discordant troponin I and 15.4% of discordant troponin T to macrotroponin complexes. Participants with myocardial injury were at increased risk of future cardiovascular events compared with those without (cardiac troponin I: adjusted hazard ratio [HR], 2.90 [95% CI, 1.99-4.22]; cardiac troponin T: adjusted HR, 1.99 [95% CI, 1.63-2.42]), whereas those with suspected macrotroponin had similar risk as those without elevated values for suspected macrotroponin I (adjusted HR, 1.59 [95% CI, 0.94-2.70]) and T (adjusted HR, 1.27 [95% CI, 1.00-1.61]). Findings were similar in the replication cohort. Assay interference due to macrotroponin complex formation is common in individuals with elevated cardiac troponin concentrations in the general population, particularly for cardiac troponin I. This has important implications for the use of cardiac troponin testing for cardiovascular risk assessment in the general population.

Sarcopenia is an emerging risk factor for cardiovascular disease (CVD). However, previous studies did not take into consideration the cardiovascular impact of the changes in sarcopenia status. We investigated the relationship between changes in sarcopenia status and incident CVD. Participants from two prospective cohorts: the China Health and Retirement Longitudinal Study (CHARLS) and the Health and Retirement Study (HRS) were included. Changes in sarcopenia status were assessed by sarcopenia status at the initial two surveys. Cardiovascular disease was ascertained by self-reported physician-diagnosed heart disease or stroke. A total of 6608 and 4316 adults from CHARLS (mean age: 59.2 years, female: 53.6%) and HRS (mean age: 63.2 years, female: 60.2%) were analysed, with a median follow-up of 5.0 and 7.5 years, respectively. Meta-analysis showed a significant relationship between sarcopenia and CVD risk. Bidirectional Mendelian randomization analysis supported the robustness and causality, and no reverse association was found between CVD and sarcopenia. Compared with stable no sarcopenia participants, multivariable-adjusted incidence rate ratio (IRR) and 95% confidence interval (CI) for incident CVD in those who progressed from no sarcopenia to possible sarcopenia/sarcopenia were 1.29 (1.02-1.64) and 1.39 (1.11-1.74) in both cohorts. In contrast, sarcopenia participants who recovered to no sarcopenia/possible sarcopenia had lower incidence of CVD (CHARLS, IRR = 0.61, 95% CI 0.43-0.87; HRS, IRR = 0.20, 95% CI 0.11-0.39) than stable sarcopenia participants did. The progression of sarcopenia status increases the risk of CVD, while the recovery of sarcopenia status reduces the risk of incident CVD.

Atrial fibrillation (AF), the most common cardiac arrhythmia, affects over 33 million people worldwide and is associated with increased risks of stroke, heart failure, reduced quality of life, and mortality. In addition to established cardiovascular risk factors, accumulating evidence suggests that psychological stress and stress-related physiological changes may influence AF onset, progression, and recurrence. However, stress remains an underexplored target in preventive cardiology. This review summarizes current evidence on the relationship between psychological stress and AF, examining perceived stress, socioeconomic stressors, stressful life events, as well as their assessment. We discuss observational studies, highlighting stress as both a potential trigger and a modifier of disease course. A unique aspect of this review is the integration of patient perspectives inquired via Dutch online citizen science initiatives, in which individuals with lived experience of AF contributed data on perceived stress, symptom severity, and coping strategies. Collectively, the evidence indicates that psychological stress is a modifiable factor in perceived AF severity, and that combining citizen-reported experiences with biomarker research may open new avenues for further understanding, personalized prevention, patient empowerment, and holistic AF management.

The comparative association of sodium-glucose cotransporter-2 inhibitors (SGLT2i) and glucagon-like peptide-1 receptor agonists (GLP-1RA) with incident atrial fibrillation (AF) or atrial flutter remains uncertain, particularly with early use of both classes. We compared three initial treatment strategies in adults with type 2 diabetes. We emulated a three-arm target trial using population-based healthcare data from 2015-2025. Participants were assigned to SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, or early combined therapy according to dispensings during a 30-day treatment-assignment period. Follow-up began at the end of this period using a landmark design. Treatment groups were balanced using inverse probability of treatment weighting, and cumulative incidence was estimated using weighted Aalen-Johansen methods accounting for competing mortality. Among 216,293 participants, 114,572 received SGLT2i without GLP-1RA, 91,524 received GLP-1RA without SGLT2i, and 10,197 received early combined therapy. At 5 years, cumulative AF or atrial flutter incidence was 4.3%, 4.8%, and 4.2% among participants receiving SGLT2i without GLP-1RA, GLP-1RA without SGLT2i, and early combined therapy, respectively. SGLT2i without GLP-1RA was associated with lower risk than GLP-1RA without SGLT2i (RR 0.88, 95% CI 0.83-0.94), while risk was similar between SGLT2i without GLP-1RA and combined therapy (RR 1.00, 95% CI 0.84-1.19). Among adults with type 2 diabetes, treatment strategies incorporating SGLT2i were associated with a lower risk of incident AF or atrial flutter than GLP-1RA without SGLT2i. These findings extend the cardiovascular evidence supporting SGLT2i and provide new comparative data regarding early combined use of SGLT2i and GLP-1RA.

