心血管科 · 本周文献汇编

The role of the nurse in the heart failure (HF) multi-disciplinary team (MDT) has become well-established, with clear evidence of improved patient outcomes and recommended by professional guidelines. Recognizing the change in the HF landscape since the publication of the first Heart Failure Association (HFA) of the European Society of Cardiology (ESC) HF nurse curriculum in 2016, and the expanding role of HF nurses of in the HF MDT, the HFA in collaboration with the Association of Cardiovascular Nursing and Allied Professions (ACNAP) of the ESC prioritized this update to the curriculum. Standardized training programmes for HF nurses improve the quality of care provided to patients with HF and their caregivers. Recognizing the variability of education background and clinical autonomy across Europe and beyond, this curriculum is designed in a flexible way to be able to be adapted and adjusted based on individual country regulations and forms. Endorsement of this curriculum from national professional bodies or Nursing Councils would ensure uniformity and enhance the profession's contribution to HF care. The updated specialist HF nurse curriculum provides the basis for the advanced level of knowledge, skills and attitudes required for the appropriate expansion of the role of the HF nurse that can be adapted across Europe and beyond, while complying with professional legislation of different healthcare systems and supporting nurses who move between countries.

Left ventricular assist device (LVAD) support has been shown to induce the reversal of neurohormonal changes and myocardial recovery. This study aimed to evaluate the prevalence, predictors, and clinical impact of left ventricular (LV) recovery after LVAD implantation using data from the European Registry for Patients with Mechanical Circulatory Support. Patients with at least one available left ventricular ejection fraction (LVEF) measurement at both baseline and post-LVAD implantation were enrolled. Left ventricular recovery was classified as 'no recovery' if LVEF increase was <5%, 'mild' if LVEF increased by 5%-15% with peak LVEF <50%, 'intermediate' if LVEF increased by >15% with peak LVEF <50%, and 'full' if LVEF increased by ≥5% with peak LVEF ≥50%. A total of 1550 patients with a median age of 57 (48-64) years were included. LV recovery occurred mostly within the first year, with marginal probabilities of no, mild, intermediate, and full recovery at 4 years being 51% [95% confidence interval (CI) 48-54%), 41% (95% CI 38-43%), 8% (95% CI 7-9%), and 1% (95% CI 0-1%), respectively]. INTERMACS Classes 2, 3, and 4 [compared with Class 1; hazard ratio (HR) .72, .64, and .51, respectively] were associated with a lower hazard of attaining any LV recovery, whereas renin-angiotensin system inhibitor use was associated with a higher hazard of attaining any LV recovery (HR 1.17; 95% CI 1.00-1.37). Each 10% higher LVEF value during follow-up was associated with an estimated 14% lower instantaneous hazard of all-cause mortality (HR .86; 95% credible interval .75-.98). The cumulative incidence of the composite major adverse cardiovascular event endpoint, including cardiovascular death, late right heart failure, and arrhythmia beyond the first year, was lower across higher LV recovery categories defined according to the LVEF value at 1 year (Gray's test, P = .042). This multicentre European study shows that LV recovery mostly occurs within the first year after LVAD implantation and is associated with better clinical outcomes. Renin-angiotensin system inhibitor use was associated with both any and intermediate/full LV recovery, while combination neurohormonal blockade strategies yielded directionally favourable but imprecise estimates, warranting further study during LVAD support.

Clinical models incompletely capture the molecular pathways driving heart failure (HF) progression. This study evaluated whether molecular risk stratification provides incremental prognostic information beyond established clinical predictors in patients with HF. A total of 2432 patients from the Global Congestive Heart Failure (G-CHF) registry with available genotyping, DNA methylation, and proteomic profiling were analysed. Three molecular scores were assessed: a composite cardiovascular polygenic risk score (PRS) from DNA sequence polymorphisms, a methylation risk score (MRS) derived from epigenome-wide associations, and a 23-protein-based score (ProteomicDeath23). Each score was tested individually and in combination with the clinical Meta-Analysis Global Group in Chronic Heart Failure (MAGGIC) risk score and N-terminal pro-B-type natriuretic peptide (NT-proBNP) levels for mortality prediction. Validation was performed in an HF subset of the UK Biobank (UKB). Over a median follow-up of 3.0 years in G-CHF, 523 patients died from any cause (7.64 per 100 person-years [PY]). In multivariable analyses, ProteomicDeath23 was the strongest independent predictor of all-cause mortality (hazard ratio [HR] per 1 standard deviation, 2.23), outperforming NT-proBNP (HR 2.00), MRSMortality (HR 1.66), PRSmetaCVD (HR 1.10), and the MAGGIC score (HR 1.70). A model combining ProteomicDeath23 with MAGGIC and NT-proBNP achieved the highest discrimination for mortality (C-index, 0.77). Addition of MRSMortality to this proteomic-clinical model resulted in only small improvements in discrimination (ΔC-index, +0.004, P = .0039), while the PRSmetaCVD provided no incremental benefit. Among patients with low NT-proBNP/MAGGIC score, mortality rates increased from 1.71 to 8.12 per 100 PY across ProteomicDeath23 tertiles. Consistent results were observed in the UKB-HF validation cohort. A proteomic score was the strongest molecular predictor of mortality in HF. Integrating proteomic signatures with clinical risk factors significantly improved risk prediction.

Durable left ventricular assist devices (dLVAD) remain a lifesaving therapy in patients with stage D heart failure that is refractory to conventional medical therapies. Owing to improvements in technology and patient outcomes, the number of patients supported with dLVADs has increased over the past decade. Despite this growing population, there are few resources for cardiovascular intensivists that integrate epidemiology, diagnostic workup and multidisciplinary medical management of acute emergencies in patients supported with dLVADs.

Heart failure with reduced ejection fraction (HFrEF) remains a major therapeutic challenge. B-cell lymphoma 2-associated transcription factor 1 (Bclaf1) is implicated in RNA splicing and cardiac disease, but its role in HFrEF pathogenesis is unknown. Here, we demonstrate that Bclaf1 expression is elevated in human HFrEF myocardium and in male murine pressure-overload models. Cardiac-specific Bclaf1 overexpression drives pathological hypertrophy and systolic dysfunction, whereas its genetic knockout or adeno-associated virus serotype 9 (AAV9)-mediated knockdown attenuates these phenotypes. Mechanistically, Bclaf1 interacts with the splicing factor serine/arginine-rich splicing factor 2 (Srsf2) to bind to heart and neural crest derivatives expressed 2 (Hand2) pre-mRNA and enhance its splicing efficiency, leading to increased mature Hand2 levels and maladaptive remodeling. Inhibition of either Bclaf1 or Hand2 rescues cardiac function and structure in experimental HFrEF. Our work defines a Bclaf1/Srsf2/Hand2 splicing axis as a critical driver of HFrEF and reveals a promising therapeutic target for heart failure.

Heart failure remains a major global health burden, driven largely by pathological cardiac hypertrophy. Mitochondrial dysfunction, particularly impaired mitochondrial complex I activity, is central to the disease progression, yet its regulatory mechanisms are poorly understood. Cross-species transcriptomic screening and UK Biobank analyses identified SBK2 (Src homology 3 domain-binding kinase 2) as a conserved, cardiac-enriched kinase potentially linked to heart failure risk. We hypothesized that SBK2 regulates cardiac hypertrophy by modulating mitochondrial complex I function. Cross-species conserved genes were identified from Gene Expression Omnibus (GEO) data sets, and variants within ±10 kb of SBK2, ADAMTSL2 (ADAMTS-like protein 2), LOX (lysyl oxidase), and SPP1 (secreted phosphoprotein 1) were assessed for heart failure association in the UK Biobank cohort. SBK2 expression was examined in experimental models and publicly available human hypertrophic cardiomyopathy data sets, and its function was investigated through loss- and gain-of-function studies in cardiomyocytes and mice. The substrates and interacting partners of SBK2 were identified by proteomic and interactome analyses and validated by in vitro kinase assays and coimmunoprecipitation. Mitochondrial protein import and respiratory supercomplex assembly were assessed by biochemical fractionation and blue native PAGE. SBK2 expression was reduced in hypertrophic hearts and primary neonatal rat ventricular myocytes. Cardiomyocyte-specific overexpression of SBK2 attenuated hypertrophy and fibrosis, improved systolic function, and suppressed maladaptive gene expression. Conversely, SBK2 knockdown exacerbated these phenotypes. Mechanistically, SBK2 directly bound and phosphorylated NDUFV1 (NADH: ubiquinone oxidoreductase core subunit V1) at serine 251. This modification enhanced the interaction between NDUFV1 and the cytosolic chaperone HSPA1A (heat shock protein family A [Hsp70] member 1A) and facilitated TOM70 (translocase of outer mitochondrial membrane 70)-dependent mitochondrial import. Increased mitochondrial NDUFV1 promoted complex I activity, respiratory supercomplex assembly, oxidative phosphorylation, mitochondrial fusion, and redox homeostasis. Pharmacological inhibition of complex I or NDUFV1 silencing abolished SBK2-mediated protection. Moreover, a phospho-deficient NDUFV1 mutant (S251A) failed to rescue hypertrophic phenotypes in SBK2-deficient cardiomyocytes. SBK2 is an upstream kinase that couples cytosolic signaling to mitochondrial protein import by phosphorylating NDUFV1, thereby sustaining complex I integrity and mitochondrial function to restrain pathological cardiac hypertrophy. These findings uncover a previously unrecognized SBK2-NDUFV1 signaling axis linking kinase signaling to mitochondrial proteostasis and identify a potential therapeutic target for heart failure.

