心血管科领域文献阅读汇编

Stroke is less common in children than in adults, yet equally devastating. Nevertheless, children with symptoms of acute stroke commonly present to community hospitals or adult stroke centers where experience and institutional protocols for pediatric stroke diagnosis and management may be limited. Despite advances in pediatric stroke awareness and the implementation of stroke pathways in many children's hospitals, significant gaps remain in the timely recognition, diagnosis, and management of pediatric stroke. A key contributing factor is the lack of system-level infrastructure to guide pediatric acute stroke care. This special report examines the challenges and barriers to achieving Pediatric Stroke Readiness at a national level in the United States and presents 5 engagement case studies highlighting efforts to establish processes and networks for pediatric stroke management across diverse care settings. The cases emphasize the development and implementation of systems of care in which pediatric stroke centers collaborate with first responders, community hospitals, and adult stroke centers to improve the delivery of acute stroke care for children. The strategies underscore different engagement approaches and identify opportunities for future research and quality improvement. These case studies also illustrate educational materials and clinical pathways that may serve as resources for others pursuing similar initiatives.

Just as my seniors nurtured me, I have continued to nurture those who come after me. Through my role as an intermediary, many of my mentors' knowledge and experience have been passed down to numerous mentees. I cannot be grateful enough to my workplaces, which brought together so many highly motivated mentees and allowed me to meet them. "One only half dies who leaves an image of themself in their mentees"; many poets have conveyed similar messages. Cultivating the next generation of leaders in stroke medicine, a field that continues to make remarkable strides, is undoubtedly one of our most important missions.

Cardiovascular diseases, particularly stroke, are leading causes of dementia. Several common cardiac interventions such as coronary artery bypass grafting and transcatheter aortic valve implantation are also associated with cognitive decline. However, cognitive outcomes continue to be poorly collected in clinical trials of cardiovascular diseases. In this article, we review the limitations of current approaches to cognitive assessment in cardiovascular disease studies. When assessed, there is wide variation in cognitive tasks used, and tasks have limited population-specific validation, are subject to floor and ceiling effects, and may suffer from sociocultural and linguistic biases. Many tasks are not available in multilingual formats and often rely on face-to-face testing with trained coordinators. All conventional cognitive outcomes in cardiovascular trials are associated with substantial incompletion, especially among older and more impaired individuals, the very people most important to capture. This nonrandom missingness generates survivor and attrition biases, an unacceptable situation for any trial outcome. Last, the meaning of measured cognitive outcomes is often unclear for patients, caregivers, clinicians, and regulators. To help address these limitations, we propose a new framework, major adverse cognitive events (MACE-Cog), to better capture cognitive outcomes in stroke and other cardiovascular populations. As an inclusive construct reflecting the multidimensional nature of cognitive decline, major adverse cognitive events do not rely solely on performance on cognitive testing but also consider inability to complete cognitive testing due to cognitive-behavioral factors, reported symptoms of cognitive decline, impairment in activities of daily living as a result of cognitive impairment, new clinical diagnoses of dementia, and care home admission. We hope that the proposed composite outcome and multiple use cases presented spark progress in cardiovascular research toward more inclusive approaches to the study of cognitive outcomes that move beyond the confines of cognitive tests alone.

Children with Down syndrome (DS) are at high risk for moyamoya syndrome (MMS) and ischemic stroke, yet early detection strategies remain poorly defined despite the condition being surgically treatable. We conducted a multicenter retrospective cohort study comparing children with Down syndrome-associated moyamoya syndrome (DS-MMS) and MMS without DS (MMS). The primary outcome was stroke as the primary presenting symptom. Secondary outcomes included diagnostic delays, angiographic features, prediagnostic systolic blood pressure percentiles, and 1-year neurological outcomes. Multivariable models adjusted for demographic and access-related covariates. In total, 271 patients were identified; 198 (73.1%) met inclusion criteria and comprised the analytic cohort. Among 198 patients (77 DS-MMS; 121 MMS), DS-MMS mean age was 9.5±5.2 years (50.6% female), and MMS mean age was 7.4±3.0 years (54.5% female). Stroke at presentation was more common in DS-MMS (71.4% versus 20.7%; absolute difference, 50.7%), corresponding to an adjusted odds ratio of 14.50 ([95% CI, 6.65-31.60]; P<0.001). Children with DS-MMS experienced longer delays from symptom onset to presentation and from presentation to diagnostic confirmation (both P<0.001). Posterior circulation involvement was more frequent in DS-MMS (adjusted odds ratio, 2.18 [95% CI, 1.09-4.37]; P=0.03), whereas angiographic severity was similar between groups. In the prediagnostic period, DS-MMS demonstrated a progressive rise in systolic blood pressure percentiles, exceeding the MMS cohort by 6 months (P<0.001). At 1 year, DS-MMS was associated with greater disability (adjusted odds ratio, 2.58 [95% CI, 1.45-4.57]; P<0.001) and spasticity (adjusted odds ratio, 6.33 [95% CI, 3.12-12.83]; P<0.001). DS-MMS represents a high-risk cerebrovascular phenotype characterized by delayed recognition and a markedly increased likelihood of stroke at presentation. Rising blood pressure percentiles preceding diagnosis may serve as an early physiological signal. These findings support targeted early detection strategies and a lower threshold for vascular imaging in symptomatic patients.

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

Older randomized trials have shown modest benefit for carotid endarterectomy for selected patients with asymptomatic carotid stenosis compared with medical treatment. However, improvements in contemporary medical therapy may have negated the benefit of carotid endarterectomy, and no large randomized trials comparing stenting with modern medical treatment have been completed. The recently reported CREST-2 trial addressed these evidence gaps. We describe the main results of CREST-2 and our interpretation of the findings for clinical practice.

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

White matter hyperintensities (WMH) are widely used to assess cerebral small vessel disease but reflect late-stage injury. Diffusion magnetic resonance imaging (MRI) biomarkers have been proposed to capture earlier small vessel disease-related microstructural damage but their temporal progression relative to WMH and risk factors associated with progression remain unexplored. We identified 2077 participants from the population-based cohort study of the Mayo Clinic Study of Aging in Olmsted County, Minnesota (aged 50-101 years) collected between 05/2005 and 09/2024 with longitudinal neuroimaging. Using multioutput nonlinear mixed-effects models in those with at least 2 FLAIR-MRI and diffusion-MRI scans, we characterized the temporal progression of WMH and 4 diffusion MRI biomarkers: fractional anisotropy of the genu of the corpus callosum, peak width of skeletonized mean diffusivity, free water, and Arteriolosclerosis-score, which were automatically estimated. Models incorporated participant-specific time shifts, correlations between biomarkers, and effects of risk factors (sex, education, APOE ε 4 status, cardiometabolic conditions). The study population had a mean age of 78 years, 47% were female, 28% were APOE ε4 allele carriers, and 80% were cognitively unimpaired, with an average follow-up of 5.2 years (SD, 4.3 years) for FLAIR-MRI and 4.3 years (SD, 3.9 years) for diffusion MRI. Arteriolosclerosis-score, fractional anisotropy of the genu of the corpus callosum, free water, and peak width of skeletonized mean diffusivity became abnormal in 50% of the study population 16, 12, 10, and 7 years before WMH become abnormal (half-width of CI <1 year), respectively. Global markers (Arteriolosclerosis-score, free water, peak width of skeletonized mean diffusivity, and WMH) were correlated, indicating shared substrates of widespread white matter injury. Fractional anisotropy of the genu of the corpus callosum, a vascular risk microstructural injury biomarker, was weakly coupled with WMH and had an earlier but more linear worsening across adulthood. Cardiometabolic conditions predicted earlier worsening of all biomarkers. Females showed earlier WMH, fractional anisotropy of the genu of the corpus callosum, and Arteriolosclerosis-score abnormalities, whereas males exhibited earlier peak width of skeletonized mean diffusivity and free water abnormalities. Diffusion MRI biomarkers were abnormal at least a decade before WMH become abnormal in the population, revealing a prolonged phase of early small vessel disease and highlighting their potential for small vessel disease prevention.

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

Administration of recombinant tissue plasminogen activator (rtPA) beyond 4.5  h after ischemic stroke exacerbates blood-brain barrier (BBB) disruption, leading to vasogenic cerebral edema and hemorrhage. However, current therapies remain ineffective. This study aimed to develop and validate an optimized multicomponent combination, termed ADR, consisting of Astragaloside IV (ASIV), 3,4-dihydroxyphenyl lactic acid (DLA), and Notoginsenoside R1 (R1), to prevent BBB damage following rtPA thrombolysis at 4.5  h after stroke onset in mice and to explore the underlying mechanisms. ADR was optimized using a uniform design-entropy weight-regression model. Its efficacy was assessed in mice receiving rtPA at 4.5  h after stroke onset. The pharmacokinetic (PK) and pharmacodynamic (PD) properties of the components were evaluated. Multi-omics analysis, molecular docking, surface plasmon resonance (SPR), and cellular thermal shift assays (CETSA) were performed to identify key targets, followed by functional validation through gene silencing or overexpression in vitro and in vivo. The optimized ADR improved cerebral blood flow, reduced infarct size and neuronal apoptosis, ameliorated neurological deficits, and enhanced survival rates. It effectively inhibited microvascular leakage, hemorrhage, and leukocyte adhesion. PK and PD studies, along with in vivo pharmacological evaluation of the individual components, demonstrated that the combination produced synergistic effects. Integrated analyses identified five key molecules. Molecular docking, SPR, and CETSA confirmed that LMO7 was exclusively modulated by ADR, whereas CAPG was regulated by both ADR and all three components. Additionally, MOBP, HMGB2, and TAGLN2 were targeted by ASⅣ, DLA and R1, respectively. These findings were further confirmed by silencing LMO7 or overexpressing CAPG, MOBP, HMGB2, or TAGLN2 in vitro and in vivo. Our study demonstrated that ADR prevented BBB disruption following rtPA thrombolysis in mice with ischemic stroke through multitarget regulation and provided valuable insights into the integration of Traditional Chinese Medicine and modern pharmacology.

Leptomeningeal collaterals form a critical vascular network that enlarges to support retrograde reperfusion after ischemic stroke, yet the cellular mechanisms governing their structural plasticity remain poorly defined. Here we identify an immune-responsive vascular niche and uncover a central role for bone marrow-derived monocytes in regulating collateral remodeling. GFP (green fluorescent protein)+ bone marrow chimeric mice and inducible monocyte-specific Ccr2-CreERT2/EphA4f/f and Ccr2-CreERT2/EphA4f/f/Tie2f/f mice underwent permanent middle cerebral artery occlusion to assess monocyte recruitment, collateral remodeling, cerebral blood flow, infarct volume, and functional recovery. Mechanistic studies evaluated EphA4 (ephrin receptor A4)/Tie2-PI3K (phosphatidylinositol 3-kinase) α signaling in macrophages, while serum sTie2 (soluble Tie2) levels and immune transcriptomic profiles were analyzed in patients with acute large vessel occlusion and correlated with angiographic collateral grade. We observed rapid recruitment of EphA4-expressing monocytes to pial collateral vessels after permanent middle cerebral artery occlusion. EphA4 knockout chimeric mice show a marked increase in monocyte recruitment, enhanced collateral diameters, improved cerebral blood flow, reduced infarct volume, and accelerated motor recovery. EphA4-null macrophages exhibited elevated Tie2, p-Akt, and PI3Kα, a phenotype reversed by PI3Kα inhibition or sTie2. We further show enhanced permanent middle cerebral artery occlusion-induced collateral enlargement, neuroprotection, and monocyte recruitment using Ccr2-CreERT2/EphA4f/f mice, which is attenuated in Ccr2-CreERT2/EphA4f/f/Tie2f/f double-knockout mice. Notably, we find that serum sTie2 levels are elevated in human patients with large vessel occlusion, and these levels correlate with improved digital subtraction angiography collateral scoring and key immune-specific bulk transcriptomic changes. Together, these findings establish immune cell-intrinsic EphA4/Tie2 signaling as a key regulator of leptomeningeal collateral enlargement and reveal a therapeutic axis for augmenting perfusion after stroke.

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

Exercise training improves exercise tolerance (peak oxygen consumption, peakV̇O2) in patients with heart failure with preserved ejection fraction (HFpEF), but it remains unclear whether the effects are comparable between sexes. To evaluate sex-specific exercise training effects on peakV̇O2 in HFpEF. This pooled analysis integrates data from patients with chronic HFpEF randomised to different modes of exercise training or usual care in the OptimEx-Clin and Ex-DHF-trials. Sex differences in changes of peakV̇O2 (absolute, relative, percent-predicted) from baseline to three, six, and 12 months of exercise training or usual care were compared using linear-mixed-models. Among 498 patients (mean age 69.3 ± 7.7 years, 62% women), 277 (57%) were randomised to exercise training. Exercise training significantly increased absolute, relative and percent-predicted peakV̇O2 compared to usual care in women (all P < 0.001), but not in men (all P > 0.05). A significant sex difference in the training response was observed for percent-predicted peakV̇O2 (sex*group*time-interaction P = 0.037). Although mean within-group changes in percent-predicted peakV̇O2 following exercise training were similar between women and men (4.7% [95% CI, 2.2 to 7.2%] vs. 3.0% [-0.3 to 6.4%] at 12 months), usual care was associated with a decline in women (-3.7% [-6.5 to -0.8%]) but not in men (1.4% [-2.0 to 4.7%]). Exercise training improved percent-predicted peakV̇O2 in women but not in men with HFpEF, a sex difference that was largely driven by differing responses following usual care. Since women are usually underrepresented in exercise programmes, more efforts should be made to increase their participation rates. (OptimEx-Clin: NCT02078947; ExDHF: ISRCTN86879094).

This report describes the design and baseline characteristics of the SPIRIT-HF trial and compares them with prior heart failure with mildly reduced or preserved ejection fraction (HFpEF/HFmrEF) trials. In this multicenter, double-blind, placebo-controlled phase III trial, 730 patients aged ≥50 years with left ventricular ejection fraction (LVEF) ≥40%, New York Heart Association (NYHA) class II-IV symptoms, and either elevated N-terminal-pro-B-type natriuretic peptide (NT-proBNP) or HF hospitalization within 12 months were randomized 1:1 to spironolactone or placebo. The primary endpoint is a composite of rate of total (first and recurrent) HF hospitalizations and cardiovascular death within 24 months from randomization, which will be analyzed using the LWYY model. Secondary endpoints in a hierarchical order include total HF hospitalizations, CV hospitalizations, all hospitalizations, and cardiovascular death within 24 months from randomization. Results will first be analyzed based on the SPIRIT-HF dataset only. Then, a pre-specified individual participant data meta-analysis combining SPIRIT-HF and TOPCAT Americas will be conducted to refine treatment effect estimates. The median age of the patients enrolled in the SPIRIT-HF was 77.8 years, and 52% were women. The median LVEF was 55% (50-60), with 18% of patients having a LVEF between 40-49%. In SPIRIT-HF, prior HF hospitalization was similarly frequent (46.4% vs. 55%), but NT-proBNP was slightly higher (970 vs. 900 pg/ml) compared to TOPCAT Americas. However, the proportion of patients with NYHA class III (33% vs. 35%), patients with comorbidities such as atrial fibrillation at baseline electrocardiogram (25% vs. 25%) and chronic kidney disease (50% vs. 48%); and background therapy, such as beta-blockers (76% vs. 79%), and diuretics (83% vs. 89%), including loop diuretics (69% vs. 78%), were similar between SPIRIT-HF and TOPCAT Americas. Compared with prior HFpEF/HFmrEF trials, SPIRIT-HF patients demonstrated a higher risk with a similar proportion of patients with recent HF hospitalization (46.4%) and slightly higher NT-proBNP concentrations (970 pg/ml) at baseline. SPIRIT-HF addresses key evidence gaps for spironolactone in high-risk HFpEF/HFmrEF, and could inform guideline recommendations on MRA use in this cohort.