Idiopathic pulmonary arterial hypertension (IPAH) is driven by progressive vascular remodeling, particularly smooth muscle cell (SMC) proliferation. Current combination vasodilator therapies have markedly improved outcomes; however, prognosis remains poor in subgroups such as patients with respiratory comorbidities. Elevation of intravascular hydrostatic pressure is a hallmark of IPAH, yet its direct role in pulmonary artery SMCs remains unclear. We aimed to identify pressure-responsive mediators using a newly developed hydrostatic pressurization system to model hypertensive hemodynamics. Pulmonary artery SMCs from 4 patients with IPAH were exposed to high hydrostatic pressure (70/40 mm Hg, 60 bpm). Transcriptomic profiling identified differentially expressed genes, which were validated by quantitative polymerase chain reaction. Functional studies included PIEZO1 (piezo type mechanosensitive ion channel component 1) modulation, rhSTC1 (recombinant human stanniocalcin-1) treatment, bromodeoxyuridine incorporation, and Western blotting for cell-cycle regulators. Chronic hypoxia-induced pulmonary hypertension was assessed in wild-type and Stc1-/- mice by hemodynamic and histological analyses, with or without intratracheal rhSTC1 administration. RNA sequencing revealed STC1 to be a pressure-induced gene in IPAH SMCs. PIEZO1 activation upregulated STC1, whereas knockdown blunted this response. STC1 was upregulated in IPAH lungs, while rhSTC1 reduced pulmonary arterial SMC proliferation and increased p-p53, p21, and p27 expression. Stc1-/- mice under hypoxia exhibited significantly higher right ventricular systolic pressure and greater pulmonary arterial medial thickness than wild-type mice. CD68-positive macrophages were increased in Stc1-/- mice under normoxia and further elevated with hypoxia. Intratracheal administration of rhSTC1 attenuated PAH in wild-type and Stc1-/- mice. Elevated hydrostatic pressure drives STC1 expression via PIEZO1, suggesting an adaptive but insufficient protective response in IPAH. Modulation of STC1 (stanniocalcin-1) may represent a potential therapeutic approach.

Pulmonary arterial hypertension (PAH) is driven by sustained vasoconstriction and structural remodelling of distal pulmonary arteries. We have previously demonstrated that osteoprotegerin (OPG, tnfrsf11b) is upregulated in PAH animal models and patient tissues, with circulating levels being prognostic. OPG knockout mice exhibit an attenuated PAH phenotype, and therapeutic inhibition using a human monoclonal anti-OPG antibody reduces disease severity in multiple rodent models. However, the key cellular source of pathogenic OPG and the mechanism underlying therapeutic blockade remain unknown. To define the main cellular source of OPG, conditional Tnfrsf11b deletion was generated by crossing OPGfl/fl mice with PGKcretg/+ (global), LysMcretg/+ (myeloid), Myl2cretg/+ (cardiac myocytes), Cdh5cretg/+ (endothelial cells, ECs), smMHCcretg/+ (VSMCs), Col1a2cretg/+ (fibroblasts, FBs). Knockouts were induced by tamoxifen injection, and PAH established using Sugen5416/hypoxia (SuHx) model. Cardiopulmonary phenotyping included echocardiography, cardiac catheterisation, and histological analysis. Mechanistic studies were performed in VSMCs using peptide-based kinase activity profiling (PamStation).PGKcretg/+/OPGfl/fl mice phenocopied the previous results obtained with global OPG knockout (OPG-/-). Only VSMC-specific deletion (smMHCcretg/0/OPGfl/fl) resulted in significantly improved haemodynamic parameters, evidenced by reduced RVSP and pulmonary vascular resistance (PVR), and reduced pulmonary vascular remodelling demonstrating that VSMC-derived OPG is the primary driver of PAH pathogenesis.Kinome profiling of control and IPAH-PASMCs treated with OPG +/- anti-OPG antibody revealed IPAH specific regulation of PI3K-Akt and enrichment of pathways involving autophagy, and longevity regulation linked to cellular stress resistance and growth. Anti-OPG antibody treatment reduced AKT phosphorylation in IPAH PASMCs. Knock-down of AKT1 by siRNA reduced OPG-induced proliferation and migration of human PASMC. These results align with emerging data implicating OPG in cellular senescence and vascular aging. Together, these findings highlight VSMC-derived OPG as a critical mediator of pulmonary vascular remodelling in PAH pathogenesis and suggest that targeting OPG via a therapeutic antibody is mediated through PI3K-Akt signalling.

Refractory ascites (RA) is a severe complication that impedes long-term survival after pediatric liver transplantation (LT), but its etiology remains complex and heterogeneous. To systematically evaluate the prognostic impact, clinical risk factors, and immunological features of RA, we retrospectively analyzed 1455 pediatric recipients who received LT in Renji Hospital between October 2016 and December 2021. RA was associated with increased mortality and graft loss after pediatric LT. Univariate analysis identified 13 clinical factors associated with RA, whereas a preliminary multivariable model showed only moderate discrimination, suggesting substantial heterogeneity among RA patients. Based on unsupervised clustering of clinical parameters, RA individuals were classified into two subgroups. Type I ascites was mainly associated with low graft-to-recipient weight ratio, decreased preoperative white blood cell count, and platelet count, indicating the involvement of persistent portal hypertension. In contrast, type II ascites was characterized by ABO incompatibility, elevated early postoperative soluble IL-2 receptor, and increased risk of T-cell-mediated rejection, suggesting excessive alloimmune activation. These findings indicate that RA after pediatric LT comprises distinct clinical entities with different pathogenic implications. Prudent graft selection and close monitoring of immune status may help prevent RA and improve post-transplant outcomes.

