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Importance Elevated low-density lipoprotein cholesterol (LDL-C) is a modifiable risk factor for cardiovascular disease, the leading cause of premature death worldwide. Assessing the LDL-C–related burden is critical for guiding prevention and treatment strategies. Objectives To estimate the global, regional, and national burden of ischemic heart disease and ischemic stroke attributable to elevated LDL-C (relative to 35-54 mg/dL) from 1990 to 2023 and to quantify the contributions of population growth, aging, risk-deleted burden, and exposure changes to burden trends. Design, Setting, and Population This comparative risk assessment, part of the Global Burden of Disease Study 2023, estimated population-level LDL-C exposure and associated health loss in 204 countries and territories. Mean LDL-C levels were estimated using spatiotemporal gaussian process regression based on 806 studies across 161 countries. Relative risks were derived from meta-analyses of 38 randomized clinical trials. Population-attributable fractions for deaths and disability-adjusted life-years (DALYs) were estimated by age and sex for adults aged 25 years or older from 1990 to 2023, with 95% uncertainty intervals. Exposure Population-level LDL-C concentrations. Main Outcomes and Measures Population-attributable fractions, counts, and rates (all ages and age standardized per 100 000) of LDL-C–attributable deaths and DALYs from ischemic heart disease and ischemic stroke, with uncertainty intervals. Results In 2023, elevated LDL-C accounted for 3.6 million deaths (95% uncertainty interval, 2.2-5.4 million; 6.0% of global mortality) and 90.7 million DALYs (95% uncertainty interval, 58.9-123.3 million; 3.2% of DALYs). Although global all-ages rates remained stable, age-standardized death and DALY rates decreased by 45.6% and 39.5%, respectively, since 1990. In 2023, age-standardized LDL-C–attributable DALY rates were highest in Eastern Europe and lowest in high-income Asia-Pacific. One-third of the global LDL-C burden occurred in India and China. Population growth and aging drove the increasing burden, with notable regional disparities in LDL-C exposure and risk-deleted DALY rates shifting toward middle-sociodemographic settings. Conclusions and Relevance Despite declining age-standardized rates, the absolute LDL-C burden has increased since 1990 due to demographic changes and has shifted toward middle-sociodemographic countries. Measurement and surveillance gaps persist. Strengthened prevention, diagnosis, and treatment access strategies are essential to mitigate the health burden of LDL-C.

Abstract Background The Charlson comorbidity index (CCI) is a validated weighted measure of comorbidity burden, but has an unclear role in heart failure (HF). Objectives To characterize age-adjusted CCI (ACCI) in HF, its association with the use of guideline-directed medical therapy (GDMT) and with outcomes. Methods In the Swedish HF registry, patients were divided into 3 groups based on ACCI scores (low 1-3, intermediate 4-6, and high ≥7). We studied its association with clinical characteristics and GDMT use. Multivariable multinominal and Cox regressions were used to analyze ACCI and its association with ejection fraction (EF) category (reduced [HFrEF], mildly reduced [HFmrEF], preserved [HFpEF]), and with outcomes up to 3 years. Results Among 117,419 patients (age 75 [66-82], 36% women, 53% HFrEF, 24% HFmrEF, 23% HFpEF, median ACCI was 5, 6 and 6 respectively. ACCI ≥7 was present in 31% with HFrEF, 35% with HFmrEF and 42% with HFpEF. A higher ACCI score was associated with higher EF category, NYHA class, serum NT-proBNP, diuretic use, and lower quality of life and GDMT use (p<0.05 for all). The risk of composite CV mortality/first HF hospitalization was higher with intermediate (adjusted HR 1.34, 95% CI 1.29-1.39) and high vs low ACCI (1.76, 1.69-1.83). High ACCI category (vs low) was significantly associated with non-CV (adjusted HR 6.36, 95% CI 5.75-7.04), but also, CV mortality (4.35, 3.99-4.74), and total hospitalizations (adjusted IRR 2.16, 2.11-2.22) but also HF hospitalizations 1.23 (1.17-1.28) Conclusion The ACCI discriminates well in HF, with higher ACCI being associated with greater severity of HF, lesser GDMT use and worse quality of life. Higher ACCI was more strongly associated with death than hospitalization. Higher ACCI was more strongly associated with non-CV outcomes but also with CV and HF outcomes.