Nutrition insecurity is a major driver of poor cardiovascular health in Indigenous communities. Medically tailored meals that reclaim traditional foods may improve heart failure outcomes and quality of life. Community-based participatory methods were used to design Medically Utilized Tailored Traditional Foods to Optimize Nutrition in Heart Failure (MUTTON-HF), a culturally and medically tailored meal program incorporating traditional Navajo foods and recipes. To determine the efficacy of a culturally and medically tailored meal program on the incidence of hospitalizations and emergency department visits. This pragmatic, open-label randomized clinical trial was conducted from May to November 2025 at 2 Indian Health Service sites in rural Navajo Nation. Eligible patients were adults with heart failure who were receiving care at the study sites and had a hospitalization or emergency department visit during the last 12 months. All patients were followed for 12 weeks for outcomes, death, and adverse events. The data were analyzed from December 2025 to February 2026. Patients were randomized in a 1:1 ratio to 8 weeks of a culturally and medically tailored meal program or usual dietary advice. The primary end point was the proportion of patients with an all-cause hospitalization or emergency department visit within 90 days. Secondary outcomes included hospitalizations or emergency department visits separately, and for heart failure specifically, and change in Kansas City Cardiomyopathy Questionnaire scores, food insecurity, financial strain, blood pressure, and weight from enrollment to 8 weeks. A total of 206 patients (mean [SD] age, 65.8 [14.2] years; 87 female individuals [42%] and 119 male individuals [58%]; 203 American Indian individuals [99%], 2 American Indian or Alaskan Native and White individuals [0.97%], and 1 White individual [0.03%]; ejection fraction, 48%) were randomized. The primary outcome was significantly less frequent in the intervention arm (43 [40.6%] vs 57 [57.0%]; relative risk, 0.72; 95% CI, 0.54-0.96; P = .02), which was driven mainly by reduced hospitalizations (13 [12.3%] vs 26 [26.0%]). There was a lower incidence of heart failure hospitalizations specifically (4 [3.8%] vs 13 [13.0%]). The Kansas City Cardiomyopathy Questionnaire score and food security measures had significantly greater increases in the intervention arm while measures of financial strain, weight, and blood pressure significantly decreased in the intervention arm. Adverse events were uncommon. In this randomized clinical trial, an Indigenous Food is Medicine intervention reduced the incidence of hospitalization and emergency department visits among patients with heart failure. Community-based interventions that leverage protective assets of Native communities are needed to advance Indigenous health. ClinicalTrials.gov Identifier: NCT06549699.

The role of myocardial revascularization in HF patients with coronary artery disease by either percutaneous coronary intervention (PCI) or coronary artery bypass graft surgery (CABG) is controversial. For patients with HFrEF, prior to the advances in pharmacological heart failure therapy over the last 10 years, evidence suggests a modest, long-term benefit of CABG over guideline-recommended medical therapy. In the era of modern medical therapy, revascularization had no benefit in HFrEF. Whether a patient with HF and CAD should be advised to have revascularization and, if so, which procedure remains unclear and should be discussed by the heart team given the limited and conflicting evidence. Evidence for viability or ischaemia-guided selection strategies is controversial. In all cases with HF, establishing and optimizing GDMT and device therapy is required. When HF symptoms dominate despite GDMT, additional invasive procedures are not indicated. When angina persists despite GDMT and device therapy, revascularization should be considered. The choice of revascularization procedure should be discussed in the heart team, considering symptoms and ischemic burden, surgical risk, coronary complexity and the applicable HF treatment.

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

Advanced heart failure (AdvHF) remains a major clinical challenge, yet contemporary epidemiological real-world data on AdvHF patients are limited. Aim was to assess 20-year trends in clinical characteristics, outcomes, and use of left ventricular assist devices (LVAD) and heart transplantation (HTx) in patients with AdvHF and reduced ejection fraction (AdvHFrEF) in Sweden. Between 2003-2022, 5,323 patients (median age 76 [IQR 68-82], 23% females) included in the Swedish HF Registry met adapted ESC-HFA criteria for AdvHF (NYHA III-IV, EF<30%, ≥1 HF hospitalizations ≤6 months). Of these, 29% were eligible for AdvHF therapies (median age 63 [IQR 57-67] years, 18% females) according to the following additional criteria: ≤70 years old, no dialysis within ≤5 years, no active cancer within ≤3 years.Unadjusted temporal trends in 1-year outcomes (all-cause, CV and non-CV death, HTx and LVAD implantation) were presented as estimated annual percent change (eAPC). 1-year all-cause mortality declined significantly in the overall cohort (eAPC -3.8; 95%CI -5.3 to -2.2) as well as in patients eligible for AdvHF therapies (eAPC -3.2; 95%CI -6.3 to -0.1) over the study period. These improvements were largely driven by reductions in CV mortality (overall cohort: eAPC -4.3; 95%CI -6.0 to -2.6; eligible cohort: eAPC -5.6, 95%CI -9.4 to -1.7). Use of LVAD significantly increased over the study period, while HTx showed a modest but non-significant rise. In a large nationwide cohort, all-cause and CV-mortality among AdvHFrEF patients markedly declined over the past 20 years, potentially reflecting improvements in treatments. Despite progress, significant opportunities remain to improve access to and adoption of advanced therapies.

Recent clinical trials have underscored the importance of early initiation of heart failure (HF) guideline-directed medical therapy (GDMT), with growing emphasis on rapid sequencing, particularly after hospitalization for acute HF (AHF). Despite the proven short-term benefit of this approach, few patients receive this therapy at discharge. In patients with AHF, we evaluated whether treatment at discharge with dual sodium-glucose co-transporter-2 inhibitors (SGLT2i)-mineralocorticoid receptor antagonist (MRA) therapy or four-class GDMT was associated with short-term mortality and incremental risk reduction. We analysed two prospective registries of AHF: the China HF-CAP (n = 441 320; main cohort) and the Swedish HF Registry (SwedeHF) (n = 2367; external validation cohort). We assessed the association between discharge prescription of dual therapy SGLT2i and MRA versus neither, and four-class GDMT vs none, with 90-day cardiovascular (CV) and all-cause mortalities, further stratified by baseline serum potassium levels and left ventricular ejection fraction (LVEF) categories. In the main cohort, for dual SGLT2i and MRA therapy (n = 71 154) vs neither (n = 81 793) therapy, adjusted odds of 90-day CV and all-cause death were 0.320 [0.283-0.361] and 0.504 [0.472-0.539], respectively. In the external validation cohort, results were directionally consistent. Association between dual SGLT2i and MRA therapy and short-term survival was consistent irrespective of hyperkalaemia and across HF phenotypes. Further, in the main cohort, adjusted odds of 90-day CV death of four-class GDMT (n = 36 301) were 0.122 (0.106-0.14) vs no therapy (n = 18 374). After AHF, early initiation of dual SGLT2i and MRA therapy was associated with lower short-term mortality, irrespective of LVEF or potassium levels. Four-class GDMT conferred the lowest risk, emphasizing the importance of timely implementation after AHF.

Large-scale perturbation atlases have transformed systems biology, yet no equivalent resource exists for the human heart, where contractile function and transcriptomic state must be measured together. Here, we establish Cardiopedia-Ligand, a comprehensive perturbation-function-transcriptome atlas generated by stimulating human cardiac organoids (hCOs) with 87 ligands targeting 98 cell-membrane receptors expressed in the human heart. We developed an automated high-throughput pipeline enabling individualized contractility measurements and single-organoid mRNA sequencing. We use this pipeline to define both recognized and previously unrecognized functional and transcriptional clusters, including inotropes, endothelin peptides, extracellular matrix regulators, and multiple inflammatory clusters. Clustering analysis, machine learning, and the "fingerprinting" of human heart failure biopsies revealed previously underappreciated similarities between ligands and an interferon-γ signaling signature driving heart failure with preserved ejection fraction (HFpEF). Together, this comprehensive Cardiopedia-Ligand dataset provides a valuable and accessible resource for interrogating cardiac biology and human disease.

Myocardial ischemia-reperfusion (MIR) injury drives adverse remodeling and heart failure after ST-elevation myocardial infarction (STEMI), yet no therapy directly targets the fibrotic response. Here, we developed a good manufacturing practice-compatible extracellular vesicle (EV)-enriched secretome from bone marrow mesenchymal stromal cells and identified a laminin-521-based production strategy suitable for clinical translation. The EV-enriched secretome exhibited in vitro immunomodulatory activity, and in murine MIR-injury models, treatment preserved left ventricular ejection fraction, reduced platelet-derived growth factor receptor beta (PDGFRβ)-associated myofibroblast activation quantified by positron emission tomography (PET) imaging, attenuated fibrosis, and promoted reparative macrophage polarization. In a clinically relevant porcine ischemia-reperfusion model, intracoronary administration was cardioprotective. We further developed a clinically approved PDGFRβ-targeted PET-imaging platform for longitudinal assessment of fibrotic activity in STEMI patients, where preliminary observations suggest that myofibroblast activation persists for up to 2 months after STEMI in selected patients. Together, these findings establish a translational therapeutic-diagnostic framework for individualized management of MIR injury.

Coronary microvascular dysfunction (CMD) is a key contributor to myocardial ischemia and cardiovascular diseases. It is characterized by abnormalities of the coronary microvasculature, leading to impaired myocardial perfusion. Although CMD has a high prevalence in patients with nonobstructive coronary artery disease and is associated with adverse cardiovascular events, its pathogenesis has not yet been fully elucidated. Current diagnostic approaches combine noninvasive and invasive methods, but there remains a lack of effective targeted therapies. This review discusses the epidemiology, pathophysiology, diagnostic strategies, and treatment options for CMD, with a particular focus on the protective role of the neuregulin-1 (NRG-1)/v-erb-b2 erythroblastic leukemia viral oncogene homolog B (ErbB) signaling pathway. We initially outline how the NRG-1/ErbB pathway affects endothelial function, ventricular remodeling, oxidative stress, and myocardial angiogenesis, highlighting its potential as a therapeutic target. In addition, we explore emerging evidence that traditional Chinese medicine (TCM) interventions may regulate the NRG-1/ErbB axis to improve microvascular function and cardiac outcomes. Overall, this review deepens our understanding of the mechanisms underlying CMD and provides new avenues for integrated precision therapies, including TCM, with the aim of improving clinical management and prognosis in patients with CMD.

Data on the prognostic value of incidental coronary artery calcium (CAC) from nongated chest computed tomography scans are limited. Using paired computed tomography scans from the MESA (Multi-Ethnic Study of Atherosclerosis) exam 5, we evaluated the relationship between nongated CAC, gated CAC, and future cardiovascular events. Between April 2010 and December 2011, a total of 2601 participants underwent same-day gated and nongated chest computed tomography scans. After excluding 106 with previous coronary heart disease or cardiovascular disease and 23 for missing covariates, 2472 participants formed the study population. Gated and nongated scans were interpreted at a core laboratory, blinded to acquisition methodology. Cox regression examined associations between CAC (gated and nongated) and incident coronary heart disease/cardiovascular disease events. Correlation was assessed with Pearson coefficients, model performance with receiver operating characteristic curves and C-statistic, and overall accuracy with Brier scores. Among the 2472 participants, 53% were female, 38% white, 13% Chinese, 26% Black, and 23% Hispanic/Latino. Compared with participants with zero CAC, those with moderate (101-299) and severe (≥300) nongated CAC had higher coronary heart disease risk (hazard ratio, 2.67 [95% CI, 1.14-6.27]; hazard ratio, 5.22 [95% CI, 2.37-11.5]) and cardiovascular disease risk (hazard ratio, 1.32 [95% CI, 1.32-4.04]; hazard ratio, 2.89 [95% CI, 1.68-4.96]). Gated and nongated log-standardized CAC highly correlated (r=0.961; P<0.001). The area under the receiver operating characteristic curves, C-statistic, and Brier scores were statistically similar for gated and nongated CAC. Nongated CAC predicts cardiovascular events with performance comparable to gated CAC. Given the large number of nongated scans performed annually, incorporating their quantification into clinical practice offers a scalable approach to personalized preventive care. Our findings are particularly relevant in light of the recent 2026 American College of Cardiology/American Heart Association dyslipidemia guidelines, which endorse the use of incidental CAC from nongated computed tomography scans for atherosclerotic cardiovascular disease risk stratification and guiding lipid-lowering therapy.

Epicardial adipose tissue (EAT) is a metabolically active visceral fat depot implicated in cardiometabolic and cardiovascular (CV) disease. Although cardiac magnetic resonance (CMR) and cardiac computed tomography (cCT) enable accurate volumetric quantification of EAT, their cost, limited availability, and-particularly for cCT-radiation exposure, restrict their use in preventive and longitudinal settings. Transthoracic echocardiography (TTE) is widely accessible and radiation-free, but its validity as a surrogate of volumetric EAT assessment and its broader clinical role remain incompletely defined. To systematically synthesize disease-specific evidence linking TTE-derived EAT thickness with major CV phenotypes and to quantitatively assess its association with volumetric EAT measured by CMR or cCT. A systematic search of PubMed and PubMed Central (January 2000-December 2025) identified adult studies evaluating associations between TTE-derived EAT thickness and coronary artery disease (CAD), atrial fibrillation (AF), or heart failure with preserved ejection fraction (HFpEF), and correlations between TTE-derived EAT thickness and CMR- or cCT-derived EAT volume. Correlation coefficients were pooled using a random-effects model after Fisher's z-transformation. An exploratory meta-analysis assessed associations with major adverse cardiovascular events (MACE). Seventeen disease-specific studies consistently demonstrated associations between increased TTE-derived EAT thickness and CAD severity, AF burden and recurrence, and adverse HFpEF phenotypes. Five validation studies were included; four comparing TTE with CMR were pooled, yielding a moderate-to-strong correlation (r = 0.77, 95% CI 0.65-0.93; p < 0.01; I² = 92.9%). Several studies reported associations between TTE- EAT thickness and cCT-derived EAT parameters. However, only one cCT study met our predefined criteria for inclusion in the quantitative validation analysis, whereas the remaining cCT studies were retained in the qualitative synthesis because of substantial methodological heterogeneity in cCT acquisition, segmentation approaches, and outcome definitions. Exploratory prognostic analysis suggested a directional association between increased TTE-derived EAT thickness and MACE. TTE-derived EAT thickness correlates with volumetric EAT and is consistently associated with major CV phenotypes. Standardization and prospective outcome-driven validation are required before routine clinical implementation.