Benefits of healthy diets for type 2 diabetes (T2D) prevention are established. It remains unclear whether such recommendations should be tailored to specific subgroups according to their susceptibility to the disease. This study aimed to assess whether the association of diet quality with T2D risk differs across subgroups with different genetic or epigenetic susceptibility. We used data from a case-cohort within the European Prospective Investigation into Cancer and Nutrition (EPIC)-Potsdam cohort (random subsample with genetic data of 2204 participants, 750 verified incident T2D cases; random subsample with epigenetic data of 1065 participants, 676 verified incident T2D cases). The Alternative Healthy Eating Index (AHEI-2010), Dietary Approaches to Stop Hypertension (DASH), Dietary Inflammatory Index (DII) and the Mediterranean Diet Pyramid score (MedPyr) were used to assess diet quality. A blood DNA methylation risk score (MRS) was used to reflect epigenetic risk. Genetic risk was characterized using global polygenic risk scores (PRS) and pathway-specific polygenic risk scores (pPRS). Cox proportional hazards models were used to assess the modification of the diet quality-diabetes risk association by the risk scores. Higher adherence to the AHEI-2010 was associated with a lower risk of T2D, while higher MRS, PRS and pPRS predictably indicated higher risk in this population. We detected significant modification of the diet quality-T2D association by the MRS for AHEI-2010 (p = 0.008) and MedPyr (p < 0.0001) and DII (p = 0.010) but only the AHEI-2010 × MRS interaction was robust across all sensitivity analyses. However, we did not find evidence of interaction between diet quality and genetic risk. The associations of healthy diets with T2D could depend on the diabetes risk captured by blood DNA methylation profiles, but they do not seem to depend on the genetic predisposition for T2D. Confirmation of the effect modification by the MRS in independent populations is further required before considering clinical application.

G protein-coupled receptor 75 (GPR75) has recently attracted considerable attention as a novel regulator of metabolic, immune, and vascular processes. Current evidence suggests that two structurally distinct molecules have been proposed as candidate endogenous ligands for GPR75: 20-hydroxyeicosatetraenoic acid (20-HETE), a cytochrome P450-derived lipid metabolite, and C-C motif chemokine ligand 5 (CCL5; RANTES), a chemokine involved in immune regulation. Among these ligands, 20-HETE functions as a potent agonist of GPR75, leading to activation of Gαq/11-dependent signaling pathways and β-arrestin recruitment. In contrast, although CCL5 has also been reported to interact with GPR75, its role as a direct receptor agonist remains controversial and may be highly context-dependent. Notably, GPR75 is broadly expressed in tissues involved in the regulation of energy homeostasis, including the hypothalamus, adipose tissue, liver, pancreas, and vascular system. Population genetic studies have demonstrated that loss-of-function variants in GPR75 are associated with a reduced risk of obesity, type 2 diabetes, metabolic dysfunction-associated steatotic liver disease (MASLD), and hypertension. Evidence from animal models further supports a role for GPR75 in the regulation of feeding behavior, insulin sensitivity, lipid metabolism, vascular tone, and inflammatory responses. This review provides a comprehensive overview of the structural characteristics, ligand recognition mechanisms, signaling properties, and tissue distribution of GPR75 and discusses its functions in both the central nervous system and peripheral metabolic tissues. Elucidating how GPR75 integrates, differentiates, and transduces signals derived from these distinct ligands may provide new opportunities for therapeutic intervention in obesity, diabetes, MASLD, and their associated complications.

Recent studies have revealed heterogeneity among ribosomes. Pathological cardiac hypertrophy is characterized by profound alterations in translation. However, how ribosome heterogeneity contributes to this process remains largely unclear. We used translating ribosome affinity purification coupled with mass spectrometry to profile ribosome-interacting proteins. Cardiomyocyte-specific gene manipulation was achieved through either genetic knockout or adeno-associated virus-mediated overexpression. Pathological cardiac hypertrophy was induced by transverse aortic constriction surgery in vivo and by phenylephrine stimulation in vitro. The cardiomyocyte-specific ribosome proteomics indicated dynamic alterations in ribosome-interacting proteins during pathological hypertrophy. Notably, multiple proteins associated with ribosome stalling were detected in the ribosome-interactome of hypertrophic hearts. Among these, we verified that CDK5RAP3 (CDK5 regulatory subunit-associated protein 3) exhibited the most specific ribosome binding in hypertrophic hearts. CDK5RAP3 was upregulated and recruited to ribosomes during pathological hypertrophy. It promoted RPL26 (ribosomal protein L26) UFMylation and ribosome-associated quality control on the mitochondrial surface. In vitro, CDK5RAP3 knockdown exacerbated cardiomyocyte hypertrophy induced by phenylephrine, whereas its overexpression attenuated it. In vivo, cardiomyocyte-specific CDK5RAP3 knockout promoted, while adeno-associated virus-mediated overexpression suppressed pathological cardiac hypertrophy induced by transverse aortic constriction. Mechanistically, ribosome stalling on the mitochondrial surface was exacerbated in hypertrophic hearts of both humans and mice, which was associated with impaired mitochondrial protein import. CDK5RAP3 enhanced ribosome-associated quality control, alleviated ribosome stalling, and restored mitochondrial protein import, thereby improving mitochondrial function. Notably, mitochondrial import of PDP1 (pyruvate dehydrogenase phosphatase catalytic subunit 1) was maintained by CDK5RAP3-mediated ribosome-associated quality control. Knockdown of PDK (pyruvate dehydrogenase kinase) 1/2, functional antagonists of PDP1, reversed cardiomyocyte hypertrophy caused by CDK5RAP3 deficiency. This study identifies CDK5RAP3-mediated ribosome-associated quality control on the mitochondrial surface as a critical protective mechanism that preserves protein import and mitochondrial function during pathological cardiac hypertrophy.