Heart failure with preserved ejection fraction (HFpEF) is a poorly understood, multisystem disease with high morbidity and mortality. To improve understanding of its pathobiology, we analyzed single-nucleus RNA sequencing in human HFpEF myocardium versus controls. Septal myocardial biopsies from 19 HFpEF and 24 nonfailing controls were analyzed using the 10× Genomics Chromium platform, with nuclei isolated from combined samples (6 patients/pool). Genotype-based demultiplexing was performed with souporcell, and gene expression was quantified with CellRanger and CellBender. After quality control, nuclei were annotated by cell types, and differential expression was performed between HFpEF versus controls using limma-voom. Functional analysis was performed using Gene Set Enrichment Analysis. Data were compared with prior single-nucleus RNA sequencing in dilated cardiomyopathy versus controls. We successfully demultiplexed pooled myocardial biopsies, assigning >70% of nuclei to individuals. After quality control, we recovered 48 886 nuclei and identified 14 cell types. Many differentially expressed genes across cell types were detected in HFpEF versus controls (fibroblasts, 5905; cardiomyocytes, 5159; endothelial cells, 2143; pericytes, 1812; and macrophages, 1405). Enriched pathways common to multiple cell types included immune activation, transcription/translation, metabolism, and protein quality control. They were particularly shared between cardiomyocytes and fibroblasts. Vascular smooth muscle cells had a more synthetic, proliferative phenotype. Immune cell analyses suggested enhanced T-cell activation and reduced macrophage clearance programs. Comparative analysis between HFpEF and dilated cardiomyopathy identified transcriptional differences primarily in cardiomyocytes. Two of 3 cardiomyocyte differential expression genes unique to HFpEF were validated to have concordant protein expression changes in HFpEF (MAP2K6 and PLPP3). Our findings reveal a distinct, cell-type-specific transcriptomic landscape in the human HFpEF myocardium. While HFpEF and dilated cardiomyopathy share significant molecular pathways across most cell types, the profound divergence within cardiomyocytes suggests a unique pathological driver for HFpEF. These signatures may provide a high-resolution roadmap for identifying precision therapeutic targets in HFpEF.

Adenosine, acting through A1 adenosine receptors (A1ARs), exerts anti-adrenergic effects by inhibiting β1-adrenergic receptor (β1AR)-mediated cyclic adenosine monophosphate (cAMP) production and contractility in the heart. While the functional interaction between A1ARs and β1ARs is well established in both atrial and ventricular myocytes, the subcellular compartmentalization of this crosstalk and how it is disrupted in heart failure (HF) remains incompletely understood. This study investigates the spatial confinement of A1AR-β1AR signalling within atrial microdomains and assesses how structural remodelling in HF alters this regulatory axis. Quantitative polymerase chain reaction (qPCR) analysis revealed that A1AR is the predominant adenosine receptor subtype in both rat and human atrial tissues. In healthy rat and mouse atrial myocytes, A1AR activation reduced β1AR-induced cAMP production and sarcomere shortening, with suppression of cAMP signals at sarcolemmal microdomains enriched in protein kinase A Type II. This was further supported by scanning ion conductance microscopy-guided scanning patch-clamp, which showed that A1AR suppressed β1AR-driven L-type Ca2+ channel activity at both T-tubule and crest membrane domains. In atrial myocytes isolated from failing rat and human hearts, A1AR-mediated inhibition of β1AR-induced cAMP production and contractility was impaired. Caveolar disruption by methyl-β-cyclodextrin in rat atrial myocytes or via cardiac-specific caveolin-3 (Cav3) knockout in mice abolished this A1AR-mediated inhibition. Notably, cholesterol repletion alone did not restore membrane cAMP regulation, whereas Cav3 overexpression rescued A1AR-dependent suppression, supporting a requirement for Cav3-dependent organization. In mouse atrial preparations isolated from failing hearts, high-resolution optical mapping showed that A1AR-mediated anti-adrenergic regulation of Ca2+ cycling was selectively lost in the intercaval region, correlating with the regional absence of T-tubule and downregulation of caveolae structures. A1ARs provide anti-adrenergic restraint of β1AR signalling through Cav3-dependent membrane organization. In HF, regional caveolar disorganization uncouples this protective pathway, contributing to spatially heterogeneous Ca2+ dysregulation in the atrium.

Heart failure with preserved ejection fraction (HFpEF) continues to increase in prevalence and has limited treatment options. HFpEF is a systemic condition with a broad phenotype including diastolic dysfunction, pulmonary oedema, exercise intolerance, and left ventricular hypertrophy, collectively resulting in enhanced morbidity and mortality. The transcription factor RUNX1 has recently been identified as a mediator of pathological changes in multiple cardiac diseases; however, its role in HFpEF remained unknown. Here, we show that inhibition of Runx1 limits adverse cardiac remodelling in a mouse model of HFpEF. Cardiomyocyte-specific tamoxifen-inducible Runx1-deficient mice with HFpEF are protected, with preservation of diastolic function, and attenuation of pulmonary oedema, exercise intolerance, and hypertrophy. Furthermore, targeting Runx1 in HFpEF by using gene transfer or small-molecule inhibitor Ro5-3335 improves diastolic function and reduces pulmonary oedema, both in female and male mice. Overall, this work enhances our understanding of RUNX1 in cardiac disease and presents a novel translational target for the treatment of HFpEF.

Heart failure with preserved ejection fraction (HFpEF) accounts for approximately half of all heart failure cases and predominantly affects older individuals, yet effective treatments remain limited. The molecular mechanisms linking cardiac aging to HFpEF are not fully understood. Here we show that the transcriptional regulator Sub1 is upregulated in aged hearts and in mouse models of HFpEF. Cardiac overexpression of Sub1 shortens lifespan, exacerbates diastolic dysfunction, and accelerates cardiac aging, whereas Sub1 knockdown delays cardiac aging and alleviates HFpEF features, even when initiated in aged mice. Mechanistically, Sub1 interacted with TAF9b and AROS to stabilize p53 by regulating its ubiquitination and acetylation, thereby promoting cardiomyocyte senescence. Furthermore, disrupting the Sub1-p53 interaction attenuates cardiomyocyte senescence in vitro. These findings identify Sub1 as a contributor to aging-associated HFpEF and provide insight into the molecular links between cardiac aging and disease progression.

Enhanced late Na+ current (INa,L) in heart failure (HF) contributes to cardiomyocyte proarrhythmia. In addition to CaMKII (Ca2+/calmodulin-dependent protein kinase II), FGF (fibroblast growth factor) homologous factors 1-4 (FHF1-4) also modulate INa,L, and targeting these pathways may provide benefits in HF. Reverse-transcriptase quantitative polymerase chain reaction analysis of cardiac Na+ channel and FHF splice isoforms was performed in human arrhythmogenic HF with reduced ejection fraction (HFrEF) and in translational animal models of HFrEF and HF with preserved ejection fraction (HFpEF). We tested the effects of an engineered peptide, FixR (FHF inhibiting x region), on cardiomyocyte INa,L and electrophysiology in rabbit HFrEF and murine models of HFrEF and HFpEF. We also tested the in vivo electrophysiological effects of FixR via adenoviral delivery in transgenic mice with cardiomyocyte-specific overexpression of CaMKIIδC. Expression of key FHF long isoforms (FHF1A in humans, FHF2S in rabbits, and FHF2VY in mice) that have inhibitory effects on INa,L was reduced in human, rabbit, and murine failing hearts. INa,L was markedly enhanced in both HFrEF and HFpEF, and the FixR cell-penetrating peptide significantly reduced pathological INa,L in both forms of HF. FixR had no effect on transient peak Na+ current, L-type Ca2+ current, or major K+ currents in rabbit ventricular myocytes. FixR markedly attenuated proarrhythmogenic action potential changes (increased action potential duration, short-term variability, and alternans susceptibility) and delayed afterdepolarizations in both rabbit and murine HFrEF and HFpEF cardiomyocytes. These cellular antiarrhythmic effects were mimicked by the selective INa,L inhibitor GS967 and the CaMKII inhibitor AIP (autocamtide-2 inhibitory peptide). FixR also attenuated QT prolongation and in vivo arrhythmia susceptibility in transgenic mice with cardiomyocyte-specific overexpression of CaMKIIδC. In HF, INa,L is increased, and FHF splice isoform expression is altered, allowing a novel mechanism to therapeutically target INa,L. FixR, an FHF1A-derived peptide, is a potent and selective INa,L inhibitor and has antiarrhythmic properties in both HFrEF and HFpEF cardiomyocytes.