A simple diagnostic method able to reliably exclude left main (LM) coronary artery disease (CAD) or LMCAD-equivalent would expand implementation of an initial non-invasive strategy in patients with chronic coronary syndrome (CCS). This study assessed the diagnostic utility of an approach using clinical and ECG stress testing (EST) variables in excluding LMCAD/LMCAD-equivalent in CCS patients. In a multicentre case-control study, CCS patients undergoing invasive coronary angiography (CAG) after a maximal EST were evaluated. Cases were patients with angiographic ≥ 50% LM stenosis or ≥70% stenosis of both proximal left anterior descending and proximal circumflex arteries, matched with similar patients without them (controls) in a 1:3 ratio. A risk model developed through logistic regression was internally and externally validated. Three hundred and thirty-five cases were matched with 797 controls. The model area under the curve (AUC) was .78. Assuming LMCAD prevalence of 5% and a misclassification cost ratio of 1:100 (ratio of cost of performing CAG in a control to cost of not performing CAG in a case), negative predictive value was 98.2%. Thus, CAG could be safely avoided in 41% of patients, missing one LMCAD/LMCAD-equivalent diagnosis for every 58 CAGs safely spared in patients without them. Among CCS patients, LMCAD/LMCAD-equivalent can be excluded with high negative predictive value through a model based on clinical and EST parameters, allowing initial non-invasive management of most patients able to exercise. This approach is potentially useful particularly in communities where access to computed tomography coronary angiography is limited.

The benefits of β-blockers in patients with acute coronary syndromes (ACS) without chronic heart failure (HF) or left ventricular ejection fraction (LVEF) < 40% remain uncertain. We evaluated the association between β-blocker therapy and clinical outcomes in a multicenter, contemporary ACS registry. In the START-ANTIPLATELET registry (NCT02219984), patients were excluded if they had HF or LVEF <40%. Participants were stratified according to β-blocker use at discharge after ACS. A target trial emulation and inverse probability of treatment weighting (IPTW) were used. The primary endpoint was a composite of all-cause death or myocardial infarction (MI) at 1 year. The primary analysis included 1,315 patients with ACS without HF or LVEF <40%, of whom 949 (72.2%) were discharged on β-blockers. At 1 year, the primary endpoint occurred in 21 (2.2%) patients receiving β-blockers versus 13 (3.6%) without β-blockers, and no significant association was observed (unweighted HR 0.63, 95% CI 0.31-1.26; p = 0.192; IPTW-adjusted HR 0.66, 95% CI 0.33-1.33; p = 0.249). Exploratory subgroup analyses suggested a potentially more favourable association of β-blocker therapy in patients with ST-segment elevation MI (p-interaction=0.049), although this finding was not uniformly reproduced across sensitivity analyses. In a contemporary real-world cohort of ACS patients without HF or LVEF <40%, β-blocker therapy was prescribed in approximately 70% of patients and was not associated with a lower 1-year risk of death or MI.

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

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

To evaluate the applicability of the RoMa classification in patients with transthyretin cardiac amyloidosis (ATTR-CM) and to assess its association with functional capacity and key cardiopulmonary exercise testing (CPET) parameters. Consecutive adults (≥18 years) with confirmed ATTR-CM from two tertiary centres who completed symptom-limited maximal CPET were included. RoMa classes were defined using predefined cutoffs for percent-predicted peak heart rate (HRpp ≥80%) and percent-predicted peak O2-pulse (O2pp ≥100%): RoMa I (high HRpp/high O2pp), RoMa II (high HRpp/low O2pp), RoMa III (low HRpp/high O2pp), and RoMa IV (low HRpp/low O2pp). We evaluated 165 patients (90% male; 77% wild-type ATTR, 20% variant ATTR). RoMa distribution was: RoMa I, n=33; RoMa II, n=73; RoMa III, n=30; and RoMa IV, n=29. Age did not differ across classes (p=0.36). Functional capacity declined across the RoMa strata: median 6MWD decreased from 420 m (RoMa I) to 313 m (RoMa IV) (overall p=0.009; p-trend=0.005), and NYHA class worsened (overall p=0.003; p-trend=0.005). Peak VO2 (% predicted) differed between groups (RoMa I: 93.0; II: 70.8; III: 75.2; IV: 51.9; overall p<0.001; p-trend<0.001), and ventilatory inefficiency increased (VE/VCO2 slope: 34; 39; 37; 47, respectively; overall p<0.001; p-trend<0.001; peak PetCO2: 30; 27; 29; 25, respectively; overall p<0.001; p-trend=0.003). 6MWD correlated with peak VO2 (r=0.626; p<0.001; n=131) and inversely with VE/VCO2 slope (ρ=-0.484; p<0.001; n=130). In ATTR-CM, application of the RoMa classification was feasible and identified distinct CPET-derived exercise-response profiles associated with functional impairment. These findings support RoMa as a promising exploratory framework for functional phenotyping in ATTR-CM.

Heart failure is a leading cause of mortality, and impaired cardiac excitation-contraction coupling represents a potentially fatal trigger for myocardial dysfunction. Long non-coding RNAs (lncRNAs) can contribute to cardiomyopathy, but comprehensive mechanistic insights remain elusive. We demonstrate that reduction of the lncRNA TRDN-AS in human cardiomyopathy or abrogating it in human iPSC-derived cardiomyocytes and mice causes a switch of cardiac TRDN/TRISK32 to skeletal muscle TRDN/TRISK95. Transcription of Trdn-as in cis is essential for stalling RNA Pol II at the 3' end of the cardiac Trdn transcript, promoting the formation of the cardiac TRDN/TRISK32 isoform. The m6A-methyltransferase METTL3 is crucial for RNA Pol II stalling, enforcing transcriptional termination and proximal polyadenylation of the Trdn transcript. Here, we establish that the switch of TRDN isoforms results in a significantly altered interactome of the cardiac calcium release complex, aberrant calcium handling, altered dyad structure, QT prolongation, and dilated cardiomyopathy in mice and humans.

Dilated cardiomyopathy (DCM) is the leading cause of heart transplantation, with a 50% risk of progression to heart failure within 5 years. Conventional disease modeling approaches fail to recapitulate the sophisticated function of the human heart. Alternatively, heart-on-a-chip (HOC) platforms enable real-time monitoring of disease progression and drug responses using miniaturized engineered heart tissues. Here, we developed a functional HOC model using patient-specific human induced pluripotent stem cells (hiPSCs), reprogrammed from the patients' blood samples. The chip contains two cell-seeding chambers with flexible silicone pillars to support tissue formation. Healthy and DCM hiPSCs were differentiated into cardiomyocytes, combined with an optimized ratio of human cardiac fibroblasts, encapsulated in a fibrin/Geltrex hydrogel (containing fluorescent beads), and seeded in the device chambers. The tissue gradually compacted and started beating spontaneously. Immunofluorescence assay revealed structural abnormalities in DCM tissues, including reduced cell alignment and elongation. The tissue functional responses (e.g., calcium transients and beating) were investigated after 2 weeks of culture, revealing arrhythmia-like behavior in DCM tissue and highlighting functional hallmarks of the disease. Finally, the platform was validated using norepinephrine to assess the functional responsiveness of the tissues. These results demonstrate the potential of this system for disease modeling and future patient-specific investigations.

Doxorubicin is a widely used chemotherapeutic agent, but its clinical application is hindered by severe cardiotoxicity. Among immune cells, Cx3cr1+ macrophages have emerged as key regulators of cardiovascular disease, with their development and maturation tightly controlled by CSF1R (colony stimulating factor 1 receptor). Using multi-omics sequencing, we observed a marked expansion of Cx3cr1+ macrophages in doxorubicin-induced cardiomyopathy, yet their precise functional role in this pathological process has remained elusive. This study employed various genetically modified mouse models, including cell depletion models, lineage tracing models, and conditional gene knockout models targeting Cx3cr1+ macrophages, alongside transcriptomic sequencing, proteomic profiling, and multi-level in vivo and in vitro experiments to elucidate the role and mechanisms of Cx3cr1+ macrophages and their receptor CSF1R in doxorubicin-induced cardiac injury. We found that Cx3cr1+ macrophages are significantly enriched in hearts affected by doxorubicin-induced cardiomyopathy, and their depletion notably improves cardiac function. Further investigation revealed that in these macrophages, CSF1R competitively binds to the E3 ubiquitin ligase NEDD4, thereby inhibiting the ubiquitination and degradation of PARP1. This process promotes inflammasome activation and pyroptosis, driving massive IL1B secretion. IL1B directly suppresses cardiomyocyte mitophagy, disrupts energy metabolic homeostasis, and ultimately leads to cardiac dysfunction. Notably, the use of the CSF1R inhibitor PLX3397 or an IL1B-neutralizing antibody effectively halted these pathological processes and significantly improved cardiac function. In summary, this study unveils a novel mechanism through which Cx3cr1+ macrophages regulate cardiomyocyte function via the CSF1R-PARP1-IL1B-mitophagy signaling axis, providing a new theoretical foundation and intervention strategy for doxorubicin-induced cardiomyopathy targeted therapy.Abbreviations: BMDM: bone marrow-derived macrophages; CKMB: creatine kinase MB isoenzyme; CSF1R: colony stimulating factor 1 receptor; csf1r-cKO: csf1r conditional knockout; DIC: doxorubicin-induced cardiomyopathy; DOX: doxorubicin; HE: hematoxylin and eosin; HW:TL: heart weight:tibial length; LDH: lactate dehydrogenase; MAP1LC3/LC3: microtuble-associated protein 1 light chain 3; NPPA: natriuretic peptide type A; PI: propidium iodide; PYCARD/ASC: PYD and CARD domain containing; TNNT2/cTnT: troponin T2, cardiac; WGA: wheat germ agglutinin.

Diabetic cardiomyopathy (DCM) is associated with impaired calcium handling and downregulation of sarcoplasmic/endoplasmic reticulum Ca²⁺-ATPase 2a (SERCA2a), though the underlying regulatory mechanisms remain poorly understood. Here, we identify KCNE2, an auxiliary β-regulatory subunit of multiple ion channels, as a key regulator of SERCA2a protein stability in the diabetic heart. KCNE2 expression was significantly reduced in high fat diet/streptozotocin-induced diabetic mice and palmitic acid-treated cardiomyocytes. Using LC-MS/MS and co-immunoprecipitation, SERCA2a was identified as a direct binding partner of KCNE2. Knockdown of KCNE2 decreased SERCA2a protein levels without affecting its transcription. Cardiac-specific overexpression of KCNE2 via adenovirus-associated virus 9 delivery restored SERCA2a expression, improved sarcoplasmic reticulum Ca²⁺ cycling, and ameliorated systolic and diastolic dysfunction in diabetic mice. Mechanistically, KCNE2 competitively inhibited the interaction between SERCA2a and the E3 ubiquitin ligase Smurf1, thereby suppressing Smurf1-mediated polyubiquitination and proteasomal degradation of SERCA2a. These results reveal a novel protective role of KCNE2 in diabetic hearts and propose KCNE2 upregulation as a potential therapeutic strategy for DCM. Upregulation of KCNE2 ameliorates cardiac dysfunction by reducing Smurf1-mediated SERCA2a polyubiquitination and degradation, and re-establishes SR Ca²⁺ homeostasis in DCM.

Copeptin, a surrogate marker for vasopressin secretion, is associated with cardiovascular disease, insulin resistance and dysglycaemia. The cardioprotective effects of sodium-glucose cotransporter 2 inhibitors (SGLT2i) may involve vasopressin modulation through fluid redistribution, but whether this effect persists long-term in high-cardiovascular-risk patients with newly detected dysglycaemia remains unknown. In this post-hoc analysis of the SOCOGAMI double-blind, placebo-controlled trial, 42 patients (mean age 67.5 years, 19% females) with impaired glucose tolerance or newly detected type 2 diabetes following an ACS and no heart failure were randomized to empagliflozin 25 mg/day (n = 20) or placebo (n = 22) for 7 months. Copeptin was measured during oral glucose tolerance tests (OGTT) at baseline, after 7 months on-treatment, and 3 months after treatment withdrawal. Treatment effects were assessed by repeated-measures ANOVA with treatment × time interaction and linear mixed-effects models. Haematocrit, but not copeptin, showed a significant between-group difference at 7 months (p = 0.03 and p = 0.63, respectively). Both markers returned toward baseline after treatment withdrawal, but the overall treatment × time interaction was not significant for either (p = 0.72 and p = 0.64 respectively). Results were unchanged after accounting for a baseline imbalance in diuretic use (35% vs. 14%). Copeptin was not associated with the glucose-lowering effect of empagliflozin and no differential copeptin response during the OGTT across groups or visits was observed. In exploratory analyses, copeptin correlated with arterial pulse wave velocity at baseline (rs = 0.40, unadjusted p = 0.03). In this post-hoc analysis, empagliflozin treatment was not associated with statistically significant sustained vasopressin secretion in post-ACS patients with newly detected dysglycaemia and preserved cardiac function. Due to the limited power and the absence of early on-treatment sampling these findings cannot exclude AVP modulation and warrant confirmation in adequately powered studies. EudraCT number 2015-004571-73.