One in four surgical patients carries a drug allergy label, of which an estimated 90% are incorrect. Avoidance of first-choice drug therapies can lead to worse postoperative outcomes. We sought to determine the nature and extent of any association between drug allergy labels and postoperative complications. A multicentre observational study was performed in 21 UK National Health Service hospitals. Eligible patients were ≥18 yr of age and undergoing common surgical procedures: primary hip or knee replacement, internal fixation of closed long bone fracture, colorectal resection, transurethral resection of prostate or bladder tumour, Caesarean delivery, or hysterectomy. Exclusion criteria were the use of antibiotics in the two weeks before surgery or previous participation in the study. The primary outcome was postoperative complications within 30 days after surgery, a composite outcome comprising all postoperative infections, anastomotic leak, acute respiratory distress syndrome, myocardial infarction, postoperative bleeding, pulmonary embolism, stroke, antimicrobial side-effects, and death. Among 13 646 patients, 3924 (29%) carried ≥1 drug allergy label. Labelled patients were more likely to develop postoperative complications (989/3924 [25%] vs 1926/9722 [20%]; odds ratio [OR] 1.21 [1.10-1.34]; P<0.001). They were more likely to develop surgical site infections (337/3924 [9%] vs 760/9722 [8%]; OR 1.19 [1.03-1.38]; P<0.018), and any postoperative infection (750/3924 [19%] vs 1472/9722 [15%]; OR 1.24 [1.11-1.38]; P<0.001). Labelled patients experienced an increased risk of allergic drug reactions (31/3924 [0.01%] vs 29/9722 [<0.01%]; OR 3.00 [1.77-5.09]; P<0.001), but no increase in mortality. Drug allergy labels are common, but often incorrect. Patients with drug allergy labels experience worse postoperative outcomes, including infective and noninfective complications and an increased risk of allergic drug reactions. ISRCTN Registry (ISRCTN15775657).

Hemodynamic insufficiency may contribute to the development of neuroimaging signs of cerebral small vessel disease (SVD). The arterial spin labeling (ASL) spatial coefficient of variation (ASL-sCoV) is a proxy marker of arterial transit time and may better capture SVD-related hemodynamic disturbances compared with ASL-derived cerebral blood flow. We investigated ASL-derived hemodynamic indices in relation to cognition and neuroimaging markers of SVD over an 11-year follow-up period. Participants without dementia or stroke were enrolled in the Vanderbilt Memory and Aging Project, a longitudinal observational cohort study in Nashville, TN. Participants underwent serial multimodal 3T brain magnetic resonance imaging to quantify SVD burden and neuropsychological assessment from 2012 to 2024 (4.9±3.5 years mean follow-up). Pseudo-continuous ASL assessed cerebral blood flow and ASL-sCoV in total gray matter. Baseline ASL-sCoV and cerebral blood flow were individually related to the cross-sectional burden and longitudinal trajectory of each SVD neuroimaging marker (white matter hyperintensities, enlarged perivascular spaces, cerebral microbleeds, and lacunar infarcts) and cognitive performances using linear and linear mixed-effects regression models. Models were adjusted for demographics, cognitive status, Framingham Stroke Risk Profile (minus age), apolipoprotein E-ε4 status, intracranial volume (for SVD outcomes), and follow-up time (for longitudinal models). Among participants (n=667, 68±9 years, 18% mild cognitive impairment, 51% female), higher ASL-sCoV was cross-sectionally associated with SVD markers, including white matter hyperintensities and enlarged perivascular spaces (pFDR-values<0.006). Higher baseline ASL-sCoV was associated with a faster longitudinal increase in the burden of white matter hyperintensities (pFDR=0.03) and accelerated decline in executive function, information processing, language, and visuospatial performances (P<0.05). Gray matter cerebral blood flow was not associated with SVD burden or cognition cross-sectionally (pFDR-values>0.05) or longitudinally (pFDR-values>0.06). ASL-sCoV may serve as an important hemodynamic measure for identifying perfusion deficits tied to SVD burden and progression. Readily derived from existing ASL data sets, ASL-sCoV could provide substantial insight into the longitudinal clinical consequences of SVD.