Sudden cardiac death (SCD) remains a devastating but potentially preventable outcome in inherited cardiomyopathies. Although its absolute incidence is low, the possibility of preventing SCD through implantable cardioverter-defibrillators renders accurate arrhythmic risk stratification a central clinical priority. Risk prediction is evolving from phenotype-based stratification towards individualized approaches integrating genotype, imaging biomarkers, and clinical variables. This review critically evaluates available SCD risk prediction models across cardiomyopathy subtypes, including well-validated tools for hypertrophic cardiomyopathy (HCM) and arrhythmogenic right ventricular cardiomyopathy (ARVC), as well as emerging gene-specific models. We explore key methodological concepts and highlight limitations, such as data sparsity, endpoint heterogeneity, overfitting, and the lack of robust external validation. The application of fixed risk thresholds across diverse patient populations poses ethical and clinical challenges, particularly when competing risks such as heart failure or non-cardiac death are not adequately considered. Synthesis of aggregate data and graphical illustrations show how risk trajectories and mortality drivers differ by genotype and disease stage. Despite recent progress, most models are not yet embedded in routine care. Future advances will require dynamic, longitudinal, and multimodal models, designed for transparency, patient-centred decision making, and real-world implementation to meaningfully reduce mortality in cardiomyopathies.

Left ventricular non-compaction (LVNC) is a genetic cardiomyopathy with presentations ranging from asymptomatic disease to heart failure, stroke, and sudden cardiac death. LVNC-related structural and functional abnormalities may increase atrial fibrillation (AF) risk, but data are limited. We assessed AF incidence in LVNC and compared outcomes in patients with versus without AF. Two cohorts of patients were identified using the TriNetX platform: (i) patients with LVNC without a prior history of AF or stroke; and (ii) patients with LVNC and AF without a prior history of stroke. The primary objective was to assess the 3-year risk of a composite of all-cause mortality, stroke, acute myocardial infarction, and heart failure in the two cohorts. Hazard ratios (HRs) were derived from univariable cox proportional models before and after propensity score matching (PSM). Matching was conducted using a greedy nearest-neighbour approach with a caliper of 0.1.Patients with LVNC and AF (N=29,356) were older and exhibited a higher burden of comorbidities compared with LVNC patients without AF (N=39,339). In this observational analysis, after PSM, AF in patients with LVNC was associated with higher risks of stroke (HR 1.466, 95% CI 1.359-1.581), new-onset heart failure (HR 1.439, 95% CI 1.358-1.526), all-cause death (HR 1.255, 95% CI 1.200-1.312), and the composite outcome (HR 1.301, 95% CI 1.269-1.334) compared with LVNC patients without AF. The 1-year incidence of AF in patients with LVNC was 36 per 1000 person-years. In this observational cohort, LVNC was associated with a high incidence of AF, and the presence of AF was associated with higher risks of stroke, heart failure, and all-cause death. Further prospective studies are warranted to assess the prognostic impact of AF in patients with LVNC.

Patients with phenotypically mild hypertrophic cardiomyopathy (HCM) do not require symptom management, but may be at an earlier stage in the disease course, with potential to benefit from disease-modifying therapies. However, little is known about the natural history and predictors of major adverse cardiovascular events (MACE). Using the Sarcomeric Human Cardiomyopathy Registry, we identified predictors of incident MACE and characterized disease progression in phenotypically mild HCM. Phenotypically mild HCM was defined as: having shorter disease duration (<10 years since diagnosis or age ≤30 years), no previous MACE, being NYHA functional class I, and having a left ventricular (LV) maximal wall thickness (MWT) <25 mm. These individuals were followed prospectively for the development of symptoms or MACE: atrial fibrillation (AF), malignant ventricular arrhythmia (MVA) (sudden cardiac death, resuscitated arrest, or appropriate defibrillator therapy), heart failure (HF) (cardiac transplantation, LV assist device implantation, LV ejection fraction <35%, or NYHA functional class III or IV symptoms), stroke, or all-cause mortality. Cox regression identified MACE predictors. Linear and latent class mixed models characterized LV remodeling trajectories and risk clusters. Of 2,500 participants with phenotypically mild HCM (mean age 43 years, 31% women) followed for a mean duration of 7 ± 6 years, 534 (21%) developed MACE, including 289 with AF, 69 with MVA, and 193 with HF. Individuals who progressed from NYHA functional class I to ≥ II symptoms during follow-up (n = 585, 23%) were 2.79 times (95% CI: 2.30-3.39 times) more likely to experience MACE. Age at baseline (HR: 1.24; 95% CI: 1.17-1.32 per 10-year increase), body mass index (HR: 1.10; 95% CI: 1.01-1.21 per 5-kg/m2 increase), left atrial (LA) diameter (HR: 1.16; 95% CI: 1.09-1.25 per 5-mm increase), LV MWT (HR: 1.27; 95% CI: 1.10-1.46 per 5-mm increase), and LV outflow tract (LVOT) gradient (HR: 1.08; 95% CI: 1.05-1.12 per 15-mm Hg increase) associated with higher MACE rates. LV late gadolinium enhancement presence was associated with 36% (95% CI: 5%-76%) higher hazard of MACE. Remodeling trajectories during follow-up predicted risk with each 0.5 mm/year steeper increase in LA diameter associating with doubled AF (HR: 2.24; 95% CI: 1.69-2.97) and HF rates (HR: 2.22; 95% CI: 1.62-3.04) and each 0.5 mm/year steeper LV MWT increase associating with doubled MVA rates (HR: 1.92; 95% CI: 1.38-2.69). Higher sustained values and/or steeper increases in LA diameter, LV MWT, or LVOT gradient associated with the highest MACE rates. Approximately 21% of patients with phenotypically mild HCM developed MACE over medium-term follow-up. Older age, symptoms development, and increasing LA diameter, LV hypertrophy, or LVOT gradient associated with MACE, particularly in instances of steeper rate of change. These findings can guide management strategies and inform future studies of disease-modifying therapies.

Trametinib (Trm) is a highly selective mitogen-activated protein kinase kinase (MEK) inhibitor that potently and persistently abrogates extracellular signal-regulated kinase 1/2 activation. Trm initially was used to treat BRAF Val600→Glu (V600E)-mutated melanoma, but its Food and Drug Administration-approved indications are expanding rapidly. Trm generally is well tolerated, but it can cause dose-limiting cardiomyopathy and heart failure. Here, we characterize a mouse model of Trm cardiotoxicity using complementary in vitro approaches to show that Trm induces mitochondrial dysfunction in cardiomyocytes and some cancer cell types. In vivo, Trm caused contractile dysfunction within 3 days and heart failure within 2 weeks. High-resolution respirometry using isolated cardiac mitochondria revealed that Trm compromises oxidative metabolism, in part, through blunted activity of electron transport system complexes. Trm-mediated mitochondrial injury led to the release of mitochondrial damage-associated molecular patterns including mitochondrial DNA in both mice and humans, triggering activation of canonical innate immune pathways including cGAS-STING. In multiple rodent and human cardiomyocyte platforms, Trm diminished mitochondrial respiratory capacity at nanomolar concentrations, but this lesion was reversed by expression of a phosphomimetic signal transducer and activator of transcription 3-S727 construct. We also found that Trm induced mitochondrial dysfunction in some but not all cancer cell lines, identifying a previously unrecognized effect that could contribute to Trm's anticancer efficacy.

Variants in PRKAG2 cause hypertrophic cardiomyopathy and conduction disturbances. Although prior studies associated PRKAG2-related hypertrophy with increased glycogen storage, many hypertrophic cardiomyopathy phenotypes remain unexplained. We aimed to uncover how PRKAG2 variants induce myocyte hypertrophy and electrical changes during early cardiac development. We generated transgenic zebrafish expressing wild-type or pathogenic variant Prkag2 cDNA (TgR299Q) under a myocardium-specific promoter, and examined cardiac electrophysiology, contractile function, and cytoarchitecture during cardiogenesis and in adult hearts. TgR299Q fish showed hypertrophic cardiomyocytes and progressive contractile abnormalities, recapitulating human hypertrophic cardiomyopathy phenotypes. Cardiomyocyte glycogen was elevated in adult but not embryonic hearts. Despite the absence of glycogen accumulation at 6 days postfertilization, TgR299Q hearts showed electrical abnormalities, including reduced conduction velocity and prolonged action potential and Ca2+ transient durations. We observed decreased AMPK (AMP-activated protein kinase) phosphorylation in the TgR299Q hearts. However, AMPK activation did not rescue the electrophysiological abnormalities in TgR299Q. Proximity ligation assays and coimmunoprecipitation identified a physical interaction between AMPKγ2 and myosin, enhanced by the R299Q variant and accompanied by increased AMPKγ2 localization to the myofilament. NCX (Na+/Ca2+ exchanger) inhibition increased Ca2+ duration and diastolic Ca2+ in transgenic zebrafish expressing wild-type Prkag2 cDNA but not TgR299Q hearts, indicating reduced free cytosolic Ca2+ for NCX-mediated extrusion in TgR299Q. These findings suggest that enhanced AMPKγ2-myosin interaction may promote myofilament Ca2+ retention, thereby prolonging Ca2+ transient duration and action potential duration in the mutant. Notably, the myosin inhibitor mavacamten reduced AMPKγ2-myosin interaction in TgR299Q hearts, and both mavacamten and vmhcl knockdown rescued the early electrophysiological abnormalities. The PRKAG2 variant altered cardiac excitability, contractility, and Ca2+ handling during cardiogenesis, independent of glycogen accumulation. Enhanced interactions between AMPKγ2 and myosin contributed to these early changes. Our study revealed a novel link between cellular energy sensing and contractile machinery, with therapeutic potential for modulating contractile function in cardiomyopathies.