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

After myocardial infarction (MI), macrophage-mediated clearance of dead cells, a process known as efferocytosis, represents a pivotal role in tissue remodeling. Efficient efferocytosis contributes to rescuing neighboring viable cardiomyocytes, drives the phenotypic transition of reparative macrophages, and facilitates the resolution of inflammation. In this study, we explored the roles of CD40 and the signals transduced by its 2 downstream adaptor-protein binding sites (TRAF2/3/5 and TRAF6) in the cardiac macrophage efferocytosis after MI. Systemic, myeloid- and macrophage-specific CD40-deficient mice were used to determine the functional significance of CD40 during post-MI repair. The effects of CD40 on macrophages functional states were evaluated with single-cell RNA sequencing (scRNA-seq). Flow cytometry, immunofluorescence staining, Western blot, and ELISA were used to assess the efferocytosis and inflammatory status of macrophages after MI. CD40-TRAF2/3/5-/- and CD40-TRAF6-/- mice were used to explore the roles of CD40 downstream signaling intermediates in MI and macrophage efferocytosis. The expression level of CD40 was increased remarkably from 3 to 7 days after MI. Myeloid-derived macrophages emerged as the dominant population expressing CD40. CD40 deficiency resulted in an augmented infarct size and compromised cardiac function after MI. Further investigations demonstrated that CD40 deficiency led to a notable decline in macrophage efferocytosis, which is associated with a reduced abundance of cluster 0 cells, identified by scRNA-seq, representing the precursor of reparative macrophages. Moreover, scRNA-seq indicated that CD40+ macrophages could be classified primarily into 2 distinct cell subsets: 1 subset was associated mainly with efferocytosis functions, and the other was involved predominantly in immune-inflammatory responses. Direct activation of CD40 failed to upregulate macrophage efferocytosis but instead induced a proinflammatory state. These implied differential effects of the signals transduced by the 2 TRAF binding sites (TRAF2/3/5 and TRAF6) downstream of CD40 on efferocytosis. Findings from CD40-TRAF2/3/5-/- and CD40-TRAF6-/- mice confirmed that the CD40-TRAF2/3/5 signaling served as a crucial determinant in mediating CD40-related efferocytosis. STAT6 was identified as a key downstream factor in this process. Adenovirus-mediated gene transfer to overexpress a CD40 variant retaining TRAF2/3/5 binding site but lacking the TRAF6 in cardiac macrophages led to improvements in cardiac function and macrophage efferocytosis after MI. Our study established a pivotal positive role of macrophage CD40 in post-MI repair by facilitating macrophage efferocytosis. Specifically, TRAF2/3/5 rather than TRAF6 serves as the crucial signaling pathway that mediates CD40-associated efferocytosis.

Myocardial ischemia-reperfusion (I/R) injury presents a significant clinical challenge characterized by a complex pathological mechanism. The role of protein ubiquitination in I/R injury has not been systematically investigated. Global ubiquitinome profiling was conducted to identify the potential key players in myocardial I/R injury. The ubiquitination levels of proteins in mouse hearts subjected to either sham surgery or I/R injury were analyzed using ubiquitinome. A combined analysis of ubiquitinome, single-cell RNA sequencing (RNA-seq), and proteomics data was employed to predict potential E3 ubiquitin ligases associated with myocardial I/R injury. Global heterozygous 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase degradation 1 (Hrd1) knockout, endothelial cell (EC)-specific Hrd1 deficiency (Hrd1f/f; Cdh5Cre), and EC-specific Hrd1 overexpression (AAV-EC-Hrd1) mice were used to assess the role of Hrd1 in myocardial I/R injury. Mass spectrometry and immunoprecipitation were used to elucidate the interaction between Hrd1 and aldehyde dehydrogenase 2 (ALDH2). Additionally, we assessed ubiquitination and vasomotor reactivity to clarify the mechanisms by which Hrd1 regulates ALDH2 activity and EC dysfunction during I/R injury. Ubiquitinome analysis revealed that protein ubiquitination exacerbates endothelial dysfunction after myocardial I/R injury. Integrative analysis of the ubiquitinome, proteomics, and single-cell RNA-seq revealed a significant upregulation of the E3 ubiquitin-protein ligase Hrd1 in CD45+ ECs. In both humans and mice, the level of endothelial Hrd1 protein was found to increase in response to I/R in vivo. Genetic ablation of Hrd1 significantly alleviated myocardial infarction, endothelial dysfunction, and infiltration of inflammatory cells after I/R injury. Mechanistically, Hrd1 promoted the K33-linked polyubiquitination of ALDH2 and then inhibited the formation of its active tetramers, which reduced the apoptosis of CD45+ ECs and exacerbated endothelial dysfunction through the NO/cGMP/PKG (nitric oxide-cyclic guanosine monophosphate-protein kinase G) signaling pathway. Furthermore, our findings demonstrated that pharmacological inhibition of Hrd1 robustly ameliorated myocardial I/R injury and endothelial dysfunction. Our findings demonstrated a previously unidentified crucial role of cardiac EC Hrd1 in myocardial I/R injury. Hrd1 may serve as a therapeutic target for preventing myocardial I/R injury.

Patients with chronic kidney disease (CKD) display a reduced survival following myocardial infarction (MI). As the underlying mechanisms remain unclear, we examined the impact of CKD on cardiac remodeling and function post-MI using a mouse model of adenine-induced CKD. After MI, CKD mice showed a stronger cardiac dysfunction compared to non-CKD controls. While immunohistochemical and immunofluorescence analyses did not reveal changes in cardiomyocyte apoptosis, infarction size, or myofibroblast content, CKD mice exhibited an increased number of circulating myeloid cells post-infarction and more neutrophil infiltration in the heart. Combining RNAseq, untargeted kinome profiling, western blotting, and mass spectrometry revealed that post-MI, CKD enhanced cardiac oxidative stress and the acute stress complex S100A8/A9 in circulation and the heart, and enforced cardiac MAP-kinase p38 activation and NR4A1 phosphorylation as pathways underlying cardiomyocyte dysfunction. S100A8/A9 also exerted an acute detrimental impact on calcium flux and sarcomere shortening in cardiomyocytes ex vivo. Increased myeloid cell-derived S100A8/A9 expression was confirmed in the infarcted human heart by single-nucleus RNAseq, and CKD patients had higher post-infarction S100A8/A9 levels compared to patients without kidney dysfunction. Furthermore, integrating metabolomics, RNAseq, and mitochondrial analysis uncovered a disturbed cardiac metabolism with impaired glycolysis, a reduced glycerol-3-phosphate-shuttle, and a reduced Coenzyme A-bioavailability in CKD vs. non-CKD mice post-MI. These alterations were associated with poorer cardiac performance post-MI, without intrinsic defects in mitochondrial function observed. Our study reveals innate immune activation, inflammation, oxidative stress, and metabolic alterations indicative of reduced glycolytic entry and CoA bioavailability along with aggravated cardiac dysfunction post-MI in CKD compared to non-CKD conditions, independent of infarct size, and with poorer cardiac performance in CKD associated with the cardiac metabolic alterations. Combined, this could contribute to the worsened outcome of CKD patients post-MI and reveals cardiac metabolism in CKD as an interesting translational research target.

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

Beyond their cardioprotective effects, polyunsaturated fatty acids (PUFAs) have also been linked to arrhythmogenicity, raising concern among individuals predisposed to atrial fibrillation (AF), including patients with heart failure with preserved ejection fraction (HFpEF). Here, we examined associations of circulating PUFA profiles and PUFA supplementation with AF prevalence and incidence. We analysed 483,372 individuals from the UK Biobank (8,503 prevalent AF; 32,671 incident AF) with nuclear magnetic resonance (NMR) metabolomics, combining systematic deconfounding, an explainable supervised classifier and generalised structural equation modelling (GSEM).Anthropometric, demographic and genetic risk factors were stronger correlates of AF prevalence and incidence than lipidomic profiles. NMR analysis indicated lower plasma PUFA concentrations in AF, atrial cardiomyopathy (AtCM) and in HFpEF, most pronounced with cholesterol-lowering medication (CLM) use and partially attenuated in participants reporting PUFA supplementation. Higher ω-6 concentrations were associated with lower AF prevalence and incidence; for AF incidence, β=-0.083 (95% CI -0.097 to -0.069; p<0.001), higher ω-3 with lower AF incidence (β=-0.093, 95% CI -0.122 to -0.065; p<0.001), and higher DHA with higher incidence (β=0.058, 95% CI 0.031 to 0.085; p<0.001), an association not evident in women. Supplementation was associated with higher circulating PUFAs and lower AF prevalence (β=-0.096, 95% CI -0.145 to -0.047; p<0.001), strongest among CLM users and women. Subgroup findings in HFpEF were directionally similar. Circulating PUFAs were lower in AF, AtCM and HFpEF. Lipid profiles indicated favourable associations for circulating ω-3 and ω-6, with a modest adverse signal for DHA. After adjustment for established risk factors, PUFA supplementation was associated with lower AF prevalence, including in patients with CLM and those with HFpEF. Formulations that substantially increase plasma DHA levels warrant careful evaluation given the observed association with AF incidence.

Screening for atrial fibrillation (AF) on the basis of AF risk may be more effective. We aimed to develop, externally validate, and prospectively test a machine learning prediction model using electronic health records (EHRs) to guide AF screening. We developed and validated a random forest prediction model for new AF within 6 months, using age, sex, and 10 comorbidities (Future Innovations in Novel Detection of Atrial Fibrillation [FIND-AF] 2.0) in EHRs in the United Kingdom (n=2 081 139), Japan (n=7 795 244), Israel (n=2 166 795), Canada (n=627 919), and China (n=149 145). We conducted a prospective study where participants ≥30 years old without AF and with a CHA2DS2-VASc score ≥2 in men and ≥3 in women, stratified by FIND-AF 2.0 into high and low risk, undertook 4 ECG recordings per day for 3 weeks using a handheld ECG recorder, with a primary outcome of newly diagnosed AF. We estimated stroke risk associated with nonanticoagulated AF in patients with high FIND-AF 2.0 risk in the FinACAF (Finnish Anticoagulation in Atrial Fibrillation) registry of patients with AF (n=229 565). FIND-AF 2.0 was applicable to all EHRs and showed good to excellent prediction performance (United Kingdom: area under the receiver operating characteristic curve [AUROC], 0.819 [95% CI, 0.809-0.829]; Israel: AUROC, 0.835 [95% CI, 0.828-0.842]; Japan: AUROC, 0.751 [95% CI, 0.745-0.757]; Canada: AUROC, 0.747 [95% CI, 0.741-0.753]; China: AUROC, 0.753 [95% CI, 0.725-0.771]), with AUROC>0.7 in men and women in all cohorts, and improved performance compared with CHA2DS2-VASc and C2HEST. Of 1923 participants from 15 sites in the prospective study (mean age, 70.2 [SD 9.4] years), with a mean of 74.8 (SD, 19.4) ECG recordings, AF was diagnosed in 5 of 902 (0.6%) with low FIND-AF 2.0 risk and 46 of 1021 (4.5%) with high FIND-AF 2.0 risk (odds ratio, 8.46 [95% CI, 3.35-21.40], P<0.001). Median AF burden among high FIND-AF 2.0 risk-detected cases was 33.4% (interquartile range, 5.1%-91.6%), and 96.1% initiated oral anticoagulants. In the FinACAF registry, the rate of ischemic stroke for patients with high FIND-AF 2.0 risk, AF, and no anticoagulants was 6.0 events per 100 patient-years. The EHR-based machine learning model, FIND-AF 2.0, identifies a high-risk subpopulation for AF diagnosis among patients at elevated risk of stroke and could enable scalable, EHR-driven, risk-guided AF screening.

P-wave prolongation and left atrial (LA) enlargement are markers of atrial cardiomyopathy and increase the risk for atrial fibrillation, stroke, and mortality. We investigated whether the cumulative burden of cardiovascular risk factors in early life is associated with P-wave duration and LA size in middle age. The Cardiovascular Risk in Young Finns Study is a prospective, ongoing, multicentre cohort initiated in 1980. Traditional cardiovascular risk factors were assessed repeatedly between 1980 and 2001 (ages 6-24 years), and transthoracic echocardiography and electrocardiography were performed in 2011. Associations between cumulative early life risk factors and P-wave duration, LA diameter, and LA volume were analysed using logistic regression. Body mass index (BMI) was the main modifiable determinant of P-wave prolongation and LA enlargement. Each standard deviation (SD) increase in early life BMI burden was associated with longer P-wave duration (0.120 SD; 1.85 ms), larger LA diameter (0.264 SD; 0.11 cm), and greater LA volume (0.235 SD; 3.31 mL). Male sex associated with all studied P-wave and LA parameters and older age associated with larger LA diameter. Higher physical activity in middle age was associated with 0.116 SD increased LA volume (1.64 mL). Participants with persistent or adult-onset high BMI were more likely to have larger LA. Excess BMI from childhood through adulthood is a key determinant of atrial remodelling in middle age. These findings highlight the long-term impact of early life adiposity and underscore the importance of lifelong weight management in preventing atrial cardiomyopathy and its clinical sequelae.

The efficacy of prophylactic mechanical circulatory support with micro-axial flow pump or veno-arterial extracorporeal membrane oxygenation (VA-ECMO) in patients with severely reduced left ventricular ejection fraction (LVEF) undergoing high-risk percutaneous coronary intervention (PCI) remains unclear. Patients with complex three-vessel disease, unprotected left main coronary disease or last patent conduit and LVEF ≤ 35% were assigned to receive either a micro-axial flow pump (SynFlow 3.0) or VA-ECMO support during a non-emergent high-risk PCI procedure in this prospective, multicentre, randomized, open-label, non-inferiority trial. The primary endpoint was the incidence of 30-day major adverse events, defined as any of: all-cause death, myocardial infarction, stroke/transient ischaemic attack, repeat revascularization, major bleeding, acute kidney injury, cardiopulmonary resuscitation/cardioversion, cardiac surgery/limb ischaemia, or serious device-related complications. Safety endpoints included adverse events and serious adverse events. The primary endpoint, 30-day major adverse events, occurred in 8 of 109 patients (7.34%) in the SynFlow 3.0 group and 13 of 113 patients (11.5%) in the VA-ECMO group (absolute difference adjusted for centre effect, -4.6%; 95% confidence interval, -12.6% to 3.5%; P for non-inferiority < .001). Patients with SynFlow 3.0 had shorter post-procedural hospital stay (4.1 days vs 5.2 days on average, P = .047) and fewer device-related adverse events (3.7% vs 11.5%; P = .041). Anaemia occurred more often with VA-ECMO than with SynFlow 3.0 (20.4% vs 9.2%; P = .023). The prophylactic use of a micro-axial flow pump during high-risk PCI procedures was non-inferior to VA-ECMO in the incidence of 30-day major adverse events. The use of a micro-axial flow pump was associated with shorter post-procedural hospital stay and fewer device-related adverse events.

In patients at high bleeding risk (HBR) undergoing percutaneous coronary intervention (PCI), abbreviated dual antiplatelet therapy (DAPT) has been shown to reduce bleeding without increasing ischemic risk. However, the optimal duration in specific subgroups, particularly anemic patients, remains unclear and was the focus of this analysis. This study included 3,364 HBR patients from three prospective trials in the XIENCE Short DAPT Program who underwent PCI with cobalt-chromium everolimus-eluting stents. Anemia was defined as Hb <11 g/dL. The primary endpoint was all-cause death or myocardial infarction; secondary endpoints included BARC 2-5 and 3-5 bleeding. Outcomes by DAPT duration (1 vs 3 months), defined according to study protocol, were assessed using propensity score stratification. Anemia was present in 514 patients (15.3%). At 1 year, anemic patients experienced higher rates of both ischemic and bleeding events compared with non-anemic patients. Among anemic patients, ischemic outcomes were similar with 1- and 3-month DAPT (15.7% vs 16.3%; adjusted hazard ratio [adjHR] 0.94, 95% confidence interval [CI] 0.59-1.52; p=0.807), whereas 1-month DAPT was associated with a lower incidence of major bleeding (6.1% vs 11.1%; adjHR 0.49, 95% CI 0.24-1.00; p=0.050). In non-anemic patients, ischemic and bleeding outcomes were similar irrespective of DAPT duration. Among HBR patients undergoing PCI, abbreviated DAPT was associated with comparable ischemic outcomes regardless of anemia status. In patients with baseline anemia, 1-month DAPT was associated with lower major bleeding without an apparent ischemic trade-off.