Background Evidence to guide the optimal timing of antiplatelet and oral anticoagulants (OACs) therapy after hemorrhagic infarction (HI) versus parenchymal hematoma (PH) is limited and inconsistent, leading to substantial variation in practice. This study's goal was to study the practice pattern and compare clinical outcomes associated with early‐versus‐delayed initiation of antiplatelet/OACs after hemorrhagic transformation (HT). Methods This multicenter, retrospective, cross‐sectional study included patients with acute ischemic stroke and HT. Patients with an HI or PH were categorized by HT to antithrombotic initiation time, and their outcomes—30‐day HT exacerbation, composite outcomes of recurrent stroke/systemic emboli, 90‐day vascular death, and functional outcomes—were compared. Results Of 748 patients, 496 received antiplatelets, and 252 received OACs after HT. The median HT‐to‐antiplatelet time was significantly shorter after HI than PH (1 [interquartile range, 0–2] versus 3 [interquartile range, 1–5] days; P <0.001). There were no statistically significant differences in HT exacerbation and composite outcomes (30‐day), as well as vascular death and unfavorable functional outcomes (90‐day), between patients who received same‐day, early (HI, <1 day; PH, <3 days), or late (HI, >1 day; PH, >3 days) antiplatelets after either HI or PH. Among patients on OACs, those with HI had shorter median HT‐to‐OAC time than PH (7 [interquartile range, 2–15] versus 15 [interquartile range, 7–32] days; P <0.001). Although HT exacerbation rates (30‐day) were comparable between early (HI, <7 days; PH, <15 days) and late (HI, >7 days; PH, >15 days) OAC initiation after either HI or PH, late initiation after PH was accompanied by higher rates of composite outcomes (30‐day) than early initiation (20.7% versus 3%; P =0.044). Regression models adjusted for demographics, National Institutes of Health Stroke Scale, and stroke severity showed no statistically significant association between early initiation of antiplatelets or OACs with HT exacerbation risk. Conclusions Our study found no statistically significant difference in HT exacerbation between early and late initiation of antiplatelets or OACs among patients with HI/PH, while prolonged delay among patients with PH were accompanied by increased systemic thromboembolic events. Although these findings offer preliminary clinical insight, prospective studies are needed.

Background Primary aldosteronism (PA), a renin-independent state of aldosterone excess, is associated with excess risk of stroke, myocardial infarction, atrial fibrillation, heart failure, and chronic kidney disease compared with essential hypertension. Emerging evidence suggests that renin-independent aldosterone excess exists on a continuum rather than as a dichotomous disease state, including subclinical primary aldosteronism (sPA), even in normotensive individuals. Whether sPA is associated with major adverse cardiovascular events (MACE) prior to overt hypertension remains incompletely characterized. Objective To synthesize available evidence linking renin suppression and mild aldosterone excess to cardiovascular outcomes. Methods A narrative review of the literature was conducted using PubMed/MEDLINE, the Cochrane Library, and Web of Science from inception through May 2025, to identify cohort studies evaluating renin phenotype, aldosterone levels, and cardiovascular outcomes. Results Suppressed renin and higher aldosterone levels, even within conventionally normal ranges, are associated with incident hypertension, left ventricular hypertrophy (LVH), atrial fibrillation, and cardiovascular events. In overt PA, significantly higher rates of cardiovascular diseases have been observed compared with blood pressure-matched essential hypertension. Emerging population-based data suggest a graded cardiovascular risk extending below traditional diagnostic thresholds. Conclusion Biochemical phenotypes consistent with sPA may represent an early cardiometabolic state associated with elevated risk of MACE, even before overt PA criteria are met. The absence of standardized diagnostic thresholds and randomized interventional data currently limits clinical translation. Prospective trials evaluating renin-guided screening and early mineralocorticoid receptor antagonism are needed to determine whether intervention at the subclinical stage reduces long-term cardiovascular harm.

RELA-related disease is a rare, autosomal-dominant condition presenting with immune dysregulation and immunodeficiency. RELA encodes the p65 subunit, a component of the canonical NFκB pathway. The underlying pathogenesis, at least in part, involves impaired NFκB activation, increased susceptibility to TNFα-induced apoptosis, and hyperinflammation. To date, only a modest number of cases have been documented worldwide, and the full clinical and functional spectrum of disease remains incompletely defined. This study represents a large global cohort identified with RELA variants, comprising 40 patients from 30 institutions, expanding our previous report of a single large kindred (1). The clinical spectrum includes arthritis, mucocutaneous ulcers, uveitis, dermatitis, irritable bowel disease, recurrent infections, lymphopenia, hypogammaglobulinemia, recurrent fevers, and susceptibility to neoplasia. The patients represent 36 kindreds with 28 unique RELA variants, of which 15 are missense, 7 nonsense, and 6 frameshift variants. Fifteen are in the Rel homology domain, 7 in the transcriptional activation domain, and 6 in the C-terminal region proximal to TAD (Fig. 1). Functional studies assessed the canonical NFκB pathway in 27% of the cohort (n = 11; healthy controls = 40). Patient peripheral blood mononuclear cells (PBMCs) were used to quantify total and phosphorylated p65 (ph-p65, Ser529) by flow cytometry after stimulation with PMA (100 ng/ml) and ionomycin (1 uM). In 8 patients, we assessed the kinetics of IκBα degradation, required for p65 phosphorylation and nuclear translocation of p65/p50. All patients tested had decreased total p65, while 64% had decreased ph-p65 with altered phosphorylation kinetics. Nearly 45% had impaired IκBα degradation. One patient (P4) demonstrated increased IκBα degradation and ph-p65, while a related proband (P1) had decreased ph-p65. Additionally, P4 did not have the same mucocutaneous clinical phenotype as P1 despite sharing the same RELA variant. This could reflect the effect of other genetic modifiers, epigenetic, environmental, or stochastic variations, which could lead to variable expressivity and/or incomplete penetrance. All patients appeared to have haploinsufficiency, as none had normal levels of p65. This study expands the clinical and genetic spectrum of RELA-related disease and provides mechanistic insights into the impact of these variants on p65 phosphorylation and downstream function, resulting in variable expressivity. Figure 1. RelA protein structure. Represents unique variant locations and categories, key domains, and phosphorylation sites. Source: UniProt. Adapted from (2). BioRender.