Hypertrophic cardiomyopathy (HCM) variants in genes encoding the myosin heavy chain (MHC) (MYH7), myosin light chains (MYL2 and MYL3), and cardiac myosin binding protein-C (cMyBP-C, MYBPC3) lead to cardiac hypertrophy, with abnormal contractility, relaxation, and energy consumption. Here, we defined the structural consequences of pathogenic and benign missense variants in these genes by mapping 233 variants (MYH7, n = 175; MYBPC3, n = 41; MYL2, n = 12; MYL3, n = 5) onto a cryo-EM-based atomic model of the human cardiac thick filament. We identified HCM variants residing in 30 molecular interfaces of the complex thick filament interactome, including the two main interfaces of the myosin interacting-heads motif (IHM), and interfaces involving the MHC, essential and regulatory light chains, and cMyBP-C. None of the 21 variants classified as benign were within interfaces. We demonstrated earlier disease onset and adverse outcomes in HCM patients with pathogenic variants within vs. outside of molecular interfaces, emphasizing their importance in normal thick filament function and improving risk stratification of patients.

Despite the limited resilience of adult mammalian hearts, the heart damaged by inflammation naturally heals in a majority of patients with myocarditis. Therefore, therapeutic activation of intrinsic healing capacity of the heart would be promising as regenerative medicine. Yes-associated protein 1 (YAP) determines organ size by regulating cell proliferation. However, the physiological roles of YAP activation in adult mammalian cardiomyocytes remain unclear. This study aimed to investigate the role of endogenous YAP activation in cardiac remodeling during myocarditis to clarify the molecular mechanisms underlying myocardial recovery. We demonstrate that YAP, which is activated in human cardiomyocytes during the myocardial remodeling after acute myocarditis, plays critical roles in myocardial healing. To elucidate the underlying mechanisms, we utilized a murine experimental autoimmune myocarditis (EAM) model. In cardiomyocyte-specific Yap1-conditional knockout (YAPCKO) mice, myocardial recovery is impaired after EAM with increased apoptotic cell death, fibrosis and ROS production, and reduced cardiomyocyte cell-cycle activity and capillary density. RNA-sequencing analysis demonstrated that IFN-γ/STAT1 signaling is activated in YAPCKO cardiomyocytes in myocarditis. IFN-γ blockade and cardiac-specific STAT1 knockdown restores the above-mentioned adverse phenotypic changes in YAPCKO hearts. Furthermore, in cultured adult mouse cardiomyocytes, the activation of YAP by GA-017, a Lats inhibitor, attenuated IFN-γ signal transduction. Mechanistically, YAP activation suppresses STAT1 nuclear localization and reduces STAT1-mediated transcription. Endogenous YAP acts as a negative regulator of IFN-γ/STAT1 signaling, promoting myocardial repair after myocarditis. Our findings presented here provide novel insights into the molecular regulation of myocardial healing, proposing a novel therapeutic strategy for patients with heart failure after myocarditis.

Influenza infection triggers cardiovascular events, and vaccination confers cardiovascular benefit in high-risk populations. Its role in preventing incident atrial fibrillation (AF) and cardiovascular outcomes in clinical practice remains uncertain. These associations were evaluated using a real-world target-trial emulation framework. A retrospective cohort study was conducted using the TriNetX Global Collaborative Federated Research Data Network including adults with a routine healthcare visit in 2022. Influenza vaccination within the preceding year defined exposure; comparators had no recorded vaccination. A 1:1 propensity score matching across 65 baseline variables was applied. Outcomes included incident AF, cardiovascular events, and mortality, with subgroup analyses by age and baseline cardiovascular disease. After matching, 276 888 patients (138 444 per group) were included with excellent covariate balance. During a mean follow-up of 2.7 ± 0.7 years, influenza vaccination was associated with a significantly lower risk of incident AF [hazard ratio (HR) 0.80, 95% confidence interval (CI) 0.76-0.84; P < .0001]. The absolute annualized incidence of AF was 0.9% in vaccinated patients vs 1.1% in non-vaccinated patients. Vaccinated patients also had lower risks of all-cause mortality (HR 0.85, 95% CI 0.82-0.89), myocardial infarction (HR 0.91, 95% CI 0.86-0.97), incident heart failure (HR 0.92, 95% CI 0.88-0.96), and cardiovascular-related hospitalization (HR 0.97, 95% CI 0.95-0.99). Associations were directionally consistent across age and cardiovascular disease subgroups, without significant effect modification. In a large retrospective observational real-world cohort, influenza vaccination was associated with lower risks of incident AF and multiple cardiovascular outcomes. These findings support vaccination as a potential upstream strategy for AF prevention and highlight the need for randomized trials specifically designed to address AF-related outcomes.

Since its introduction in 2002, left atrial appendage closure (LAAC) has rapidly expanded as an alternative to anticoagulation in patients with atrial fibrillation at high risk of stroke. Harmonized processes for data collection, analysis, and reporting in LAAC trials are essential to enhance research quality and improve clinical practice. The Left Atrial Appendage Academic Research Consortium (LAARC) initiative is an independent collaboration of academic research organizations, cardiology and neurology experts, clinical trialists, and regulatory authorities from the USA, Europe, and Asia. The consortium engaged clinical experts, regulators-including the US Food and Drug Administration (FDA), European Notified Bodies, and Japan's Pharmaceuticals and Medical Devices Agency (PMDA)-and industry leaders to define standardized study elements and endpoints for LAAC trials. Key considerations included alignment with prior Academic Research Consortium initiatives, procedural and mechanistic insights, and clinical relevance. Consensus definitions were proposed for mortality, stroke, bleeding, and device performance, along with composite endpoints for safety and effectiveness. The proposed LAARC consensus definitions aim to standardize endpoint reporting, improve comparability across studies, and support regulatory and clinical trial applications for this evolving therapy through broad dissemination in the peer-reviewed literature.

Atrial fibrillation (AF), a common cardiac arrhythmia, presents significant challenges for early detection and management due to its asymptomatic and paroxysmal characteristics. In this study, we introduce the RetiAF score, a multimodal foundation-model-based biomarker derived from retinal fundus images for early detection of AF. We identified that the RetiAF score demonstrated a robust performance across multi-ethnic, multi-center datasets, achieving AUROCs of 0.8610 and 0.8019 on the UK Biobank (UKBB) development and internal testing datasets, and an AUROC of 0.7803 on an external dataset acquired in Shanghai, China. In addition, we identified that the RetiAF score consistently outperformed the traditional risk scores such as CHARGE-AF (AUROC: 0.7553) and C2HEST (AUROC: 0.7246) for the UKBB internal testing dataset. Multivariable logistic regression and propensity score analyses further demonstrated that the RetiAF score was independently associated with AF risk (p < 0.001). When stratified by higher C2HEST scores (≥3), the RetiAF score achieved an AUROC of 0.9619, highlighting its potential for identifying high-risk patients before the clinical onset of AF. The multimodal hybrid version of RetiAF (Hybrid_RetiAF) score, which incorporated clinical features (e.g., Age, BMI, etc) into the deep learning model, further enhanced predictive performance and achieved AUROCs of 0.8924 and 0.8381 on the UKBB Cohorts. As a secondary exploratory analysis, we evaluated whether RetiAF-derived scores were associated with chronic ischemic heart disease in UKBB, suggesting shared cardio-retinal risk information. These findings underscore the potentials of non-invasive retinal imaging as a scalable tool for AF and cardiovascular risk assessment, offering a promising alternative for large-scale screenings and personalized interventions.

GIM/FP/GP: [Formula: see text] Cardiology: [Formula: see text].

Young athletes and adolescents with high cardiorespiratory fitness appear to have a higher risk of atrial fibrillation (AF), but the extent to which this reflects causal effects or shared genetic, behavioral, and environmental factors remains uncertain. This cohort study with sibling control analysis comprised Swedish men who participated in mandatory military conscription examinations from 1972 to 1995 and completed cardiorespiratory fitness testing. The outcomes were AF and non-AF cardiovascular disease (CVD; eg, stroke and ischemic heart disease), defined as a composite end point of diagnosis or death in the National Patient Register and the Cause of Death Register, until December 31, 2023. Flexible parametric survival models estimated standardized cumulative risk differences (RDs) by deciles of fitness. Among 1 124  049 men (mean age, 18.3 years), 45 179 (4.0%) had a first AF event and 96 404 (8.6%) had a first non-AF CVD event at a median age of 54.8 and 54.4 years. In population-wide analysis controlling for measured confounders, compared with the lowest decile of fitness, the highest decile had a small excess in AF that exceeded the reduction in non-AF CVD during early adulthood, whereas the reduction in non-AF CVD became larger from 45 years of age onwards. In full-sibling comparisons controlling for shared familial factors, the age-dependent trade-off disappeared entirely, leaving no age window with a net cardiovascular disadvantage. Already from 35 years of age, the reduction in non-AF CVD was larger (RD, -0.11% [95% CI, -0.21% to -0.01%]) than the excess in AF (RD, 0.06% [95% CI, -0.01% to 0.12%]). By 65 years of age, the gap further widened, with an even larger reduction in non-AF CVD (RD, -3.91% [95% CI, -5.40% to -2.42%]) compared with the excess in AF (RD, 2.30% [95% CI, 1.15% to 3.45%]). High adolescent cardiorespiratory fitness is associated with a small excess in AF risk during early adulthood that is outweighed by larger reductions in non-AF CVD after controlling for familial confounders. These findings support population-level efforts to improve youth cardiorespiratory fitness and provide reassurance about the safety and benefits of high fitness levels.