Hypertension induces structural and functional damage in multiple organs. Evidence of subclinical damage increases risk of vascular events and death but can be difficult to identify in the clinic. We developed a novel machine learning approach that quantifies current hypertension-associated multiorgan damage, mapping progression from health to advanced disease, in a pseudotemporal manner and predicts organ-specific disease progression trajectories. We analyzed 566 multimodal imaging and nonimaging variables from 27 099 participants in the UK Biobank imaging substudy to develop a semisupervised contrastive trajectory inference (cTI) framework that models multiorgan alterations associated with hypertension exposure, including heart, brain, kidneys, vasculature, lungs, liver, and metabolic information. Model stability was validated through multiple internal validation steps, and external validity was tested on 5507 participants from the Atherosclerosis Risk in Communities study (ARIC). Clinical relevance was evaluated against existing risk scores and through ability to predict survival and incident multiorgan disease for up to 7 years, across both UK Biobank and ARIC. In the UK Biobank (mean age 63.27±7.48 years; 53.4% women) our global organ damage score (HyperScore) achieved an area under the curve of 0.964 (0.941-0.987) for identification of individuals with severe end-organ disease and robust stability in cross-validation with a mean root mean square error of 0.104±0.084. Survival odds differed significantly across HyperScore stages (P<0.001), whereas stratification by blood pressure was nonsignificant. We further revealed 6 hypertensive disease phenotypes (HyperTrajectory), characterized by predominant cardiac, lipoprotein, atherothrombosis, brain, cardiorenal, and liver features, respectively. External testing in ARIC confirmed stability of the model, with Jensen-Shannon distances as low as 0.10 for HyperScore distributions, without significant deviation in organ damage progression patterns (P>0.05) and consistent end-organ and outcome characteristics between ARIC and UK Biobank across HyperTrajectories. Machine learning-derived global organ damage scores are feasible in hypertension and enable identification of distinct hypertension-associated organ-disease phenotypes. New frameworks for hypertension assessment and monitoring using imaging to derive personalized risk assessment and phenotype-specific intervention may be achievable.

Hypertension is a major cardiovascular risk factor arising from endothelial dysfunction driven by dysregulated endothelial nitric oxide synthase (eNOS) activity. Although eNOS turnover is regulated by post-translational modifications, the precise mechanisms remain unclear. Endophilin A2 (EndoA2) is uniquely enriched in the cardiovascular system and may influence eNOS activity and endothelial function. The primary objective of this study was to investigate the function of EndoA2 in blood pressure homeostasis with particular emphasis on elucidating its mechanism in regulating eNOS protein stability. Global and endothelial cell-specific EndoA2 knockout mice were generated to determine the effects of EndoA2 on hypertension, employing radiotelemetry, alongside histological, cellular, molecular, and biochemical approaches. Reduced EndoA2 expression was consistently observed in the aortic tissues of three hypertensive animal models. Global or endothelial cell-specific ablation of EndoA2 in mice induced spontaneous hypertension, vascular remodelling, and impaired endothelium-dependent vasodilation. Conversely, endothelial cell-specific EndoA2 overexpression ameliorated vascular remodelling and hypertension by maintaining endothelial homeostasis. Mechanistically, EndoA2 interacted with eNOS through its proline-rich domain (PRD), competing with the E3 ubiquitin ligase Itch for eNOS binding. This competition suppressed the Itch-mediated K48-linked ubiquitination of eNOS at lysine 834, thereby stabilizing eNOS. Notably, the PRD-mimetic peptide recapitulated the beneficial effects of EndoA2 by attenuating eNOS degradation and hypertension in mice. EndoA2 is a critical regulator of eNOS stability by antagonizing Itch-dependent ubiquitination. The PRD-mimetic peptide preserves eNOS homeostasis and alleviates hypertension, suggesting the therapeutic potential of targeting the EndoA2-Itch-eNOS axis in endothelial dysfunction-related cardiovascular diseases including hypertension.

Biomarkers have been identified to predict, diagnose and prognosticate acute kidney injury (AKI) but existing studies are heterogenous and contradictory. To compare diagnostic performance of AKI biomarkers, evaluate the quality of AKI biomarker studies and to develop standards for reporting studies of diagnostic test accuracy (DTA) of AKI biomarkers. A systematic literature review was conducted to identify studies focusing on the diagnostic performance of AKI biomarkers published before February 2025. Retrieved DTA studies were assessed for methodological quality and completeness using the QUADAS-2 and Standards for Reporting Diagnostic Accuracy (STARD) 2015 checklists. An international 17 member expert panel was convened to agree consensus standards for AKI biomarker studies (STARDaki) via a modified Delphi process. 122 DTA studies for AKI biomarkers were identified, but 15 were insufficiently reported. Of the remaining 107 studies, only 19 reported on diagnosis of AKI within 48 h of sampling. Of these studies, only 16 were considered high-quality based on the QUADAS-2 criteria. The compliance level with the STARD checklist was too low to permit meta-analysis. The expert panel agreed criteria for patient selection, reference standards, and reporting of test-retest reliability to supplement the STARD guidance for AKI biomarker studies. Most studies examining AKI biomarker performance fail to conform to the STARD standards for reporting, leading to poor diagnostic accuracy estimates and reduced clinical applicability and generalizability. An expert panel proposed STARDaki criteria to advance the development and clinical use of AKI biomarkers ( www.stardaki.icu ).

Chronic kidney disease (CKD) is more prevalent in women than men, but men progress faster to kidney failure (KF). Equations may estimate glomerular filtration rate (eGFR) differently by sex. This study assessed sex-specific reclassification using the creatinine- and cystatin C-based European Kidney Function Consortium (EKFC) versus the Chronic Kidney Disease Epidemiology Collaboration (CKD-EPI) eGFR equations and evaluated KF prediction. We compared classification in Kidney Disease: Improving Global Outcomes (KDIGO) GFR stages at baseline by sex based on GFR estimated with EKFC vs CKD-EPI equations in the German CKD study (GCKD); (5085 persons). Findings were validated in the National Unified Renal Translational Research Enterprise (NURTuRE)-CKD cohort (2589 persons) and the population-based RENIS-3 (Renal Iohexol Clearance Survey) study (1383 persons), the latter with gold-standard measured GFR (mGFR). Among GCKD participants, men (60%) had a higher urine albumin-to-creatinine ratio (UACR), whereas women had higher eGFR. Over 8.5 years, 181 women (3.6%) and 459 men (9.0%) developed KF. Using EKFC formulas based on cystatin C only or combined with creatinine, women were consistently and more frequently reclassified into milder eGFR stages and 4-5.7-fold more frequently classified as not having CKD than men. Sex-specific reclassification patterns were replicated in NURTuRE-CKD (2589 persons). In RENIS-3, comparison with mGFR showed sex-specific misclassification for both equations, with better alignment in the lower eGFR ranges for EKFC. Predictive performance for progression to KF was similar between the EKFC and CKD-EPI equations and became equivalent after adjusting for age, sex, and UACR. Women were more frequently reclassified into a less severe stage of CKD using the EKFC eGFR than the CKD-EPI equation, yet the prognostic performance for KF did not differ significantly between the two equations for both women and men. This suggests that the reclassification has limited clinical influence on KF risk prediction.

Cardiac dyssynchrony disrupts coordinated chamber activation and is associated with impaired cardiac function and adverse clinical outcomes. While ventricular dyssynchrony has been targeted through biventricular and conduction system pacing, atrial dyssynchrony remains underrecognized and largely untreated. Interatrial dyssynchrony commonly arises from delayed or impaired conduction through Bachmann bundle or from nonphysiological atrial pacing. It is associated with impaired ventricular filling and increased atrial arrhythmia risk. Importantly, conventional atrial pacing strategies may exacerbate rather than correct abnormal atrial activation. Bachmann bundle pacing represents a potential strategy to restore physiological atrial activation by engaging the dominant interatrial conduction pathway. Emerging data suggest that this approach may improve atrial synchrony, optimize atrioventricular timing, and reduce arrhythmia burden. In this review, we summarize the mechanisms and clinical consequences of interatrial dyssynchrony and evaluate the role of Bachmann bundle pacing as a novel target for atrial resynchronization and a potential next step in physiological pacing. Further studies are required to define optimal implantation strategies and determine Bachmann bundle pacing's clinical impact.

In patients with asymptomatic severe aortic stenosis (AS), exercise stress testing is recommended to unmask symptoms and guide the timing of intervention, yet it is infrequently used in clinical practice. This registry-based follow-up of the Evaluation of TAVR Compared to Surveillance for Patients With Asymptomatic Severe Aortic Stenosis (EARLY TAVR) trial evaluates how treadmill stress testing (TST), used during screening for EARLY TAVR to confirm asymptomatic status, informed subsequent aortic valve replacement and clinical outcomes. To evaluate clinical outcomes in patients with asymptomatic severe AS and a positive TST result and to identify predictors of a positive TST result. This prespecified TST registry of the EARLY TAVR trial involved 75 clinical sites across the US. Between July 2017 and December 2021, apparently asymptomatic patients with severe AS underwent standardized TST. Those with normal TST results were randomized to transcatheter aortic valve replacement or clinical surveillance, whereas those with positive TST results were invited to enroll in a prospective registry and were followed up with through 2 years. Of 1250 patients screened, 962 met trial criteria. Of these, 816 (84.8%) had a normal TST result and 146 (15.2%) had a positive TST result. Of these, 105 consented to enroll in the EARLY TAVR Treadmill Registry. Data were analyzed from August 2025 to January 2026. Positive TST result. TST-related safety, 2-year all-cause mortality, and rates of subsequent aortic valve replacement (AVR). Baseline predictors of a positive TST result were identified using multivariable logistic regression models. Of the 105 patients included in the present analysis, the mean (SD) age was 76.1 (6.5) years, and 80 participants (76.2%) were male. TST was found to be safe, with no reported deaths, syncope, or cardioversions. Multivariable baseline predictors of a positive TST included higher peak velocity, lower ejection fraction, prior coronary artery bypass, and prior stroke. The 2-year Kaplan-Meier rate for all-cause mortality was 5.7%. Among patients with positive TST results, the rates of AVR at 1 and 2 years were 79.9% and 85.9%, respectively. Rates of mortality and AVR were similar for patients who had a class I indication for AVR (symptoms during testing) and those with a class IIa indication (drop in systolic blood pressure). In patients with asymptomatic severe AS, TST was found to be safe and identified symptoms and AVR indication in approximately 15% of patients. However, 20% of those patients remained untreated at 1 year, despite having an indication for prompt treatment. ClinicalTrials.gov Identifier: NCT03042104.

Genetic testing is routinely recommended in dilated cardiomyopathy (DCM), yet the prevalence and implications of pathogenic/likely pathogenic (P/LP) variants in patients with DCM and left bundle branch block (LBBB) remain unclear. We therefore investigated the electromechanical profile of genotyped patients with DCM and LBBB, and its relationship with cardiac resynchronization therapy (CRT) response and clinical outcomes. Patients with LBBB were selected from a multicenter cohort of 1206 consecutive DCM patients undergoing genetic testing. All underwent sequencing of 20 clinically validated DCM-related genes (ClinGen) and comprehensive electro- and echocardiographic phenotyping, including speckle-tracking strain analysis, categorizing septal strain curves into five stages (LBBB-0 to LBBB-4). CRT response was assessed as end-systolic volume (ESV) reduction and left ventricular ejection fraction (LVEF) improvement. The clinical endpoints were a composite of all-cause mortality, heart transplantation/left ventricular assist device implantation, and heart failure hospitalization (HFH). Among 347 DCM patients with LBBB (median age 60[53-68], median LVEF 31%[23-39]), 22 (6%) exhibited P/LP variants. Genotype-positive patients less frequently fulfilled strict LBBB criteria (Strauss:P<0.001) and exhibited less mechanical dyssynchrony (predominantly LBBB-0/1;P<0.001). They showed attenuated reverse remodeling after CRT (ΔLVEF 1%[-6-6] vs. 14%[7-22];P<0.001) and worse clinical outcomes (both composite outcome and HFH;P<0.001). Conversely, advanced LBBB stages excluded an underlying rare genetic variant. P/LP variant status, LVEF, and LBBB stage independently predicted CRT response and composite outcome. Genetic testing has a low diagnostic yield in patients with DCM and LBBB. Genotype-positive variants exhibit a distinct electromechanical profile, characterised by atypical electrocardiographic features and markedly reduced mechanical dyssynchrony, poor CRT response, and worse long-term outcomes. Integrating genetic and electromechanical phenotyping may improve individualized risk stratification and management.

The COVID-19 pandemic created a unique situation in which researchers repurposed human models of varying complexity to investigate SARS-CoV-2, providing the opportunity to analyse their contribution across organs. We conducted a systematic review of 558 studies, divided into pandemic and post-pandemic periods, to assess how human models were applied to investigate host factors, viral replication of SARS-CoV-2, immune responses, and to evaluate reporting quality. Our analysis revealed substantial limitations that were only partially alleviated in post-pandemic studies. These limitations included heterogeneity of outcome measures, incomplete documentation of model characteristics and experimental procedures, and variable reporting quality, which were associated with reduced cross-study comparability, more difficult risk-of-bias assessment, and limited reliability and interpretability of evidence synthesis and meta-analytical results. Strengthening community-driven reporting standards and methodological transparency is essential to enable robust evidence synthesis and to fully realise the potential of human organ models in future pandemics and translational research. The study was supported by Einstein Foundation Berlin; Federal Ministry of Research, Technology and Space; European Union; Else Kröner-Fresenius-Stiftung; Volkswagen Foundation; Charité 3R; Foundation Charité.

Long-term exposure to high-intensity endurance exercise induces significant physiological cardiovascular remodelling. However, recent evidence suggests that prolonged exercise in athletes, particularly those exposed to decades of intensive training, may be associated with features of cardiovascular "wear and tear". These include electrical changes such as an increased risk of sinus node dysfunction and atrial fibrillation as well as structural abnormalities such as focal non-ischemic fibrosis and coronary artery calcification, more frequently observed in middle-aged and older endurance athletes. These observations support that long-term high-intensity exercise may have deleterious cardiovascular effects in susceptible individuals, although the available data are primarily derived from male Caucasian athletes. While the clinical significance of these potentially maladaptive changes at the individual level remains uncertain, at a population level high intensities and volumes of physical activity are consistently associated with reduced cardiovascular and all-cause mortality compared with sedentary behaviour, although the incremental survival benefit may plateau at very high exercise volumes. This review critically appraises the available evidence on chronic adverse cardiovascular adaptations associated with intense endurance exercise, highlighting unresolved controversies, sex- and ethnicity-related knowledge gaps, and the need to balance potential risks against the well-established survival benefits of lifelong physical activity.