Post-transplant thrombotic microangiopathy (PT-TMA) is a serious and underrecognized complication of kidney transplantation, associated with substantially reduced allograft survival. Its heterogeneous presentations, ranging from systemic to renal-limited forms, and multifactorial etiologies complicate timely diagnosis and management. Complement activation is central across all etiologies, either as a primary driver of disease in recurrent complement-mediated TMA (also known as atypical hemolytic uremic syndrome or aHUS) or as an amplifier in de novo PT-TMA (dnTMA). Accurate diagnosis requires a combination of clinical assessment, laboratory evaluation, and histopathologic examination, with particular attention to complement abnormalities, donor/recipient risk factors, and potential triggers. Management must be individualized, encompassing supportive care, optimization of immunosuppression, complement blockade, and plasmapheresis in select cases. Histologic features and clinical risk factors can guide prognosis, and scoring systems provide valuable tools for risk stratification. Despite advances in therapy, long-term outcomes remain suboptimal, particularly in antibody-mediated rejection (AMR)-related cases. Ongoing research is essential to clarify the optimal context for the use of anti-complement therapy, and to develop effective prophylactic and therapeutic strategies while maintaining adequate immunosuppression.

Summary Background Idiopathic pulmonary fibrosis (IPF) is a progressive and fatal lung disease characterized by aberrantly activated, apoptosis-resistant profibrotic lung (myo)fibroblasts. Prior research has demonstrated that lung fibroblasts from patients with IPF exhibit resistance to DNA damage, suggesting that this behavior contributes to their persistent survival and continuous proliferation. We propose that elevated levels of the DNA damage repair protein RAD51 regulate myofibroblast activation and apoptosis and provide a potential therapeutic target to impede fibrosis progression. Methods Human lung fibroblasts were transfected with siRNA against RAD51 or treated with RAD51-specific inhibitor B02 and markers of fibrosis, DNA damage, apoptosis, metabolic reprogramming, and mitochondrial dynamics were assessed. The preclinical efficacy of B02 was evaluated in human precision cut lung slices (PCLS) and in a mouse model of pulmonary fibrosis. Findings RAD51 expression was significantly upregulated in the lungs and lung fibroblasts of IPF patients. Knockdown or inhibition of RAD51 in fibroblasts reduced profibrotic marker expression, suppressed mTORC1 signaling and mitochondrial function, and increased apoptosis susceptibility. Pharmacological inhibition of RAD51 shifted the profibrotic phenotype towards a fibrosis-resolving state in human and mouse PCLS, and in a bleomycin-induced mouse model of lung fibrosis. Interpretation The inhibition of RAD51 exerts therapeutic benefits in lung fibrosis by promoting apoptosis. Our findings identify that inhibiting RAD51 with B02 in fibroblasts impairs DNA repair and induces metabolic reprogramming, making it a potential therapeutic target. Research in context Evidence before this study Pulmonary fibrosis (PF) is characterized by excessive fibroblast activation and subsequent deposition of extracellular matrix (ECM) proteins, which ultimately disrupt normal lung architecture. A significant contributing factor to the pathogenesis of pulmonary fibrosis is the presence of fibroblasts that are resistant to apoptosis, preventing normal wound healing. Recent studies highlight the DNA repair protein RAD51 as effective in protecting fibroblasts from death induced by chemotherapy and ionizing radiation. These finding suggested that RAD51 could have a role in fibroblast activation and apoptosis resistance in pulmonary fibrosis. Added value of this study We demonstrated that RAD51 is important for maintaining apoptosis-resistant fibrotic fibroblasts and their metabolic abnormalities. Our findings indicated that TGFβ-mediated upregulation of RAD51 reduces DNA damage, activates multiple pathways related to fibroblast activation and proliferation, and induces metabolic reprogramming, ultimately regulating apoptosis. Mechanistically, RAD51 inhibition enhanced p53 acetylation at lysine 120 and upregulated the expression proapoptotic proteins PUMA/BAK in mitochondria, promoting apoptosis. Pharmacological inhibition of RAD51 using the specific inhibitor B02 during the fibrotic phase of experimental lung disease effectively ameliorated pulmonary fibrosis. Implications of all the available evidence Our findings establish that RAD51 plays an important role in the survival of apoptosis-resistant fibrotic fibroblasts. We propose that reducing RAD51 expression leads to the metabolic reprogramming of activated fibroblasts, resulting in decreased mitochondrial respiration, reduced ATP levels, and diminished glycolysis or glutaminolysis. These observations suggest that targeting energy metabolism through RAD51 inhibition could be a viable strategy to enhance apoptosis, thereby creating a therapeutically targetable pathway in fibrotic cells. These findings highlight the potential of RAD51 as a therapeutic target for the treatment of IPF.