Inflammation is associated with atrial fibrillation, but its precise impact on the long-term progression of the atrial fibrillation substrate, also called atrial cardiomyopathy, remains debated. Here, using spatial gene expression analysis, macrophage subpopulations mainly confined to the epicardial fat tissue were identified in the human atria. In a mouse model of obesity and atrial cardiomyopathy, macrophage recruitment was associated with atrial adiposity. Single-cell RNA sequencing allowed the identification of Lyve1+-resident and CCR2+ monocyte-derived macrophages in obese mouse atria. In obese mice, depleting Lyve1+-macrophages prevented early fat expansion and led to myocardial dystrophy, while CCR2+-macrophage depletion prevented fibro-fatty remodeling, atrial dilation, and atrial fibrillation. These data highlight the pivotal role of macrophages in atrial adiposity, in particular that of Lyve1+-macrophages during adipose tissue expansion.

Viral infections may influence stroke pathophysiology. Several infections have been linked to increased risk of stroke, however our understanding of these viral interactions with immune and host tissue is limited. We performed a transcriptomic analysis of the blood virome following ischemic stroke to study these interactions. Viruses were measured by RNA sequencing of blood from 37 patients with ischemic stroke and 32 matched controls. RNA reads are aligned against a human reference genome, as well as a comprehensive database of human virus genomes. Host gene expression following stroke is examined in relation to the presence of viral transcripts. Viral RNAs were detected in the blood samples of both ischemic stroke and control groups. Viral reads with a prevalence > 3% and raw counts > 2 were from a total of 6 viral families. This included several human herpesviruses (HHVs), adenoviruses, and papillomaviruses, as well as human pegivirus, respiratory syncytial virus, and human endogenous retrovirus K (HERV-K). Combined, counts from HHVs were higher in stroke compared to control by a fold change of 2.13. Coinfection with multiple HHVs was more common in stroke, with a 1.23 fold increase in the number of detected herpesviruses. Reads from two viral genes were increased in stroke, UL95 from cytomegalovirus (CMV), and EBNA2 from Epstein-Barr virus (EBV). Genes associated with stroke, including APOE, C3, PDGF, and CXCL2 were differentially expressed in stroke samples which contained high counts of one or both of UL95 and EBNA2. Viral RNAs from multiple families can be detected within the human blood virome. HHV transcripts were the most abundant of viral RNAs detected. Among stroke patients, HHV transcripts were more prevalent, with higher counts, and indicated a higher rate of coinfection with multiple HHV species. Expression of the EBV gene EBNA2 and the CMV gene UL95 may relate to changes in immune gene expression following stroke. Further evaluation is needed to determine the effects that the human virome have on stroke risk, immune response to stroke, and long-term outcome.

Cardiac complications rank among the leading contributors to poor outcomes in ischemic stroke patients along with the neurological impairment, while the risk stratification and prognostic significance of post-stroke acute heart failure (PSHF) remain poorly characterized. This study aimed to investigate the incidence, predictors, and impacts of PSHF in patients with large vessel occlusion stroke (LVO) undergoing endovascular treatment (EVT). Given that cardioembolic stroke inherently involves underlying cardiac pathology, a secondary aim was to test whether the effect of stroke severity on PSHF was modified by cardioembolic etiology and whether PSHF mediated the effect of stroke severity on functional outcome in these patients. In a pooled analysis of individual patient data from four multicenter prospective studies conducted in China between January 2014 and June 2023, we included 3,415 patients with LVO who underwent EVT. The primary outcome was very poor functional outcome, defined as 90-day modified Rankin Scale (mRS) 5-6. Multivariable regression models, interaction testing, and mediation analysis were used, with adjustment for clinically relevant covariates including demographic characteristics, vascular risk factors, baseline stroke severity, imaging characteristics, and treatment-related factors. PSHF developed in 278 patients (8.14%), with its incidence reaching peak at 1 day after stroke onset. PSHF was significantly associated with a higher rate of very poor outcome (62.23% versus 31.08%, adjusted odds ratio (aOR) 3.09, 95% confidence interval (CI) [2.25, 4.24]). A significant interaction was observed between cardioembolism and the baseline National Institutes of Health Stroke Scale (NIHSS) score (p for interaction = 0.016). Moderate-to-severe stroke significantly increased the risk of PSHF in patients with cardioembolic stroke (aOR 1.91, 95% CI [1.28, 2.87]), but not in those with non-cardioembolic stroke (aOR 0.97, 95% CI [0.81, 1.82]). Mediation analysis showed that PSHF mediated 7.70% (95% CI [2.40, 12.40]) of the effect of moderate‑to‑severe stroke on very poor outcome among cardioembolic patients. The main methodological limitations were the pooled design using studies with different protocols and the potential for residual unmeasured confounding. PSHF was significantly associated with very poor outcome in LVO patients undergoing EVT. Moderate-to-severe cardioembolic LVO substantially elevated the risk of PSHF, with PSHF partially mediating the adverse prognostic impact of stroke severity. Early risk assessment and monitoring for PSHF may optimize management in this high-risk population.

Brain capillaries sense neural activity and direct blood flow to active regions-a process termed neurovascular coupling that underlies activity-dependent increases in local perfusion (functional hyperemia). A key contributor to functional hyperemic responses is the capillary endothelial cell (cEC) inward rectifier K+ (Kir2.1) channel, which, when activated by neuronal activity-derived extracellular K+, initiates vasodilatory electrical signals that propagate through the vascular network. Kir2.1 channel function requires continual production of its lipid cofactor, phosphatidylinositol-4,5-bisphosphate (PIP2), and is compromised in mouse models of cerebral small vessel (cSVD). Although decreased PIP2 availability is a common feature of cSVDs, mechanisms underlying PIP2 synthesis remain poorly understood. We hypothesized that Arf6, a small GTPase expressed in cECs that stimulates PIP2 production, is critical for this process. Using patch-clamp electrophysiology, we demonstrate that inhibiting Arf6 activity progressively decreased cEC Kir2.1 channel activity. This deficit manifested as loss of capillary-to-arteriole electrical signaling in isolated vessels and diminished functional hyperemia in vivo. Exogenously provided PIP2 restored Kir2.1 currents and functional hyperemia after Arf6 inhibition or genetic knockdown. Collectively, our data suggest that cEC Arf6 sustains Kir2.1 activity by maintaining PIP2 levels and demonstrate that diminished PIP2 synthesis is sufficient to impair functional hyperemia. Furthermore, we identify Arf6 as a mechanistic link between PIP2 production and endothelial electrical signaling, highlighting Arf6 as a potential therapeutic target for restoring functional hyperemia.

Chronic neuroinflammation gives rise to diverse microglial states across the brain, yet how region-specific microglial remodeling contributes to cognitive dysfunction remains unclear. Here we report that synapse-engulfing microglia in the thalamus drive cognitive impairment after cortical brain damage in mice, primarily studied in females. Region-specific manipulations of microglia during the chronic phase show that reactive microglial changes in the thalamus, but not in the hippocampus, impair recognition memory. Single-cell RNA sequencing reveals an enrichment of synapse-engulfing CD9hi microglia in the thalamus. Antibody-based CD9 blockade in the thalamus, as well as microglia-selective CD9 disruption, rescues thalamic synaptic loss, restores neuronal activity, and improves recognition memory. Further analysis shows that the blood-brain barrier disruption and subsequent γ-immunoglobulin (IgG) extravasation facilitate the generation of CD9hi microglia in an Fcγ receptor III-dependent manner. These findings demonstrate that the induction of synapse-engulfing CD9hi microglia in the thalamus by IgG/FcγRIII signaling drives recognition memory deficits following cortical damage.

Patients who survive stroke usually experience rapid muscle wasting and an increased risk of physical disability. Although multifactorial interactions, including malnutrition, disuse, systemic catabolic imbalance, and neurohormonal dysregulation, are thought to contribute to the progression of stroke-related sarcopenia, the underlying mechanisms of this brain-muscle crosstalk remain elusive. Muscle-resident fibro-adipogenic progenitors (FAPs) are indispensable for maintaining muscle homeostasis and function as initial sensors of external perturbations. In the present study, we report that FAPs rapidly respond to the overactive sympathetic nervous system (SNS) and egress from the muscle niche into circulation during the acute phase of stroke. FAP-specific ablation of adrenoceptor beta 2 (Adrb2) markedly ameliorated stroke-related sarcopenia, highlighting the central role of SNS-mediated FAP loss in its pathogenesis. Mechanistically, increased norepinephrine release initiates FAP mobilization through the activation of pro-migratory signals and the degradation of extracellular matrix components. Using transcriptomic profiling, we further characterized insulin growth factor-1 (IGF-1) as a key anti-atrophic executive factor predominantly derived from FAPs. Collectively, our work demonstrates that the SNS-mediated loss of FAPs and subsequent compromised IGF-1 secretion contribute to sarcopenia in mice following stroke. Targeting this mechanism by early anti-sympathetic treatment with propranolol may effectively restore muscle homeostasis and mass after stroke.