This systematic review and meta-analysis included 34 studies encompassing 983 438 adult cancer survivors and evaluated the performance of both general-population and cancer-specific cardiovascular risk-prediction models across vascular events, cancer therapy-related cardiac dysfunction or heart failure, arrhythmias, and composite cardiovascular event outcomes. In total, 27 unique risk scores were assessed. Approximately one-third of model-outcome evaluations demonstrated acceptable-to-good discrimination, defined as an area under the curve of ≥0.70. Among general-population models, four risk scores demonstrated acceptable-to-good discrimination for vascular events, three models were acceptable for CTRCD/heart failure, and two models for arrhythmias. The New Zealand CVD score was the only composite outcome model with an AUC ≥0.70. Cancer-specific scores, such as HFA-ICOS and the Ezaz score, showed high specificity for selected outcomes and may support rule-in decisions, although their lower sensitivity limits use for ruling out risk of CTRCD/heart failure. In our subgroup analysis, model performance varied by cancer type, with more consistent discrimination in breast cancer cohorts and substantially poorer performance in survivors of haematologic malignancies, indicating limited transportability across cancer populations. In summary, these findings provide a comprehensive overview of available cardiovascular risk-prediction tools and may assist clinicians in selecting appropriate models for primary cardiovascular prevention in cancer survivors while highlighting the need for exposure-aware, externally validated models tailored to specific cancer populations.

The "2026 AHA/ACC/ADA/ASN Guideline for the Prevention, Detection, Evaluation, and Management of Cardiovascular-Kidney-Metabolic Syndrome" retires, replaces, and expands upon the "2013 AHA/ACC/TOS Guideline for the Management of Overweight and Obesity in Adults." The primary intended audience for this guideline is clinicians who care for patients across the spectrum of cardiovascular-kidney-metabolic syndrome, an interrelated condition characterized by the interconnections among metabolic risk factors (including obesity and type 2 diabetes), chronic kidney disease, and cardiovascular disease. A comprehensive literature search was conducted from October 29, 2024, to April 14, 2025, to identify clinical studies, systematic reviews and meta-analyses, and other evidence conducted on human subjects that were published since 2015 in English from MEDLINE (through PubMed), EMBASE, the Cochrane Library, the Agency for Healthcare Research and Quality, and other selected databases relevant to this guideline. The focus of this clinical practice guideline is to create a living, working document that provides current knowledge in the field of cardiovascular-kidney-metabolic syndrome aimed at all practicing cardiologists, endocrinologists, nephrologists, and primary care and specialty clinicians who manage these patients.

Current clinical practice guidelines for the primary prevention of cardiovascular disease recommend risk assessment to align the type and intensity of preventive efforts with an individual's risk. The 2025 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of high blood pressure in adults and the 2026 American Heart Association/American College of Cardiology guideline on the management of dyslipidemia incorporate quantitative risk assessment, recommending the PREVENT (Predicting Risk of Cardiovascular Disease Events) equations to guide initiation and intensification of antihypertensive and lipid-lowering therapies, respectively. Given the growing awareness of the clustering of cardiovascular-kidney-metabolic risk factors along with the expanding armamentarium of cardioprotective therapies for obesity, diabetes, and chronic kidney disease, a harmonized approach that comprehensively assesses and addresses risk across these interconnected conditions is needed. The 2026 American Heart Association/American College of Cardiology guideline for the prevention, detection, evaluation, and management of cardiovascular-kidney-metabolic syndrome provides recommendations for the use of the PREVENT equations with outcome-specific risk thresholds for staging, detection of subclinical cardiovascular disease, and decision-making regarding initiation and intensification of cardiovascular-kidney-metabolic therapies. This approach integrates predicted risk (using PREVENT-CVD [cardiovascular disease], PREVENT-ASCVD [atherosclerotic cardiovascular disease], and PREVENT-HF [heart failure]) with the relative risk reduction expected from treatment for each outcome to estimate the expected benefit (ie, absolute risk reduction) from drug therapy. This scientific statement details the rationale for using outcome-specific PREVENT equations, the evidence base for selected risk thresholds, and the potential population-level impact of these recommendations. This scientific statement also offers practical guidance for applying risk assessment as the first step in shared decision-making and for addressing gaps in awareness, risk communication, and optimal implementation of evidence-based preventive therapies to improve outcomes in individuals with or at risk for cardiovascular-kidney-metabolic syndrome.

Inhibitors of the sodium-glucose cotransporter 2 (SGLT2) provide cardiovascular and renal protection in both diabetic and non-diabetic patients at least in part independently of glycaemic control. Some underlying mechanisms for these clinically beneficial effects were suggested, but the picture is far from complete. In this study we aimed to apply untargeted metabolomics in order to identify new mechanistic leads. Plasma and 24-hour urine samples of 48 diabetic patients taken before and after 6 weeks of treatment from two prospective, randomized, double-blind, placebo-controlled, cross-over trials with dapagliflozin or empagliflozin were used. Additionally, plasma and urine samples of 24 diabetic patients from a prospective, randomized, controlled, parallel-arm, interventional, open-label, single centre study with either empagliflozin and linagliptin or metformin and insulin glargine for 12 weeks were used for confirmation. Changes of metabolite patterns in plasma and urine were determined by untargeted high-resolution mass spectrometry. Moreover, parameters of arterial stiffness and retinal vascular remodelling were correlated with treatment effects of the SGLT2 inhibitors on the modified nucleoside N4-acetylcytidine (ac4C), a potential biomarker for the activity of the enzyme N-acetyltransferase 10 (NAT10). In accordance with previously reported results treatment with SGLT2 inhibitors led to a reduction of glucose (log2fc: - 0.23, adj. p < 0.01) and uric acid (log2fc: - 0.23, adj. p < 0.001), while 3-hydroxybutyric acid (log2fc: 0.84, adj. p < 0.001) and 3-hydroxybutyrylcarnitine (log2fc: 0.57, adj. p < 0.001) were increased in plasma. As a new finding, plasma concentrations of ac4C were reduced (log2fc: - 0.32, adj. p < 0.001) by SGLT2 inhibitors but not by the non-SGLT2 inhibiting glucose lowering treatment. Reduction of urinary concentrations of ac4C corresponded to its reduction in plasma in groups treated with the SGLT2 inhibitors. Wall thickness of retinal arterioles and central systolic blood pressure were significantly correlated to ac4C in plasma. Treatment with dapagliflozin and empagliflozin reduced plasma concentrations of ac4C, which was correlated with parameters for vascular health. These exploratory findings may indicate inhibition of NAT10 activity as a potential contributor to the beneficial effects on cardiovascular and renal health by SGLT2 inhibitors. http://www. gov : NCT02383238, NCT02471963, NCT02752113.

The molecular diagnosis of autosomal dominant tubulointerstitial kidney disease due to MUC1 variants (ADTKD-MUC1) using high-throughput (short-read) sequencing methods remains challenging due to the presence of a coding long variable-number tandem repeat (VNTR) region wherein most known pathogenic variants are located. Here, we used targeted amplicon long-read sequencing to study the MUC1 VNTR in a retrospective cohort study of 78 individuals. Using a bioinformatic pipeline including newly developed specialized software, VNTRtools, we reconstruct patient-specific complete VNTR haplotypes, generate a synthetic VNTR reference, perform long-read realignment to this reference and finally perform variant calling. VNTRtools proved efficient, requiring seconds or minutes per sample to accurately identify all pathogenic MUC1 frameshift variants in positive controls, including atypical variants. Ten new diagnoses of ADTKD-MUC1 were made. Furthermore, we report a confirmed de novo case of ADTKD-MUC1 in a 32-year-old patient. We were able to structurally resolve and phase the inter-individually highly variable VNTRs in most probands, enabling the high-confidence detection of pathogenic frameshift variants in 24 individuals. We also detected 18 previously unreported VNTR repeat unit types, demonstrating the highly polymorphic nature of MUC1's VNTR. We propose a combined approach in which short-read VNTR analysis using the published alignment-free bioinformatic tools is used as a first line test, followed by targeted long-read sequencing with VNTRtools analysis for confirmatory testing and in-depth VNTR characterization. This combined approach will lead to a higher diagnostic confidence in ADTKD-MUC1 - especially in sporadic cases. Complete VNTR haplotype information will likely enable a better genetic understanding of this currently underdiagnosed disorder and may become relevant for future therapeutic approaches like targeted silencing of the pathogenic MUC1 allele.

The clinical course of systemic amyloidosis reflects the equilibrium between amyloid deposition and clearance, which varies across disease contexts. The mechanisms underlying amyloid clearance in vivo remain unclear, though experimental data implicate macrophage-mediated phagocytosis. Here we evaluated the impact of CD68+ macrophage infiltration in diagnostic kidney biopsies on kidney outcomes in immunoglobulin light-chain amyloidosis (AL) and examined the prognostic value of amyloid regression among patients with deep hematological response following chemotherapy. Kidney biopsies from 708 consecutive patients with kidney AL treated at the United Kingdom National Amyloidosis Centre between 2000-2022 and achieved a deep and sustained hematologic response to chemotherapy were retrospectively stained with anti-CD68 antibody. Macrophage infiltration was scored on a scale of 0-3 and the relationship between macrophage score, interstitial fibrosis and tubular atrophy (IFTA) and kidney survival was evaluated. Among 396 patients in the cohort who had serial serum amyloid P component (SAP) scans at diagnosis and at two-years of follow-up, the relationship between change in amyloid burden and long-term kidney outcomes was characterized. At five years, cumulative incidence of renal replacement therapy (RRT) was 14%, 22%, 40%, and 52% across macrophage scores 0-3 respectively. On multivariable Cox regression analysis, each one-point macrophage score increase independently and significantly predicted higher risk of RRT (hazard ratio 1.31, 95% confidence interval 1.09-1.56) alongside baseline estimated glomerular filtration rate, proteinuria, and IFTA. In two-year landmark analysis, amyloid accumulation by SAP scintigraphy conferred a significant nine-fold increased risk of RRT versus amyloid regression (9.44, 3.25-27.39) Hematologic complete response was strongly associated with amyloid regression and prolonged renal survival. In AL amyloidosis, kidney CD68+ macrophage infiltration at diagnosis is independently associated with risk of progression to RRT even among patients with deep hematologic response. Regression of amyloid is associated with prolonged kidney survival. These findings highlight kidney CD68+ macrophage infiltration and subsequent SAP-defined amyloid regression as complementary predictors of kidney outcome in AL amyloidosis.

JCOG1212 is a multi-institutional prospective single-arm trial evaluating the efficacy and safety of superselective intra-arterial cisplatin infusion with concomitant radiotherapy (RADPLAT) for locally advanced maxillary sinus squamous-cell carcinoma (MS-SCC). We previously reported the results for the T4aN0M0 cohort (n = 64), in which RADPLAT was shown to be feasible and to provide favorable survival outcomes. This report presents the results for the T4bN0M0 cohort. Patients with previously untreated T4bN0M0 MS-SCC received weekly intra-arterial cisplatin (100 mg/m2) for seven cycles in combination with radiotherapy (70 Gy in 35 fractions). The primary endpoint was 3-year overall survival (OS), with a predefined efficacy threshold of 35% and a one-sided alpha of 5%. Secondary endpoints included event-free survival (EFS), local EFS (LEFS), clinical response, and toxicity. Sixty-four patients were enrolled from 20 institutions. The 3-year OS was 68.8% [90% confidence interval (CI) 58.1% to 77.2%], exceeding the efficacy threshold. The clinical complete response rate was 54.7%. The 3-year EFS and LEFS was 51.6% (95% CI 38.8% to 63.0%) and 57.8% (95% CI 44.8% to 68.8%), respectively. With regard to acute adverse events, neutropenia ≥ grade 3 (18.0%), mucositis ≥ grade 3 (23.0%), hearing impairment ≥ grade 2 (3.3%), and stroke ≥ grade 2 (1.6%) were observed. No grade 2 ≥ creatinine increase was observed. There were no treatment-related deaths. RADPLAT achieved favorable survival outcomes with acceptable toxicity in patients with T4bN0M0 MS-SCC. These results establish RADPLAT as a feasible and effective organ-preserving treatment and demonstrate the potential of intra-arterial chemoradiotherapy for unresectable MS-SCC.

Food allergy (FA) is increasing worldwide, and early life may be a critical window for immune training. We systematically reviewed observational human studies linking early-life microbiota (infant, maternal, environmental, or extraintestinal) profiled using culture-based and/or culture-independent methods (including sequencing-based approaches) to subsequent FA or food sensitization outcomes in infants, children, and adolescents up to 18 years of age. PubMed, Web of Science Core Collection, Embase, Scopus, and LILACS were searched from database inception to March 2026. Inclusion required microbiota sampling during pregnancy or childhood and clinically ascertained FA/sensitization; non-human studies and studies without sequencing or clinical outcomes were excluded. Risk of bias was assessed using QUIPS. Owing to heterogeneity, we performed narrative synthesis. Forty studies were included (n = 6530 participants; 2077 cases). Across cohorts, cases were associated with lower diversity, early beta-divergence (1-6 months), neonatal enrichment of Proteobacteria (Pseudomonadota)/Enterobacteriaceae and selected taxa (Clostridium, Streptococcus, Sutterella), and depletion within the first year of Bifidobacterium, Blautia, and butyrate producers (Roseburia, Faecalibacterium). Functional profiles often suggested delayed maturation and reduced short-chain fatty acid capacity. Evidence was limited by moderate risk of bias, residual confounding, and heterogeneous outcome definitions. These findings support distinct early-life microbial configurations associated with FA susceptibility versus tolerance, informing mechanism-based prevention. Trial Registration: PROSPERO CRD420251234739.

Microvascular inflammation (MVI) on kidney biopsy is associated with reduced graft survival following kidney transplantation (KT). CD38- targeting regimens, including the monoclonal antibody daratumumab, have recently emerged as a promising therapeutic strategy to counteract MVI and stabilize graft function. Here, we retrospectively collected data on eGFR, albuminuria, kidney allograft pathology, donor specific antibodies (DSA) and donor-derived cell-free DNA (dd-cfDNA) levels from 70 KT patients both prior to and after initiation of daratumumab treatment. Safety signals were also documented. The study cohort consisted of 59 patients diagnosed with antibody mediated rejection (AMR) and 11 patients showing DSA- and C4d-negative MVI. Median time between transplantation and diagnosis of MVI was 36 months. Daratumumab treatment was initiated at a median of 1.6 months following diagnosis of MVI. A mixed linear model showed stabilization of eGFR from -1.6 ml/min/1.73m2/month in the year prior to the diagnosis of MVI to +0.3 83 ml/min/1.73m2/month after starting daratumumab. Six patients lost their graft during follow-up. Median albuminuria and dd-cfDNA levels decreased early during treatment, whereas the effect on DSA was heterogeneous. Both the number of doses and treatment duration had no measurable impact on outcome. Our preliminary data suggests efficacy of daratumumab in stabilizing kidney function in KT recipients with MVI.