Targeting ACKR3/CXCR7 regulates enzymatic generation of prothrombotic lipids while favoring antithrombotic lipids that inhibit platelets through the AC-cAMP-PKA pathway in coordination with prostacyclin IP receptor. This investigation validated the effect of CXCR7 in modulating nonenzymatic lipid (per)oxidation, platelet response to lipoproteins, mitochondrial metabolism, and procoagulant functions. CXCR7 agonist VUF11207 preserved mitochondrial membrane integrity, counteracted activation-induced mitochondrial superoxide generation, and reduced nonenzymatic lipid (per)oxidation. Moreover, it regulated lipoprotein-induced platelet adhesion to thrombogenic matrices, degranulation, αIIbβIII-integrin activation, aggregation, and thrombotic responses by reducing lipoprotein uptake through CD36 and ApoER2. CXCR7 ligation triggered the activation of AMP-dependent kinaseSer-172 and prompted AMPK-mediated inhibitory phosphorylation of acetyl-coenzyme A carboxylaseSer-79 to foster lipolysis over lipogenesis. Consequently, the AMPKSer-172-ACCSer-79 pathway increased generation of anticoagulant FXa-inhibitory long-chain acylcarnitines (LC-CAR) in platelets of healthy subjects and patients with coronary artery disease. Enrichment of intraplatelet LC-CARs was not attributable to dysregulated mitochondrial respiration because VUF11207 improved maximal respiration, spare respiratory capacity, and ATP-linked respiration in thrombin-activated platelets, suggesting sustained mitochondrial metabolism. Exerting a 2-pronged effect on procoagulant function, VUF11207 downregulated phosphatidylserine exposure on activated platelets and reduced FX/FXa binding, while platelet-derived anticoagulant LC-CARs regulated thrombin generation. VUF11207 administration reduced thrombus formation, platelet degranulation, αIIbβIII-integrin activation, procoagulant activity, and circulating platelet-leukocyte aggregates in murine venous thrombosis model, also decreased plasma procoagulant lipids derived from platelet cyclooxygenase-1 and 12-lipooxygenase (LOX), and leukocyte 5/15-LOX, decreased thromboinflammatory mediators (IL-1β, IL-6, IFN-γ, TNF-α, and MCP-1), and increased plasma LC-CAR levels. Therefore, pharmacological targeting of CXCR7 could regulate (non)enzymatic lipid processing and promote anticoagulant LC-CAR generation to limit platelet-driven thrombotic propensity and hypercoagulability, also replenish reduced levels of circulatory LC-CARs in patients with STEMI and VTE.

Primary aldosteronism (PA), characterised by autonomous aldosterone excess, accounts for a substantial proportion of patients with hypertension, particularly those with resistant disease. Current clinical management is largely guided by a binary classification into unilateral and bilateral PA; however, accumulating clinical, pathological, and molecular evidence indicates that this framework inadequately captures the underlying biological heterogeneity. Variable surgical outcomes, biochemical recurrence following adrenalectomy, and refined aldosterone synthase (CYP11B2)-based histopathological classifications highlight PA as a disease spectrum driven by disrupted adrenal zonation, cellular plasticity, and diverse aldosterone-driving somatic mutations. Despite major advances in defining the molecular basis of PA over the past decade, most insights have been derived from bulk genetic analyses of surgically excised tissue, limiting resolution of cellular heterogeneity and disease evolution. In this review, we integrate current understanding of PA pathophysiology with recent advances in single-cell and spatial technologies that have transformed adrenal research. We outline key methodological approaches enabling high-resolution interrogation of adrenal development, tumour heterogeneity, and the adrenal microenvironment. Finally, we discuss the translational implications of single-cell insights for PA, including improved patient stratification, identification of pre-operative biomarkers, and the development of mechanism-based, genotype-informed therapies beyond conventional mineralocorticoid receptor antagonism. Collectively, these advances support a paradigm shift from lateralisation-based management toward precision approaches targeting the cellular and molecular drivers of aldosterone excess.

Ischemic stroke triggers profound neuroinflammation and autophagic stress, driven predominantly by microglial overactivation. However, effective therapies targeting this pathogenesis remain elusive. Here, we report the use of 3-hydroxydehydroleucodin (3-Hyd), the primary active component from Kudiezi injection used in China for ischemic stroke patients, as a potent neuroprotective agent that markedly reduces the cerebral infarct area and improves neurological deficits in a mouse model of transient middle cerebral artery occlusion (tMCAO). Integrated bulk RNA sequencing and in vitro assays revealed that 3-Hyd significantly suppressed the microglial proinflammatory phenotype and excessive autophagic flux. Mechanistically, through chemical biology approaches, we discovered that 3-Hyd directly binds to the V51 and R128 residues of peroxiredoxin 1 (PRDX1), which physically disrupts the pathological binding of PRDX1 to its E3 ubiquitin ligase TRIM21, thus preventing the polyubiquitination of PRDX1 at the K109 residue and its subsequent proteasome degradation. Consequently, stabilized PRDX1 impedes TRAF6 ubiquitination, effectively blocking the downstream NF-κB signaling cascade. Strikingly, the anti-neuroinflammatory and cerebroprotective effects of 3-Hyd were largely abolished in microglia-specific Prdx1 conditional knockdown (Cx3cr1Cre/ERT2) mice. Together, our findings elucidate a novel TRIM21-PRDX1-TRAF6 signaling axis that governs microglial homeostasis and highlight the pharmacological stabilization of PRDX1 by 3-Hyd to block the binding of TRIM21 with PRDX1 as a promising therapeutic strategy for ischemic stroke.