Astrocytes regulate brain metabolism and homeostasis, but how oxidative stress reshapes astrocytic metabolism to drive neuronal damage remains unclear. Here, we demonstrate that oxidative stress turns on astrocytic type I collagen (COL1) production via a redox-glycosylation coupling mechanism. Hydrogen peroxide (H2O2) suppresses miR-29 and enhances fucosyltransferase 8 (FUT8)-mediated core fucosylation, integrating post-transcriptional and glycosylation-dependent regulation of COL1. Astrocyte-derived COL1 activates integrin signaling and promotes neuronal death. In a photothrombotic stroke model, an H2O2 surge induces astrogliosis, glycosylation remodeling, and COL1 expression, leading to glial barrier formation, neuronal loss, and neurological deficits. These pathological cascades are mitigated by astrocyte-specific silencing of COL1 or FUT8 or by KDS12025, a peroxidase enhancer that reduces H2O2 burden. Notably, KDS12025 exerts potent neuroprotection in a non-human primate stroke model. Together, our findings identify an unprecedented astrocytic metabolic pathway linking oxidative stress to glycosylation-driven COL1 production, highlighting the H2O2 surge, astrocytic COL1, and FUT8 as promising therapeutic targets for recovery after stroke.

Hypertension and diabetes prevalence are increasing across Africa. We investigated the prevalence, associated factors, achievement of stages within the care cascade (diagnosis, treatment, control), and health-related quality of life (HRQoL) in three countries in Africa. This cross-sectional study recruited adults aged ≥40 years in five settings: rural (n = 1,052) and urban (n = 1,218) The Gambia, rural (n = 948) and urban (n = 968) South Africa (SA), and urban (n = 1,110) Zimbabwe between 2022 and 2024. Data were collected using researcher-administered questionnaires and assessments. Hypertension and diabetes were defined using self-reported diagnosis, medication use, and blood pressure and glucose measurements. HRQoL was assessed using EuroQol-5 Dimension 5 Level questionnaire, with a minimally important difference (MID) defined as half a standard deviation (SD). Diabetes complications included neuropathy, cardiovascular disease, and kidney disease. Associations between hypertension and diabetes and risk factors were assessed using study site, age, sex, educational attainment, and wealth index-adjusted Generalised Linear Mixed Effects Models. Associations between care cascade stages and HRQoL were assessed using linear models. Analysis included 5,296 adults, 53% female, and 52% age ≥60 years. Overall hypertension prevalence was 55.6% (95% confidence intervals [CI] 54.2%-56.9%); ranging from 39.6% (95% CI: 36.7-42.7) in rural The Gambia to 66.9% (64.1-69.7) in urban Zimbabwe. Overall, diabetes prevalence was 14.0% (13.1%-15.0%), ranging from 9.2% (7.6-11.0) in urban Zimbabwe to 19.4% (16.9-22.1) in rural SA. Both overweight and obesity, compared to normal weight, were associated with higher odds of hypertension (adjusted odds ratios: 1.73 (95% CI [1.47, 2.03]; p < 0.001) and 2.08 (95% CI [1.74, 2.49]; p < 0.001), respectively and diabetes (1.53 (95% CI [1.22, 1.91]; p < 0.001) and 2.12 (95% CI [1.67, 2.69); p < 0.001), respectively. The proportion with treated and controlled hypertension was 31.0% (913/2944), with 27.2% (800/2944) undiagnosed, and 26.0% (766/2944) treated but uncontrolled. Overall, 21.9% (161/735) had treated and controlled diabetes, whilst 49.7% (365/735) were undiagnosed, and 15.4% (113/735) were diagnosed and untreated. Underdiagnosis and inadequate treatment and control of both diseases were more common in men and in The Gambia. Overall, hypertension targets of 80-80-80% in diagnosis, treatment, and control were 72.8%(2144/2944), 78.3% (1679/2144), and 54.4% (913/1679), respectively. Diabetes targets of 80-80-80-60% in diagnosis, glucose control, hypertension control, and statin use were 50.8%(377/742), 65.7% (243/370), 60.4% (224/371), and 17.8% (67/377), respectively. For both disease targets, South Africa performed better than The Gambia and Zimbabwe. The overall mean±SD HRQoL utility score was 0.829 ± 0.107 (MID = 0.054). Compared to being nonhypertensive, having diagnosed and untreated hypertension was associated with a -0.07 (95%CI [-0.05, -0.08]; p < 0.001) lower HRQoL utility score. Compared to being nondiabetic, having treated and controlled diabetes was associated with lower HRQoL: -0.07 (95% CI [-0.01, -0.13]; p = 0.028) in The Gambia and -0.08 (95% CI [-0.03, -0.12]; p < 0.001) in Zimbabwe. Having ≥1 complication was associated with lower HRQoL: -0.04 (95% CI [-0.03, - 0.05]; p < 0.001). Study limitations are the cross-sectional design and reliance on single measurements of blood pressure and glucose concentrations. The high prevalence of hypertension and diabetes in mid-age and older adults in rural and urban Africa necessitates urgent diagnostic, preventive, and control interventions. This can include interventions targeted at obesity, screening of all adults aged ≥40 years, prompt and optimal treatment for those diagnosed, and ongoing monitoring to limit complications.

Both high and declining blood pressure (BP) are associated with risk of cognitive decline in older adults, and women have higher rates of hypertension and faster cognitive decline in late-life. In old age, the relationship between changes in BP and changes in cognition is complex, and although sex differences in cognitive function and decline are recognized, little is known about the relationship of longitudinally collected BP and cognition, simultaneous changes in BP and cognition, or whether they differ by sex. We investigated the association of simultaneous change in BP and cognition in older adults followed annually for an average of 9 years. A total of 4,719 older adults without baseline dementia (mean age = 76.7 [standard deviation = 7.7] years; 74% women) from 5 prospective community-based cohort studies completed annual assessments of BP and cognition, yielding composite global and 5 domain-specific scores. BP and cognition were modeled simultaneously using joint bivariate linear mixed-effects models. Among 3,502 women and 1,217 men, faster decline in systolic BP was associated with faster decline in global cognition (r = 0.20, p < 0.01). Stratified models revealed a stronger relationship in women (r = 0.26, 95% confidence interval [CI]: 0.17-0.37) than men (men: r = 0.01, 95% CI: -0.13 to 0.11). In secondary analyses, decline in systolic BP was related to decline in 5 cognitive domains in women but none in men. This large longitudinal study reports evidence of a relationship between simultaneous decline in systolic BP and cognition in women, but not men. As women experience a disproportionate burden of both hypertension and cognitive decline in late-life, declining systolic BP, a routine clinical measure, may serve as an important indicator of concurrent cognitive decline in older women. Understanding these sex-specific associations may help advance the understanding of drivers behind sex differences in cognitive decline. ANN NEUROL 2026.

To compare the effects of exercise training modalities on 24-hour ambulatory blood pressure in adults with hypertension. Systematic review and network meta-analysis. MEDLINE, Embase, Cochrane Central and Regional Portal of the Virtual Health Library were systematically searched from November 2024 to August 2025. Randomised controlled trials evaluating the effects of exercise training (intervention duration ≥4 weeks) compared with a non-exercise control condition or another exercise modality on 24-hour systolic and diastolic blood pressure were included. 31 trials were included, with 67 arms and 1345 participants. In the network meta-analysis, compared with the control, combined training (mean difference (MD) -6.18 mm Hg, 95% credible interval (CrI) -11.45 to -1.21), aerobic training (MD -4.73 mm Hg, 95% CrI -7.53 to -2.01), and high-intensity interval training (MD -5.71 mm Hg, 95% CrI -11.31 to -0.002) reduced 24-hour systolic blood pressure. Reductions in 24-hour diastolic blood pressure were observed with combined training (MD -3.94, 95% CrI -6.47 to -1.34), aerobic training (MD -2.76, 95% CrI -4.21 to -1.34), high-intensity interval training (MD -4.64, 95% CrI -8.21 to -0.72) and pilates (MD -4.18, 95% CrI -7.18 to -1.17). Exercise-versus-exercise comparisons were inconclusive with respect to superiority between modalities. Aerobic training (continuous and interval) and combined training significantly reduced 24-hour blood pressure. Evidence for dynamic and isometric resistance training remains uncertain. Data on non-conventional exercise modalities such as pilates and recreational sports are limited and imprecise for the management of ambulatory blood pressure.