Artificial intelligence (AI), particularly foundation and generative models, is reshaping the practice of hepatology through enhanced knowledge synthesis, quantitative and reproducible analysis of multimodal data, and personalized clinical decision support. This narrative review examines the transition from task-specific discrimination AI to large language models (LLMs), multimodal foundation models, and agentic AI. We synthesize evidence from original and validation studies, clinical evaluations, and benchmark studies, as well as expert reviews and regulatory frameworks across metabolic dysfunction-associated steatotic liver disease, chronic hepatitis B, cirrhosis and portal hypertension, hepatocellular carcinoma, and liver transplantation. LLMs can convert free-text notes into structured data, summarize longitudinal electronic health records, support patient education, and retrieve guideline-based information. Retrieval-augmented generation and agentic AI may improve traceability and workflow support, but current evidence is largely retrospective or proof-of-concept. In digital pathology and imaging, discriminative AI has enabled more quantitative and reproducible histologic scoring and biomarker analysis. Pathology and multimodal foundation models offer transferable representations, report generation, and cross-modal reasoning, but hepatology-specific validation remains limited. Key risks include hallucination, automation bias, domain shift across centers and devices, and inequities due to under-representation of patient subgroups. We outline the future directions for safe AI model deployment based on multimodal foundation models, prospective and federated evaluation, lifecycle governance, and continuous monitoring for performance, calibration, and equity. Most generative AI applications in hepatology remain at the proof-of-concept stage, and rigorous prospective validation with human-in-the-loop oversight is required before clinical integration.

Hereditary hemorrhagic telangiectasia (HHT), an autosomal dominant vasculopathy affecting 1 in 5000 individuals, is the second most common inherited bleeding disorder worldwide. Despite this prevalence, comprehensive data on disease manifestations and complications remain limited. To address this gap, the US Congress allocated funding leading to the Comprehensive HHT Outcomes Registry of the United States (CHORUS), a prospective, 15-center longitudinal registry enrolling unselected patients with confirmed HHT. In this initial report, we describe findings from the first 600 participants, with a median age of 53 (range, 0-88) years and 60% female. Despite most participants developing typical HHT manifestations by age 13 years, the majority (63%) were not diagnosed until mid-to-late adulthood. Recurrent spontaneous epistaxis occurred in 95% of participants, chronic gastrointestinal bleeding in 30%, and heavy menstrual bleeding in 35% of postmenarche females, together resulting in moderate-to-severe mucosal bleeding in 76%. Iron deficiency and/or anemia were diagnosed in 68%, with 41% requiring IV iron and 25% requiring red cell transfusions. Serious complications of solid-organ arteriovenous malformations were frequent, including intracranial hemorrhage (3%), pulmonary hemorrhage (2%), venous thromboembolism (7%), arterial thromboembolism (11%), heart failure (7%), and pulmonary hypertension (7%). These data from CHORUS, the first national US registry of its kind, provide reliable, real-world estimates of the incidence, prevalence, and severity of numerous HHT manifestations and complications. HHT has a high burden of moderate-to-severe bleeding, anemia, thrombosis, and major neurologic and cardiopulmonary complications. There is a mean interval between first symptoms and diagnosis of >2 decades, during which substantial, serious, and preventable HHT morbidity, including early intracranial hemorrhage, may occur. This trial was registered at clinicaltrials.gov as NCT06259292.

Hematopoietic stem cell transplantation (HSCT) remains the only curative option for sickle cell disease (SCD), but its use in adolescents and adults is limited by toxicity concerns. We evaluated the risk-benefit profile of HSCT in this population through a comparative analysis of transplant versus nontransplant strategies. HSCT was analyzed as a time-dependent variable in consecutive adolescents and adults with an indication for transplantation who were referred for HSCT counseling. At the last follow-up, patients had either undergone HSCT or not. HSCT procedures involved matched related donor (MRD) transplants after myeloablative or non-myeloablative conditioning, and haploidentical transplants after reduced-intensity conditioning. The primary endpoints were overall survival (OS) and composite event-free survival (cEFS), calculated from the initial consultation. Events included death, grade III-IV acute or moderate-to-severe chronic graft-versus-host disease (GVHD), graft rejection, overt stroke, third hospitalized painful crises within two years, acute chest syndrome (ACS), delayed hemolytic transfusion reaction, or initiation of new SCD modifying therapy. Ninety-four patients were included (median follow-up: 2.9 years), of whom 58 underwent HSCT. The 2-year OS was 98% with HSCT versus (vs.) 97% without HSCT (P = 0.55). cEFS was significantly higher post-transplant (72% vs. 28%, P < 0.0001), with marked reduction in painful crises and ACS. Among patients who underwent transplantation, the 2-year rejection-free survival from the time of transplant was 91% for MRD and 82% for haploidentical HSCT (P = 0.40). HSCT substantially improves cEFS without excess short-term mortality, supporting its broader use in adolescents and adults with SCD, particularly when an MRD is available.

Life expectancy is a key indicator of population health and an important guide for health policy1,2. Although Asia represents approximately 60% of the global population, studies of longitudinal trends in life expectancy and their underlying drivers across Asian countries remain limited, with most previous research focused on western or high-income settings3-6. Here we provide a comprehensive analysis of life expectancy, cause-specific mortality and risk factors in 1990-2023 across 34 Asian countries and territories, utilizing data from the Global Burden of Disease Study 20231,7. Life expectancy increased in all countries and territories between 1990 and 2023, with the largest annual gains observed in South Asia and the smallest annual gains in high-income Asia Pacific countries and territories. Reductions in cardiovascular disease mortality were the primary contributors to life expectancy gains in Central Asia, East Asia and high-income Asia Pacific, whereas declines in diarrhoeal diseases and tuberculosis contributed most in South and Southeast Asia. In 2019-2023, life expectancy declined in several Asian regions, largely driven by the COVID-19 pandemic, with a nearly two-year loss in the first year of the pandemic. The causes of changes in life expectancy and the contributing risk factors varied across regions and countries/territories. Therefore, under the principles of proportional universalism, proactive and effective policies at both regional and national levels are essential to reduce premature mortality and reduce life expectancy inequalities across Asia.

Longevity is a relevant cardiovascular (CV) endpoint because survival integrates incident CV disease (CVD), competing non-CVD risks, and the physiological reserve that determines resilience to aging and chronic illness. Two related constructs, physical activity (PA; a modifiable behavior) and cardiorespiratory fitness (CRF; an integrative phenotype reflecting habitual PA, genetics, cardiopulmonary function, skeletal muscle oxidative capacity, and comorbidity), are consistently associated with lower all-cause and CVD mortality across diverse populations. In this invited narrative review, we synthesize evidence linking PA and CRF to longevity, highlight the dose-response nature of benefits and the importance of activity domain and intensity, and explain why CRF generally outperforms self-reported PA for risk prediction. We address challenges in causal inference, residual confounding variables, reverse causation, and selection/measurement bias, and emphasize approaches that strengthen inference, including device-based PA assessment (e.g., accelerometry), repeated measures, and triangulation with mechanistic and trial evidence. Mechanistic pathways plausibly linking PA and CRF to survival include favorable effects on blood pressure, glycemia and insulin sensitivity, adiposity and body composition, vascular reactivity, autonomic balance, inflammation and immune function, thrombosis, and preservation of skeletal muscle and mitochondrial reserve. We review evidence in particularly relevant subgroups and discuss the "extreme exercise hypothesis", distinguishing mortality from risks, such as atrial fibrillation and accelerated coronary calcification, in endurance athletes. We conclude with practical actions for clinicians and health systems, such as prescribing activities based on the frequency, intensity, time, and type (FITT) principles, incorporating resistance training, treating CRF as a vital sign, and addressing common implementation barriers.

Complement-mediated thrombotic microangiopathy can be difficult to recognize when it presents in the setting of an apparent clinical trigger, such as pregnancy, severe hypertension, or kidney transplantation. These conditions can each cause endothelial injury directly, but may also unmask complement dysregulation in susceptible individuals. In these situations, the critical question is not whether a trigger exists but whether it fully explains the syndrome and whether urgent complement blockade is warranted to prevent irreversible kidney injury. In this How I Treat article, we use three real-world cases to illustrate how we approach this decision in practice. We emphasize the bedside features that most influence our threshold to treat, including the pattern and severity of kidney injury, tempo of disease progression, and lack of improvement with supportive or trigger-directed care. We also address the interpretation of complement genetic findings, pregnancy- and transplant-specific risk stratification, and individualization of treatment duration. Functional assays can support mechanistic assessment in selected cases but remain an adjunct to the diagnosis and should not drive management decisions.

Periodontal remodeling is a continuous, adaptive process essential for maintaining the structural and functional integrity of periodontal tissues. While external factors such as bacterial biofilm, excessive forces, and poor oral hygiene are recognized triggers of periodontal pathologies, they do not fully explain their persistent prevalence. This opinion paper emphasizes the impact of systemic diseases on periodontal homeostasis and considers periodontal disease as a manifestation of systemic dysfunction rather than solely a bacterial local disease. This paper is conceptually designed as a narrative review and synthesizes the molecular and cellular mechanisms through which systemic diseases converge to disrupt periodontal remodeling. Emerging evidence underscores the critical role of systemic diseases, including chronic kidney disease, cardiovascular disease, liver dysfunction, and hematologic malignancies, in addition to studied uncontrolled diabetes mellitus, in destabilizing periodontal homeostasis. These systemic conditions are all associated with excess systemic inflammation that impairs regenerative capacity, mineralization, vascularity, and immune responses, fostering a subclinical environment prone to periodontal tissue pathologies with clinical impact. This opinion paper is conceptually designed as a narrative review and synthesizes the molecular and cellular mechanisms through which systemic diseases converge to disrupt periodontal remodeling, including periodontal pathologies as a consequence of systemic dysfunction rather than a purely bacterially induced local disease. Clinically, this understanding demands intensified dental surveillance to uncover modifiers of susceptibility and interdisciplinary care for systemically compromised patients. Future research should identify early biomarkers of systemic impact and inform strategies that integrate oral and systemic health to reduce the periodontal disease burden.

The intricate balance between angiotensin-converting enzyme 1 (ACE1) and 2 (ACE2) in the pulmonary vasculature is pivotal for the pathogenesis of pulmonary arterial hypertension (PAH). Catalysing the K48-linked deubiquitination, ubiquitin carboxyl-terminal hydrolase 10 (USP10) is involved in tumour suppression, autophagy, and cell proliferation. This study aims to determine whether a positive feedback loop of USP10 and AMP-activated protein kinase (AMPK) in pulmonary endothelium is protective against PAH. In silico data analyses and in vitro culture cell experiments were used to investigate the role of USP10 in human idiopathic PAH (IPAH) and rodent pulmonary hypertension (PH) as well as the underlying mechanism involving a positive feedback loop of AMPK and USP10 in lung endothelium. Endothelial cell (EC)-specific USP10 transgenic (Tg) mice and mice administered liraglutide were used to explore the efficacy of the AMPK/USP10 loop in mitigating PH in rodents. USP10 level was decreased in the lung endothelium of human IPAH and rodent PH. AMPK/USP10 loop activation increased ACE2 Ser-680 phosphorylation and Lys-788 deubiquitination, thus contributing to the homeostatic level of ACE2 and lung vascular patency. Mice with liraglutide administration phenocopied the mitigated PH in EC-specific USP10 Tg mice, in part because of the activated AMPK/USP10 loop in the pulmonary endothelium. Genetic or pharmacologic [via glucagon-like peptide-1 receptor agonists (GLP-1 RAs)] interventions in the AMPK/USP10 loop can augment ACE2 level in lung endothelium. This type of ACE2 enhancement garners protection against PAH in humans and PH in rodents, which provides a rationale for using GLP-1 RAs to alleviate PAH.

The nature of the aqueous proton has been traditionally interpreted through two limiting structural motifs: the Zundel and Eigen cations. However, experimental infrared (IR) spectra of the solvated proton reveal a far more dynamic character, as evidenced by distinct intensity modulations within the characteristic continuum absorption band. In fact, recent ultrafast two-dimensional IR spectroscopy suggests that solvation-induced structural distortions around H2O⋯H+⋯OH2 motifs critically shape the IR response. Here we investigate the role of such asymmetry through full-dimensional quantum dynamics simulations of the extended Zundel complex H+(H2O)6, which structurally encompasses both Zundel and Eigen motifs. Systematic removal of one water molecule from the second solvation shell gradually introduces deviations from the perfectly symmetric Zundel-like complex towards Eigen-like spectral features. These results provide a direct map between the asymmetric solvation environment and the structural response of the first and second solvation shells of the aqueous proton, offering a structural and dynamical basis for understanding how this asymmetry governs proton mobility in aqueous environments.

Thrombosis drives myocardial infarction, acute ischemic stroke and pulmonary embolism, yet more than half of patients undergoing mechanical thrombectomy fail to achieve functional independence, and residual thrombus is detected in up to 91% of cases after catheter-directed thrombolysis. These persistent clinical failures reflect a fundamental gap: thrombus removal is not merely dissolution or extraction, but a multiphysics process governed by the fracture, deformation and fragmentation of a highly anisotropic composite material whose mechanical behavior remains poorly understood and insufficiently predicted. In this review, we examine physics-based and data-driven numerical models of thrombus mechanics, fracture, and fragmentation from a failure-oriented perspective and assess their potential clinical impact. A thrombus is a hierarchically organized composite in which a fibrin network scaffold, functionally differentiated platelet subpopulations and red blood cells interact across scales spanning six orders of magnitude, thus residual thrombus and fragment migration emerge as the fundamental challenges shared by all recanalization strategies from pharmacological thrombolysis to mechanical thrombectomy. We survey six major computational paradigms, including continuum-based approaches, lattice Boltzmann method, particle-based mesoscopic simulation, discrete fiber network models, multiscale coupling frameworks and artificial intelligence/machine learning-assisted methods, and trace the field's evolution over four decades from reaction kinetics to multiphysics fracture coupling. Finally, we delineate critical gaps in current simulation frameworks and argue that AI-driven surrogate models, physics-informed digital twins and generative virtual patient cohorts could transform thrombus simulation from a predominantly academic endeavor into a clinically actionable platform for real-time decision support. STATEMENT OF SIGNIFICANCE: Blood clots cause heart attacks, strokes, and pulmonary embolism, yet current treatments fail to fully remove clots in over half of cases. A key reason is that we still cannot predict how clots break apart during treatment. This review is the first to systematically examine thrombus simulation from a mechanical failure perspective, synthesizing six computational paradigms-from continuum mechanics to artificial intelligence-and tracing their four-decade evolution from modeling how clots form to predicting how they fail. By establishing residual thrombus and fragment migration as the shared unresolved challenges across all treatment strategies, we identify critical modeling gaps and propose AI-driven translational pathways, including digital twins and virtual patient cohorts, that could transform clot simulation into a real-time clinical decision-support tool.