Immune checkpoint inhibitors (ICIs) have transformed cancer outcomes but may be associated with an increased risk of myocardial infarction and ischemic stroke. Whether this risk is mediated by inflammatory plaque activation and whether coadministered vascular endothelial growth factor inhibitors (VEGFIs) modify the effect remain unresolved. To prospectively characterize the arterial and systemic inflammatory outcomes associated with ICIs, VEGFIs, and combined ICIs plus VEGFIs in patients with cancer. This prospective longitudinal cohort study was conducted between August 2022 and June 2024 at the West of Scotland regional cancer hospital network. Adults with cancer who were planned to receive ICI monotherapy, VEGFI monotherapy, or combined ICI plus VEGFI therapy underwent imaging and venous blood sampling at baseline (before treatment) and at 24 weeks. Data were analyzed from June 2024 to October 2025. Undergoing (18F)fluorodeoxyglucose positron emission tomography computed tomography ([18F]FDG-PET/CT) imaging. Arterial inflammation was quantified by (18F)FDG-PET/CT using imaging protocols optimized for vascular assessment. The primary outcome was the between-group difference in change in maximal tissue to background ratio (TBRmax) over time, evaluated by analysis of covariance adjusted for baseline. Systemic inflammatory biomarkers were measured by enzyme-linked immunosorbent assay and a proteomic panel. Circulating immune cell phenotypes were profiled using spectral flow cytometry. Of 55 evaluable patients (mean [SD] age, 66 [10] years; 39 male [71%] and 16 female [29%]), 20 received ICIs, 15 received VEGFIs, and 20 received ICIs plus VEGFIs. At 24 weeks, TBRmax did not exceed baseline in any group (ICIs: mean [SD], 1.71 [0.14] vs 1.67 [0.14]; VEGFIs: mean [SD], 1.72 [0.22] vs 1.72 [0.17]; ICIs + VEGFIs: mean [SD], 1.74 [0.18] vs 1.64 [0.15]; among groups: P = .13). Findings were consistent across artery type, calcification status, prior atherosclerotic disease, and steroid exposure. ICI therapy was associated with selectively altered T-cell subsets, an outcome attenuated by concurrent VEGFI therapy, while VEGFI therapy alone had no significant association with circulating immune cells. Across all 3 regimens, systemic inflammatory biomarkers showed only modest changes. Intracellular adhesion molecule-1 and vascular cell adhesion molecule-1 increased in patients exposed to ICIs. In this prospective cohort study, ICIs and VEGFIs, alone and in combination, were not associated with (18F)FDG-PET/CT-detectable arterial inflammation, and systemic inflammatory outcomes were limited. These findings argue against macrophage-driven plaque activation as a primary mechanism of ICI-associated atherothrombosis and support prioritization of endothelial and thrombotic pathways in future mechanistic and preventive studies.

Pericoronary adipose tissue (PCAT) density on coronary computed tomography angiography (CCTA) has emerged as a non-invasive marker of perivascular inflammation and a potential prognostic biomarker in heart transplant recipients. However, relationship between the longitudinal changes in PCAT attenuation and cardiac allograft vasculopathy (CAV) progression remains poorly defined. To evaluate whether static PCAT density values and their longitudinal change predict CAV progression and adverse evolution in stable heart transplant recipients. We retrospectively enrolled 127 recipients with clinical, echocardiographic, and biopsy-proven stability undergoing paired CCTA at Padua University Hospital. Proximal, pancoronary, and right coronary artery pericoronary fat attenuation were measured at baseline and follow-up CCTA. Baseline CCTA was performed a median of 7.5 years after transplantation and follow-up 2.0 years later. Radiological CAV progression occurred in 14 patients (11.0%) according to International Society for Heart and Lung Transplantation criteria; 20 patients (15.7%) met the composite radiological or clinical endpoint (worsening of New York Heart Association functional class, or hospitalization for cardiovascular causes). Cohort-level PCAT density values and in event-free patients were stable, while subjects presenting composite events showed longitudinal increases in all six attenuation metrics. A newly proposed biomarker, the dynamic PCAT ratio (baseline/follow-up) was consistently higher than 1 in patients with radiological or clinical progression, while remaining close to 1 in event-free subjects. In Firth penalized regression, dynamic PCAT ratios remained associated with the composite endpoint after multivariable and multiplicity adjustment, whereas associations with static measurements did not remain significant after correction. In heart transplant recipients, temporal evolution of PCAT density, rather than single measurements, appears to capture the biological activity associated with subsequent clinical deterioration, but warrants prospective multicentre validation.