Obstructive sleep apnoea-hypopnoea syndrome (OSAHS) has emerged as a global epidemic with profound cardiovascular and renal consequences, yet its early pathogenic mechanisms remain poorly understood. Whether red blood cells (RBCs) act as the primary hypoxia sensor that transduces intermittent apnoea into irreversible outcomes remains enigmatic. This study aims to define the pathogenic nature of RBCs during the progression of OSAHS with a goal of identifying early biomarkers and targeted treatments to prevent detrimental outcomes. A large OSAHS cohort and matched controls underwent quantification of RBC O2 off-loading capability and nitric oxide (NO) bioactivity. Untargeted metabolomics and [13C6, 15N4] arginine flux mapping identified specific metabolic pathway bottlenecks. The effect of OSAHS erythrocytes on endothelial function was evaluated by measuring acetylcholine-induced vasodilation in rat aortic rings incubated with the erythrocytes and perfused in a microfluidic system. Erythrocyte-specific sphingosine kinase-1 knockout mice (eSphK1-/-) and controls were exposed to chronic intermittent hypoxia (CIH). Therapeutic studies include a preclinical manipulation with the arginase inhibitor nor-NOHA, and a pilot continuous positive airway pressure (CPAP) observational study. OSAHS patients display dysfunctional RBCs with reduced O2 delivery and NO bioactivity alongside excessive oxidative stress, driven by impaired glucose and arginine metabolism. Moreover, arginine metabolism is preferentially channelled into ornithine and urea rather than NO production due to reduced endothelial nitric oxide synthase (eNOS) activity. Dysfunctional RBC-mediated blunted endothelium-dependent vasodilation is rescued by co-infusion of sodium nitroprusside (SNP) and pretreatment with S1P or nor-NOHA. These RBC anomalies correlate with peripheral hypoxia, hypertension, and metabolic disorders in patients and precede measurable hypertension and tissue damage in a CIH-exposed OSAHS murine model. Preclinically, nor-NOHA restores RBC-NO bioactivity and O2 delivery, normalizes blood pressure, and prevents tissue fibrosis. A three-circulating-metabolite fingerprint, including sphingosine, S1P, and arginine, is validated as an early and sensitive biomarker for its diagnosis and stratifies OSAHS severity. Genetically, CIH-challenged eSphK1-/- mice exhibit decreased eNOS activity and O2 offload capacity, severe tissue hypoxia, hypertension, and fibrosis. Mechanistically, this study revealed that decreased intracellular S1P and AMPK activity underlie reduced eNOS activation in RBCs of OSAHS by blocking its trafficking from the membrane to the cytosol and phosphorylation. In contrast, CPAP-treated patients exhibited lower erythrocyte dysfunction and arginine and sphingolipid metabolic impairment compared to untreated OSAHS patients. Altogether, this study demonstrates that OSAHS is a systemic RBC disease in which S1P-mediated O2 delivery and eNOS trafficking act as the master toggle between physiological O2 delivery and hypoxic vasculopathy. Circulating S1P, sphingosine, and arginine configuration constitute a sensitive metabolic signature enabling early diagnoses, while pharmacological or CPAP-mediated repair of the RBC S1P-eNOS axis offers precision cardiovascular and renal protection upstream of irreversible vascular injury.

The carotid body (CB) is a multimodal chemosensory organ, yet how it encodes differential external stimuli to drive distinct peripheral chemoreflex responses remains unclear. This study aimed to define differences in intrinsic cellular mechanisms underlying CB signalling and to investigate how these processes are altered in pre-hypertension. We used potassium cyanide (KCN) as a hypoxia mimetic to activate the CB.K+ channels implicated in hypoxia sensing were pharmacologically inhibited, with TWIK-related acid-sensitive K+ (TASK) channels targeted using Ba2+ or ML365 and BK/Kv channels targeted using TEA + 4AP or iberiotoxin. We combined in vitro Ca2+ imaging of dissociated glomus cells, ex vivo carotid sinus nerve (CSN) recordings, and an in situ double-perfused working heart-brainstem preparation to investigate chemosensory signalling in juvenile Wistar and age-matched pre-hypertensive spontaneously hypertensive rats (SHRs). KCN application to the CB ex vivo evoked a biphasic CSN response, consisting of two temporally distinct components. This biphasic response was exaggerated in SHRs, with disproportionate changes in the magnitude of each component. Ca2+ imaging revealed that these components reflect distinct glomus cell subpopulations, characterized by transient vs. prolonged KCN-evoked Ca2+ events, with their relative proportions shifted in hypertension. Pharmacological dissection suggested that differential inactivation of K+ channels contributes to these divergent Ca2+ dynamics. In situ, we confirmed that localized Ba2+ applied to the CB facilitated stronger tachypnoeic and bradycardic chemoreflex evoked responses than TEA + 4AP, consistent with functional heterogeneity among glomus cell populations. Compared with Wistar rats, in vitro TASK and BK/Kv channel expression and activity were differentially altered in SHRs, accompanied by corresponding changes in in situ chemoreflex characteristics. We identify, for the first time, distinct glomus cell subpopulations defined by their K+ channel expression that differentially contribute to CB signalling patterns and distinct chemoreflex pathways. These findings provide mechanistic support for the recently proposed 'ribbon cable' hypothesis, whereby discrete glomus cell populations couple to specific chemoreflex outputs. These findings offer new insight into CB signalling complexity and its role in autonomic dysfunction during the early stages of hypertension.

Innate and adaptive immune cells play important roles in the pathogenesis of hypertension. B cells play a crucial role in mammalian adaptive immunity via processing antigens and producing antibodies. However, whether B cells and immunoglobulins are involved in regulating blood pressure in hypertension remains unclear. We aimed to reveal the protective role and the potential immunoregulatory mechanisms of B1a cells in hypertension. Wild-type and CD19 knockout (CD19-/-) mice received angiotensin II (Ang II) to induce hypertension. Blood pressure measured by radiotelemetry and tail cuff. Vascular damage was assessed by histology and immunofluorescence. Immune cells were analyzed by flow cytometry. Adoptive transfer of different B-cell subsets was performed. In vitro cocultures examined B1a cell effects on CD4+T cells. We found that the frequency of B1a cells was reduced in the blood and peritoneal cavity in wild-type mice after Ang II infusion. We showed that CD19-/- male mice, which exhibit a marked reduction in B1a cells, largely exacerbated the elevation of both systolic and diastolic blood pressures after Ang II treatment compared with wild type. Vascular dysfunction and damage, including CD4+T cells and macrophage accumulation, aortic structural remodeling, and fibrosis, were worse in CD19-/- male mice compared with wild-type male mice in response to Ang II. Adoptive transfer of B1a cells, but not B2 cells, protected against Ang II-induced hypertension and vascular damage. The serum level of IgM was reduced in CD19-/- mice but increased after transferring with B1a cells. In vitro, B1a cells and natural IgM inhibited the activation and IFNγ (interferon gamma) production of CD4+T cells. Furthermore, transferring B1a cells deficient in the secretion of IgM blocked the protective effects in response to Ang II infusion. Our data demonstrated that B1a cells play a protective role in the development of hypertension via producing natural IgM and inhibiting IFNγ production by CD4+T cells.

Despite rapid percutaneous coronary intervention (PCI) for ST-segment elevation myocardial infarction (STEMI), large infarcts contribute to heart failure and mortality. Left ventricular (LV) wall tension and load are major determinants of infarct size. Preclinical studies identified that delaying reperfusion to permit LV unloading with a transvalvular microaxial flow pump (TV-mAFP) reduces infarct size. We tested whether this combination reduces infarct size compared with reperfusion alone in patients with anterior STEMI without cardiogenic shock. The STEMI-Door to Unload (DTU) pivotal trial tested the central hypothesis that the combination of mechanical LV unloading plus a 30-minute delay before PCI reduces infarct size compared with immediate PCI alone in patients with anterior STEMI without cardiogenic shock. We conducted an open-label, randomized controlled trial at 55 hospitals in the United States, Germany, Italy, United Kingdom, Switzerland, and Canada. Adults aged 18 to 85 years with no prior myocardial infarction and presenting with acute anterior STEMI within 1 to 6 hours of symptom onset before hospital arrival were eligible for inclusion. Patients were randomly assigned (1:1) by study site personnel to either LV unloading with a TV-mAFP for 30 minutes before PCI (treatment group) or PCI alone (control group). The primary outcome was infarct size normalized to LV mass (IS/LVM) evaluated by cardiac magnetic resonance imaging 3 to 5 days after PCI and was evaluated in all randomized patients. The trial is closed to new participants. Between December 12, 2019 and September 3, 2024, 527 patients were randomized; 262 patients were assigned to the treatment group and 265 to the control group. Mean patient age was 61 ± 11 years, and 417 patients (79.1%) were men. Total ischemic time was longer in the treatment arm. IS/LVM was 30.8% ± 16.2% in the treatment group and 31.9% ± 16.9% in the control group (mean difference: -1.1%; 95% CI: -4.2 to 2.0; P = 0.50). Major bleeding or vascular complications at 30-day follow-up occurred more frequently in the treatment group when compared with either a prespecified performance goal or the control group. Combination of a TV-mAFP plus delayed PCI did not reduce infarct size in patients with anterior STEMI without cardiogenic shock compared with PCI alone. (Primary Unloading and Delayed Reperfusion in ST-Elevation Myocardial Infarction: The STEMI-DTU Trial [DTU-STEMI]; NCT03947619).