Abstract Primary liver cancers, including hepatocellular carcinoma (HCC) and cholangiocarcinoma (CCA), arise from the neoplastic transformation of hepatocytes and cholangiocytes, respectively. Loss or downregulation of PTEN, a tumor suppressor negatively regulating the PI3K/AKT pathway, is frequently observed in CCA and HCC. Notably, PTEN mutations are observed at nearly twice the frequency in combined CCA-HCC tumors than either HCC or CCA alone. Using lineage-specific liver-targeted PTEN-deficient mouse models, we demonstrate that PTEN loss drives cellular dedifferentiation and tumorigenesis, a process that is critically dependent on AKT2. Mechanistically, PTEN deficiency induces activation of NOTCH and upregulation of transcriptional factor SOX9, which plays a central role in tumor cell transformation. In parallel, PTEN loss increases SMAD4 expression and sensitizes the tumor cells to TGFβ signaling, with TGFβ treatment repressing SOX9 expression in tumor cells lacking PTEN. Together, our study defined a critical role for PTEN-AKT2 signaling in maintaining liver epithelial lineage fidelity and revealed how its disruption promotes the conversion of mature hepatocytes or cholangiocytes into liver cancer stem-like cells (LCSCs). Furthermore, we identify a PTEN-dependent crosstalk between NOTCH and TGFβ pathways that governs liver tumor development. Together, this work provides mechanistic insight into lineage plasticity in liver cancer with implications for pathway-directed therapy.

Background: Studies have suggested that administering antithrombotics—oral anticoagulants (OACs) and antiplatelets (APLT)—after acute ischemic stroke(AIS) with hemorrhagic transformation (HT) is safe and can reduce ischemic recurrence. However, the safety of their early initiation after HT remains unclear. Method: This study utilized data from nine centers across several countries. The study population included patients with AIS who subsequently experienced HT. Patients with a specific HT type—hemorrhagic infarction(HI) or parenchymal hematoma(PH)—were categorized based on the time between HT and antithrombotic initiation, and their outcomes were compared. Outcomes included 30-day HT exacerbation and composite outcomes of recurrent stroke and systemic emboli, as well as 90-day vascular death and functional outcome. Results: Of 748 patients,496 received APLT, and 252 were prescribed OACs after HT. The median HT-to-APLT time was significantly shorter among HI patients than PH patients(1[IQR:0-2] vs. 3[IQR:1-5] days,p<0.001). The rates of 30-day HT exacerbation and composite outcomes, as well as 90-day vascular death and unfavorable functional outcomes, did not significantly differ between patients who received same-day, early (HI:<1day;PH:<3days), or late (HI:>1day;PH:>3days) APLTs after either HI or PH. Among patients who received OACs, those with HI had a significantly shorter median HT-to-OAC time than PH (7[IQR:2-15] vs. 15[IQR:7-32] days,p<0.001). However, 30-day HT exacerbation rates were comparable between early (HI:<7days;PH:<15days) and late (HI:>7days;PH:>15days) OAC initiation among patients with either HI or PH, late initiation among patients with PH was associated with higher rates of 30-day composite outcomes than early initiation(20.7% vs. 3%,p=0.044). Based on regression models adjusted for NIHSS and stroke severity, early initiation of APLTs or OACs was not associated with increased risk of HT exacerbation. Conclusion: Findings suggest that the same-day initiation of APLTs after HI or PH-1, and within 1-3days following PH-2, might not be associated with HT exacerbation or worsening outcomes. Similarly, OACs initiated 2-7days after HI and 7-15days after PH may not be associated with worsened patients' outcomes, whereas delays beyond these timeframes can be associated with higher thromboembolic risk.