Vasomotor symptoms in perimenopause are associated with increased future cardiovascular (CVD) risk. Most clinical trials on menopausal hormone therapy (MHT) and CVD risk have focused on postmenopausal women, with limited study of the perimenopausal period when hormonal fluctuations and symptoms are greatest. Moreover, these trials were not designed to evaluate CVD risk with MHT among women with vasomotor symptoms. To estimate the effect of MHT on CVD risk among perimenopausal and recently postmenopausal women with vasomotor symptoms and assess the extent to which timing of MHT use relative to menopause and race and ethnicity modify this effect. Cohort data from the Study of Women's Health Across the Nation (SWAN, 1997-2017)-a multiethnic, multicenter, longitudinal study of the menopause transition-were used to emulate a sequence of target trials. Eligible participants were women who self-reported any vasomotor symptoms (ie, hot flashes and/or night sweats over the past 2 weeks) and who were CVD-free, with no prior MHT use. Data were analyzed from January 2023 to December 2025. MHT use (systemic estrogen with/without progestogens, verified from medication containers). CVD events (myocardial infarction, stroke, heart failure, and revascularization) were self-reported. CVD-related death was recorded from death certificates. Of 2737 women who reported any vasomotor symptoms, 755 initiated MHT (mean [SD] age, 53.7 [4.6] years) over the 20-year follow-up period, during which 224 fatal and nonfatal CVD events occurred. Overall, the estimated adjusted hazard ratio (aHR) of CVD events for MHT initiation vs noninitiation was 0.78 (95% CI, 0.62-0.98). The estimated aHR was 0.73 (95% CI, 0.58-0.93) and 1.53 (95% CI, 0.66-3.52) among women initiating MHT 10 or fewer years vs more than 10 years from the onset of menopause, respectively (P value for interaction: .02). Race and ethnicity modified the MHT initiation effect, with Black women showing protective effect (aHR, 0.51; 95% CI, 0.33-0.81), while no clear effects were observed in White women or women of other races (P value for interaction = .007). The presented results are pooled from all target trials and found that MHT initiation during perimenopause or recently postmenopausal women with vasomotor symptoms was estimated to reduce CVD risk by 22%. Benefits were more pronounced in Black women and women who initiated MHT within 10 years of menopause onset. However, all estimates warrant caution given the potential for residual confounding. Given the inconsistency of the cardiovascular benefits and the need to consider overall risk-benefit balance, these findings should not be used to support MHT for CVD prevention.

Fibrosis assessed through late gadolinium enhancement (LGE) in cardiac magnetic resonance imaging and genetics have emerged as risk markers of ventricular arrhythmias in nonischemic dilated cardiomyopathy. Conduction corridors detected within LGE (ie, LGE corridors) have been associated with ventricular arrhythmias in ischemic cardiomyopathy. This study sought to evaluate major ventricular arrhythmic events (MVAs) according to the presence of LGE corridors combined with high-risk genotypes (HRGs) in nonischemic dilated cardiomyopathy. We studied consecutive patients with nonischemic dilated cardiomyopathy from 22 European centers who had undergone genetic testing and cardiac magnetic resonance imaging. Among 925 patients (mean age, 54.5 years [interquartile range, 43.7-63.9 years]; 64% men; mean left ventricular ejection fraction, 37.6% [26.9%-44.8%]; LGE in 24.3%), LGE corridors were present in 160 patients (17.3%), and HRG in 119 (12.9%). After a median follow-up of 5.4 years (interquartile range, 3.3-7.7), 95 patients (10.3%) experienced an MVA. In multivariable competing-risk analysis adjusted for left ventricular ejection fraction and extent of LGE, the number of LGE corridors and HRGs were independently associated with MVA (subdistribution hazard ratio, 1.25 [95% CI, 1.11-1.42]; P<0.001; and subdistribution hazard ratio, 2.28 [95% CI, 1.32-3.96]; P=0.003, respectively). An optimal cutoff of ≥4 LGE corridors predicted MVA. A stepwise risk stratification algorithm to predict MVA integrating LGE, the presence of ≥4 LGE corridors, and HRG outperformed left ventricular ejection fraction ≤35%-based classification proposed in guidelines (5-year time-dependent area under the curve, 0.72 [95% CI, 0.65-0.78] versus 0.57 [95% CI, 0.51-0.64]; P=0.001), showing a progressive increase in arrhythmic risk across categories (Gray test P<0.001), and allowing clinically meaningful arrhythmic risk classification. LGE corridors and HRGs provide additive value for arrhythmic risk stratification in patients with nonischemic dilated cardiomyopathy. These findings support MVA multiparametric prediction over the traditional left ventricular ejection fraction ≤35% threshold.

Pediatric heart failure-related cardiogenic shock carries high morbidity and mortality but is understudied. Improving outcomes in pediatric cardiogenic shock hinges on timely diagnosis and appropriate triage, medical management tailored to the cause and phenotype of cardiogenic shock, and optimal timing of escalation to appropriate mechanical circulatory support. This scientific statement provides a diagnostic framework for the bedside clinician, in addition to proposing a pediatric cardiogenic shock definition and severity staging aligned with systems previously validated in other studies. It outlines the initial approach to diagnosis and stabilization of a child with suspected cardiogenic shock and offers guidance on optimal noninvasive and invasive monitoring strategies to determine clinical trajectory because a significant proportion of children with cardiogenic shock will continue to deteriorate in the first 24 hours. Last, it identifies future directions for the field, including educational interventions for the frontline clinicians seeing these patients, studying the role of a multidisciplinary shock team, evaluating the prognostic and clinical relevance of known and novel biomarkers, and leveraging all these to develop clinical decision tools or algorithms to guide nuanced management of these patients.