Thrombotic microangiopathy (TMA) is classically defined by the triad of haemolytic anaemia, thrombocytopenia, and organ injury, most notably kidney involvement. Secondary TMA, which arises in association with specific diseases or external triggers, is more common than primary or complement mediated TMA. Current evidence supports an important role for complement activation in the pathogenesis of secondary TMA, and emerging data highlight the contribution of the endothelial glycocalyx (eGC) to complement dysregulation at the endothelial surface. The eGC is an integrated matrix lining the luminal aspect of endothelial cells and plays a central role in maintaining endothelial homeostasis and preventing thrombosis. Its unique structure may represent a missing mechanistic link in several forms of secondary TMA that are relevant to children, including Pneumococcal associated TMA (Pneu-TMA), Shiga toxin-producing Escherichia coli-hemolytic uremic syndrome (STEC-HUS), calcineurin inhibitors associated TMA, and hypertension associated TMA. This mini review summarises current evidence and understanding of the central role of the eGC in these conditions, and discusses the implications for future therapeutic innovation. Editor's Note Thrombotic microangiopathy (TMA) in children is not a single entity but a mechanistically heterogeneous group of disorders whose causes differ substantially from those seen in adults. Shiga toxin-producing Escherichia coli hemolytic uremic syndrome accounts for the majority of pediatric cases, yet secondary TMA as a whole, arising in the context of an underlying condition or external trigger, is far more common than primary, complement-mediated disease, and its pathophysiology has remained incompletely understood. In this timely mini review, Ma et al. propose a unifying framework centered on the endothelial glycocalyx (eGC), the sugar-rich matrix lining the luminal endothelial surface that safeguards vascular homeostasis and restrains complement activation. Injury to the eGC, with shedding of heparan sulfate and impaired complement factor H binding, provides the "second hit" that couples complement dysregulation to endothelial injury. The authors summarize how this mechanism links otherwise disparate triggers, including pneumococcal infection, Shiga toxin, calcineurin inhibitors, and severe hypertension. This perspective helps explain why complement blockade benefits only selected children with secondary TMA, and potentially reframes eGC thickness as a candidate biomarker and its restoration as a therapeutic target. Further studies are needed to define which children with secondary TMA are most likely to benefit from complement blockade (see the Pediatric Nephrology series at https://www.kidney-international.org/content/pediatric-nephrology).

Transcranial focused ultrasound (tFUS) is a promising technique that has been shown to have high spatial precision, deep brain penetration, and cell-type specificity. Intracranial electrophysiological recordings can measure neural responses to tFUS with high spatial and temporal resolution, but conventional silicon-based multi-electrode arrays cause vibration artifacts induced by increased tFUS pressure. In this study, using an ultraflexible nanoelectric thread electrode, we demonstrate the cell-type selective effects of tFUS under high acoustic pressure with a broad range of ultrasound parameters. We observe that their flexibility mitigates vibrations, eliminating artifacts even at high pressure levels. We observed a positive nonlinear relationship between pressure levels and both time-locked and delayed spiking responses in multiple cell types. We show that higher pressure levels produce distinct response curves across independently varied ultrasound pulse repetition frequency and duty cycle, suggesting the need for further investigation of pressure effects.

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

Genome-wide association studies (GWAS) have uncovered over a thousand loci associated with kidney function, but the effector genes and mechanisms remain largely unknown. Here, we demonstrate that ELF3 is the effector gene at a kidney function GWAS locus and acts as an epithelial proinflammatory amplifier of the reprogramming of injured proximal tubules (iPTs). E74-like factor 3 (ELF3) expression is induced in iPTs in both mouse models and human chronic kidney disease (CKD), where it defines transitional epithelial states enriched for inflammatory gene programs and surrounded by leukocyte infiltrates. Conditional deletion of Elf3 in mice after injury reduced iPT accumulation, cytokine production, and immune cell recruitment. Mechanistically, ELF3 directly bound and activated components of the noncanonical nuclear factor κB (NF-κB) pathway (Nfκb2, Map3k14, and Il6r) and was required for NFκB2 nuclear translocation and cytokine induction. Spatial transcriptomics and immunofluorescence of human CKD kidneys confirmed that ELF3 expression correlates with epithelial inflammation, disease progression, and loss of kidney function. Together, these findings establish ELF3 as a genetically validated effector gene that drives inflammatory reprogramming in iPTs, nominating it as a therapeutic target to blunt maladaptive inflammation in CKD.

Genetically encoded voltage indicators have emerged as a tool for resolving neuronal spiking activity with high spatiotemporal resolution within genetically specific populations; however, their fast temporal dynamics, low signal-to-noise ratio (SNR) and fast photobleaching have posed substantial challenges limiting their broader utility and, together with suboptimal optical acquisition schemes, preventing their efficient scale-up to larger neuronal populations. Here we introduce a versatile, scalable, spatiotemporally and energetically efficient two-photon optical imaging system scheme based on a flexible lateral-temporal multiplexing (FlatMux) platform. We demonstrate FlatMux's capability and its flexible reconfigurability for meeting different recording requirements. This includes a large field-of-view mode, a 2-kHz high-speed mode, a deep-tissue imaging mode allowing recordings of cortical spiking activity at up to 500-µm depth, a dual-plane imaging mode allowing for simultaneous recording of population spiking activity of neurons in cortical L2/3 and L4, and a high-SNR imaging mode for recording of subthreshold neuronal activity and high-SNR spiking activity, all while minimizing pixel crosstalk and bleaching. Thus, FlatMux meets the challenging demands of multiphoton voltage imaging across the mammalian cortex and can be expected to enable a range of studies of complex brain functions at single-spike and single-trial level for large neuronal populations.

Maternal inflammatory response (MIR) during early mouse gestation induces a cascade of physiological and behavioral changes associated with autism spectrum disorder (ASD). We have shown that mild MIR causes chronic systemic and brain inflammation, mTOR pathway activation, mild brain overgrowth with regionally specific volumetric changes, sensory processing dysregulation, and repetitive behavior abnormalities. Prior rapamycin studies in autism models focused on chronic treatments that alter or prevent physical brain changes. Here, we focus on acute rapamycin effects to uncover novel mTOR pathway-mediated mechanisms of dysfunction. Within 2 hours, rapamycin rescues neuronal hyperexcitability, seizure susceptibility, functional network connectivity, brain community structure, repetitive behaviors, and sensory over-responsivity in adult MIR offspring. These CNS-mediated effects coincide with altered expression of genes associated with ASD, ion channels, and epilepsy. Our findings demonstrate that mTOR dysregulation drives dysfunctional brain development in MIR offspring but the adult brain remains amenable to rapid functional normalization, rescuing core and comorbid ASD-associated brain and behavior phenotypes. Restoring excitatory/inhibitory imbalance and sensory functional network modularity may be important targets for therapeutically addressing multiple ASD phenotypes.

Podocyte adhesion to the glomerular basement membrane is essential for kidney function, and adhesion failure leads to podocyte loss and glomerulosclerosis. However, how initial adhesion impairment progresses to irreversible podocyte dysfunction remains poorly understood. Here, we investigated early molecular changes following adhesion impairment to identify new therapeutic targets. We performed single-cell RNA sequencing on kidneys from doxycycline-inducible podocyte-specific Tln1 knockout (Tln1-cKO) mice, an established model of impaired focal adhesion, before overt kidney dysfunction. To test the function of a key downregulated gene, we generated podocyte-specific Nsf knockout (Nsf-cKO) mice and analyzed them using biochemical, cell biological, and live-cell imaging approaches. We also examined publicly available human kidney single-nucleus RNA sequencing datasets. Nsf was among the most significantly downregulated genes in Tln1-cKO podocytes. NSF (N-ethylmaleimide-sensitive factor) is an AAA+ ATPase essential for vesicular trafficking through disassembly of SNARE complexes. Nuclear Yes-associated protein (YAP) was reduced in Tln1-cKO podocytes, and pharmacological inhibition of TEA domain transcription factor (TEAD) or soft-substrate culture lowered NSF expression, indicating that YAP/TEAD signaling links mechanotransduction to Nsf expression. Podocyte-specific Nsf deletion caused massive proteinuria, podocyte loss, glomerulosclerosis, and death by three weeks. NsfcKO podocytes showed impaired spreading and defective integrin regulation: integrin α3 maturation was blocked, while integrin β1 underwent ER stress-induced proteasomal degradation. Trafficking of nephrin and podoplanin was also affected. Live-cell imaging showed markedly delayed ER-to-Golgi trafficking in Nsf-cKO podocytes (90-120 minutes versus 15 minutes in controls). In human datasets, NSF expression was reduced in podocytes from patients with diabetic and hypertensive chronic kidney disease. Adhesion impairment suppresses NSF through reduced YAP/TEAD activity, disrupting ER-to-Golgi trafficking and integrin maturation, and generating a feed-forward cascade of progressive adhesion failure. NSF-mediated trafficking is essential for podocyte homeostasis and a potential therapeutic target in proteinuric kidney diseases.

The brain must efficiently clear protein waste to maintain homeostasis, yet physiological drainage pathways remain poorly defined. Standard tracer injection approaches may not reflect endogenous efflux. Here, we develop a non-invasive genetic system to trace neuron-derived protein clearance from the brain to cerebrospinal fluid (CSF) and border tissues. We identify distinct drainage routes and border hotspots missed by tracer injection, confirmed by bioorthogonal labeling of endogenous neuronal proteins. Pulse-chase kinetics reveal slow skull outflow versus rapid dural and nasal clearance. Transcriptomic analyses uncover border cells sampling neuronal antigens, including tolerogenic skull-resident B cells. Region-restricted reporter expression demonstrates compartmentalized clearance following a "nearest exit" principle, where anatomical origin dictates drainage pathway. Disease disrupts clearance through distinct mechanisms: inflammation drives vascular leakage into blood, while amyloid pathology causes parenchymal retention and border exit obstruction. These findings define brain clearance as a compartmentalized system of organized pathways and immune niches whose dysfunction may underlie regional vulnerability in neurological disease.

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

Pulmonary arterial hypertension (PAH) is a severe, progressive hemodynamic disorder characterized by pathological pulmonary vascular remodeling and right ventricular dysfunction, in which metabolic reprogramming is recognized as a pivotal pathogenic mechanism driving disease progression. This review synthesizes the metabolic pathways, key regulatory targets, and therapeutic implications underlying PAH pathogenesis, focusing on the major cell types involved in its pathogenesis: dysfunctional pulmonary arterial endothelial cells (PAECs), abnormally proliferating pulmonary arterial smooth muscle cells (PASMCs), activated pulmonary artery adventitial fibroblasts (PAAFs), infiltrating immune cells, and right ventricular cardiomyocytes (RVCMs) that undergo compensatory remodeling to counteract increased pressure overload. The primary highlight is its cell-specific analytical framework, which systematically delineates shared metabolic hallmarks and distinct cell-type-specific mechanisms. Shared metabolic features across these cell populations include enhanced aerobic glycolysis, impaired mitochondrial oxidative phosphorylation, and dysregulated amino acid metabolism. Cell-specific mechanisms encompass dysfunction of PAECs, phenotypic switching of PASMCs, PAAFs-mediated adventitial fibrosis, metabolic inflexibility of RVCMs, and inflammatory polarization of immune cells. By integrating these multifaceted findings, the review provides critical insights into the metabolic underpinnings of PAH, emphasizing cell-specific metabolic regulation as a strategy for targeted therapy to reverse vascular remodeling, mitigate right ventricular dysfunction, and improve clinical outcomes.

Cadherin-11 (CDH11) is a mechanosensitive protein capable of creating cell-cell and cell-substrate junctions governing responses to environmental stimuli. It is known to perpetuate fibroblast activation and an inflammatory environment, so we hypothesized that CDH11 is a viable target to suppress kidney injury. Three models were used to test the efficacy of Cdh11 ablation and the CDH11 blocking antibody SYN0012 on kidney injury outcomes in: unilateral ureteral obstruction, aristolochic acid nephropathy, and uninephrectomy with angiotensin II infusion. Kidney fibroblasts were isolated to test CDH11-mediated response to environmental cues. Cytokine arrays were used to quantify secretory changes, and atomic force microscopy was used to measure tissue stiffness. CDH11 increased after injury and was localized to the interstitium. Cdh11-/- mice had reduced fibrosis and decreased circulating levels of inflammatory, fibrotic, and kidney injury markers after unilateral ureteric obstruction. Cdh11-/- mice had improved survival and kidney function (plasma BUN) in the aristolochic acid nephropathy model, while in the uninephrectomy model with angiotensin II infusion, Cdh11-/- mice had improved function and muted cardiorenal injury markers. Contractility and sensitivity to strain in Cdh11-/- kidney fibroblasts were decreased, and these effects are further supported by limited tissue stiffening of the fibrogenic niche after unilateral ureteric obstruction. SYN0012 recapitulated the major findings in all three injury models. Targeting CDH11 attenuates kidney injury in multiple models to improve kidney function, decrease fibrosis and inflammation, and protect from downstream cardiac remodeling. This establishes CDH11 as a major player in renal fibroblast mechanobiology, limiting tissue stiffening and therefore propagation of injury. Hence, CDH11 targeting may be a novel strategy to limit expansion of chronic kidney disease.

Human T-cell leukemia virus type 1 (HTLV-1) is the causative agent of adult T-cell leukemia/lymphoma (ATLL) and the neuroinflammatory disease, HTLV-1-associated myelopathy/tropical spastic paraparesis (HAM/TSP). The HTLV-1 Tax regulatory protein plays a critical role in HTLV-1 persistence and pathogenesis; however, the underlying mechanisms are poorly understood. Here we show that Tax dynamically regulates mitochondrial reactive oxygen species (ROS) and membrane potential to trigger mitochondrial dysfunction. Tax is recruited to damaged mitochondria through its interaction with the IKK regulatory subunit IKBKG/NEMO and directly engages the ubiquitin-dependent PINK1-PRKN/parkin pathway to induce mitophagy. Tax also recruits autophagy receptors CALCOCO2/NDP52 and SQSTM1/p62 to damaged mitochondria to induce mitophagy. Furthermore, Tax requires PRKN to limit the extent of CGAS-STING1 activation and suppress type I interferon (IFN) induction. HTLV-1-transformed T-cell lines and PBMCs from HAM/TSP patients exhibit hallmarks of chronic mitophagy, and inhibition of PRKN in HTLV-1-transformed cell lines downregulates p19 Gag expression and induces cell death. Collectively, our findings suggest that Tax manipulation of the PINK1-PRKN mitophagy pathway represents a new HTLV-1 immune evasion strategy important for maintaining viral gene expression and cell survival.