Undertreatment and delayed treatment of aortic stenosis (AS) are common, both of which are associated with increased mortality. Historically, assessment of quality for AS care has focused on peri- and postprocedural outcomes. The American Heart Association Target: AS registry is the first national registry to provide data and evaluate quality for upstream processes of care for patients with AS. Randomly selected patients from 2023 and 2024 with moderate or severe AS from 58 sites in the Target: AS registry were included. The 2 primary quality measures were (1) timely diagnosis (percentage of patients with an echocardiogram consistent with possible severe AS who had all assessments to clarify AS severity and symptoms within 30 days) and (2) timely treatment (percentage of patients with a Class I indication for aortic valve replacement treated within 90 days). Secondary measures included documentation of key echocardiographic parameters in the report, clinical recommendations in the echocardiogram report summary, multidisciplinary heart valve team evaluation, guideline-based performance of multimodality testing, and timely surveillance echocardiograms. Among 8097 patients, 47% were women, 7% Black, 6% Hispanic, and 3% Asian. Timely diagnosis occurred in 54% in 2023, improving to 61% in 2024 (P=0.027) with gaps caused by lack of timely symptom assessment (23% [2023]; 16% [2024]), lack of stroke volume index (35% [2023]; 18% [2024]), or lack of timely multimodality testing (87% [2023]; 75% [2024]). Among those with a Class I indication for aortic valve replacement, timely treatment occurred in 82% (2023) versus 85% (2024) (P=NS). Multidisciplinary heart valve team evaluation occurred in 78% (2023) versus 84% (2024) (P=0.008). Key findings in the echocardiography report were documented in 83% (2023) and 85% (2024) (P=NS), but a clinical recommendation was included in <10% of the time. Timely surveillance echocardiograms for moderate (2 years) and severe AS (1 year) were not performed in ~40% of patients. The national American Heart Association Target: AS registry demonstrates opportunities for improvement in timely diagnosis, surveillance, and treatment for patients with AS at participating centers. By providing an infrastructure to measure performance and identify best practices, the Target: AS registry has the potential to elevate and optimize care and patient outcomes.

This document aims to review current scientific evidence on exercise and nutrition as a treatment for sarcopenia in the context of cardiovascular disease (CVD). First, we introduce the topic of sarcopenia and its estimated prevalence in patients with CVD. Then, we critically analyse the available evidence to support the use of exercise and nutrition, both alone and combined, for treating sarcopenia in patients with CVD followed by discussing factors that may optimize management. We further discuss the relevance of how medications used in CVD impact sarcopenia and how they may negatively interact with exercise/nutritional interventions. Finally, we provide insights into the practical implications and future directions for managing sarcopenia in patients with CVD. In summary, optimized physical exercise interventions (dedicated resistance training in addition to endurance training and other modalities) together with adequate nutritional intake (avoiding malnutrition and ensuring sufficient protein consumption) is advised for the prevention and management of sarcopenia. However, there currently remains a lack of high-quality evidence to support these approaches in the context of CVD, where baseline sarcopenia status has typically not been evaluated. Future work, therefore, is required in CVD populations with confirmed sarcopenia to better understand what optimal exercise and nutritional strategies are required to further improve sarcopenia management. Keywords Cardiovascular disease, Exercise, Heart failure, Nutrition, Sarcopenia, Skeletal muscle.

In the modern era of cardiovascular medicine, clinicians and researchers stand at a pivotal crossroads between the paradigms of evidence-based medicine (EBM) and personalized medicine (PM). This tension is particularly palpable in the management of heart failure (HF) and inherited cardiomyopathies, heterogeneous conditions with complex pathophysiology and variable individual trajectories. While EBM has shaped practice through robust clinical trials and guideline-directed therapies, PM challenges us to consider the uniqueness of the patient beyond population averages. This dilemma is clear when considering that EBM is extensive and robust in the field of HF, instead, high-quality evidence remains relatively scarce for inherited cardiomyopathies, which may often result in HF, further highlighting the critical role of PM in this domain. The divergence underscores a critical epistemological and practical issue: how can clinicians reconcile the generalizability of EBM with the specificity demanded by PM? This review critically examines the philosophical foundations and clinical implications of this paradigm interplay, with a focus on HF and cardiomyopathies. It explores emerging strategies that aim to bridge the gap between standardized care and individualized management. Finally, it proposes a conceptual framework for harmonizing EBM and PM, advocating for a dynamic, context-sensitive approach that leverages the strengths of both paradigms to optimize patient outcomes in an era of personalized cardiovascular care.

Patent foramen ovale (PFO) is a highly prevalent cardiac abnormality, affecting approximately 25% of the population worldwide. Although a PFO may be discovered incidentally and remain asymptomatic throughout life, it can also be a conduit for paradoxical emboli or vasoactive substances and has been associated with neurological disorders, including cryptogenic stroke, transient ischemic attack, migraine, epilepsy, as well as systemic embolism, hypoxemic disorders, and decompression sickness, particularly in individuals with high-risk anatomy or traditional cardiovascular risk factors. However, accurate identification of pathogenic PFO remains a challenge in current clinical practice, and the indications, timing, and long-term safety of PFO closure remain controversial. In this review, we summarize the epidemiology, risk factors, pathophysiological mechanisms, clinical manifestations, diagnostic strategies, and management of PFO, with particular emphasis on risk stratification, emerging imaging tools, novel closure devices, procedure-related complications, and the application of closure in special populations. In addition, we focused on the current evidence regarding when and who may benefit from PFO intervention and the surveillance of postprocedural complications. Overall, this review provides a comprehensive overview of the current findings and future perspectives for the management of PFO.