Cardiac fibrosis, a common pathological outcome of various heart diseases including myocardial infarction (MI), is primarily driven by the activation and trans-differentiation of cardiac fibroblasts that demand substantial adenosine triphosphate production (ATP) for energy. Although sodium-glucose co-transporter 2 (SGLT2) inhibitors such as dapagliflozin have been shown to improve outcomes in heart failure, their direct impact on cardiac fibrosis, particularly through the modulation of fibroblast energy metabolism remains unexplored. We employed an integrated strategy combining metabolomics and metabolic flux analysis to investigate metabolic reprogramming in cardiac fibroblasts under ischaemic conditions. Our findings confirmed that treatment with an SGLT2 inhibitor confers anti-fibrotic benefits post-MI. Multi-omics analysis identified a key metabolic pathway modulated in fibroblasts from SGLT2 inhibitor-treated mice under ischaemia: the conversion of N-acetyl-glutamate (NAcGlu) to fumarate, catalysed by argininosuccinate lyase (ASL). This pathway serves as a metabolic bridge linking the urea cycle to the tricarboxylic acid (TCA) cycle. Exogenous supplementation with either NAcGlu or fumarate significantly improved cardiac function and reduced fibrosis after MI. In contrast, targeted deletion of ASL in activated cardiac fibroblasts impaired cardiac performance, even with NAcGlu supplementation. Mechanistically, we found that fumarate accumulation under stress presses the TCA cycle in cardiac fibroblasts, resulting in reduced ATP production. These findings identify the NAcGlu/ASL/fumarate axis as an important regulator of fibroblast metabolism and trans-differentiation during ischaemic stress. Our data are consistent with a model in which targeting key metabolites (NAcGlu, fumarate) or enzymes (ASL) in the urea cycle pathway of cardiac fibroblasts may point to a potential therapeutic strategy to combat adverse cardiac fibrosis following MI.

The post-infarction microenvironment, dominated by oxidative stress, hypoxia, and dysregulated inflammation, severely limits cardiac regeneration. Existing injectable hydrogels for myocardial infarction (MI) rarely address these factors simultaneously, and excessive reactive oxygen species (ROS) scavenging may paradoxically cause oxidative damage. To develop an injectable hydrogel capable of concurrently scavenging ROS, sustaining oxygen release, and modulating immune responses without inducing oxidative damage. A chitosan oligosaccharide-hyaluronic acid hydrogel (C-COS-OHA) was synthesized, incorporating a mild Fe3+/adenosine monophosphate (AMP) nano-enzyme for oxygen generation and redox stability. Carboxyl-modified chitosan oligosaccharide (C-COS) was designed to promote M2 macrophage polarization. The hydrogel was evaluated in vitro for oxidative stress protection and hypoxia tolerance, and in MI mouse models for oxygen retention, inflammation modulation, and cardiac repair. Compared with catalase (CAT)-loaded hydrogels, C-COS-OHA-Fe3+/AMP enhanced HUVEC survival by 28.9% under oxidative stress and accelerated scratch closure by 26.9% under hypoxia. In vivo, photoacoustic imaging confirmed prolonged oxygen retention; qRT-PCR revealed a 4.1-fold increase in TGF-β expression. After 28  days, MI mice showed 49% reduced fibrosis, 37% thicker ventricular walls, and improved left ventricular ejection fraction (58.3 ± 3.1%), all exceeding C-COS-OHA-CAT performance. The C-COS-OHA-Fe3++/AMP hydrogel integrates ROS scavenging, oxygen modulation, and immunoregulation into a single injectable platform, representing a shift from single-mechanism MI hydrogels to comprehensive microenvironmental regulation for enhanced cardiac regeneration.

Metabolic disturbances are key contributors to myocardial ischemia-reperfusion (I/R) injury, yet the underlying molecular mechanisms remain largely unclear. Rho family GTPase 3 (RND3), a cytosolic small guanosine triphosphatase (GTPase) known to antagonize ROCK1 (Rho-associated coiled-coil kinase 1), has been implicated in several cardiovascular disorders. However, its mitochondrial localization and functional role in cardiac energy metabolism and I/R injury remain unknown. A murine model of myocardial I/R injury was established through left anterior descending coronary artery ligation. Mice with cardiomyocyte-specific knockout and overexpression of Rnd3 were generated. To investigate the role of RND3 in cardiac metabolism and I/R injury, we used 13C-nuclear magnetic resonance, 18F-fluorodeoxyglucose positron emission tomography/computed tomography scanning, seahorse mitochondrial energy metabolism assays, and 13C-metabolic flux tracing. Mechanistic studies were conducted using RNA sequencing, coimmunoprecipitation, mass spectrometry, and glutathione S-transferase (GST) pulldown assays. Cardiomyocyte-specific deletion of Rnd3 (Rnd3 conditional knockout, Rnd3cKO) resulted in impaired glucose oxidation and compensatory upregulation of fatty acid oxidation, leading to pronounced cardiac dysfunction and increased mortality. Rnd3cKO hearts exhibited reduced pyruvate/malate-driven complex I respiration and marked uncoupling between glycolysis and the tricarboxylic acid cycle. Mechanistically, RND3 was identified as a novel mitochondrial matrix-localized small GTPase that directly binds to ACAT1 (acetyl-coenzyme A [CoA] acetyltransferase), disrupting its interaction with PDHA1 (pyruvate dehydrogenase E1α subunit) and thereby promoting PDHA1 acetylation and glucose oxidation. It is important to note that RND3 expression was significantly downregulated in both human and murine hearts after I/R insult. Loss of RND3 sensitized the hearts to I/R injury, as evidenced by reduced levels of phosphocreatine and ATP. Conversely, cardiac-specific overexpression of Rnd3 conferred protection against I/R injury, an effect that was abolished upon Pdha1 knockdown. Our results identify RND3 as a novel mitochondria-localized regulator of glucose oxidation that safeguards the heart against I/R injury. Therapeutic reconstitution of Rnd3 may represent a promising strategy to restore metabolic homeostasis and mitigate myocardial damage in the context of I/R.

Monocytes/macrophages orchestrate myocardial remodeling through efferocytosis, the calcium-dependent clearance of apoptotic cells. While the mechanosensitive channel Piezo1 is known to modulate calcium influx in cardiac and immune contexts, its myeloid-specific role in postinfarction healing remains elusive. Myeloid Piezo1-specific knockout mice (Piezo1∆LysM) were established, and left anterior descending coronary artery ligation was used to induce myocardial infarction. Cardiac function was detected by echocardiography and magnetic resonance imaging, and infarct size was measured by 2,3,5-triphenyl-tetrazolium chloride staining and hematoxylin and eosin staining. Inflammatory mediators were measured by flow cytometry, immunofluorescence, and real-time polymerase chain reaction. Intracellular Ca2+ measurements and patch-clamp were conducted to detect calcium influx and current. Through single-cell RNA sequencing, the underlying mechanisms of efferocytosis were subsequently validated via Western blot, targeted cell transfection, and macrophage-cardiomyocyte coculture assays. Myeloid-specific Piezo1 deficiency improved cardiac function and alleviated myocardial fibrosis at 3, 14, and 28 days post-myocardial infarction. Moreover, Piezo1 deletion increased production of antiinflammatory cytokines 3 days post-myocardial infarction. Single-cell RNA sequencing revealed that the efferocytosis-associated genes were upregulated in the Piezo1∆LysM group. Mechanistically, myeloid Piezo1 deletion enhanced Orai1 expression and calcium influx, which facilitated macrophage efferocytosis. In vitro, these changes were recapitulated by Orai1 knockdown and Orai1 overexpression in bone marrow-derived macrophages. In vivo, Orai1 knockdown impaired efferocytosis and attenuated cardiac protection, whereas Orai1 overexpression enhanced it. Furthermore, Piezo1 deletion promoted Rac1 activation and cytoskeletal remodeling, thereby enhancing apoptotic cell clearance. In addition, myeloid Piezo1 deletion augmented lysosomal acidification and phagosome maturation, contributing to efficient apoptotic cell degradation. Our study uncovered a previously unrecognized Piezo1-Orai1-Rac1 signaling axis that regulates macrophage efferocytosis and lysosomal maturation following myocardial infarction.

GLP-1 (glucagon-like peptide-1) receptor agonists (RAs) have emerged as a major therapeutic advance in cardiometabolic medicine. Initially developed as glucose-lowering therapies for type 2 diabetes, these agents have demonstrated broad benefits that extend well beyond glycemic control. GLP-1 RAs enhance glucose-dependent insulin secretion and reduce appetite, leading to improved glycemia and sustained weight loss. In addition, GLP-1 signaling exerts vascular and myocardial effects, including improved endothelial function, reduced inflammation and oxidative stress, and favorable changes in cardiac metabolism and remodeling. Large randomized cardiovascular outcomes trials have consistently shown that several GLP-1 RAs reduce major adverse cardiovascular events, including myocardial infarction, stroke, cardiovascular death, and heart failure. Benefits have been observed across diverse populations, including individuals with established cardiovascular disease and those with obesity but without diabetes. Emerging therapies targeting multiple incretin pathways, such as dual GIP (glucose-dependent insulinotropic polypeptide)-GLP-1 RAs, may further extend these benefits. Collectively, these findings suggest that GLP-1 RAs influence multiple cardiometabolic pathways and may shift the underlying metabolic milieu toward a more favorable physiological state. In this Clinical Primer, we review the physiology of GLP-1 signaling, the evidence supporting cardiovascular risk reduction, and practical considerations for the clinical use of incretin-based therapies.

Unblinded studies have demonstrated superior procedural and clinical outcomes of percutaneous coronary intervention (PCI) in focal compared with diffuse coronary artery disease. However, data from the first placebo-controlled study did not demonstrate a differential impact of disease pattern on symptom endpoints. The study sought to test the ability of pattern of coronary artery disease to predict the placebo-controlled efficacy of PCI. In the ORBITA-2 (Objective Randomised Blinded Investigation with Optimal Medical Therapy of Angioplasty in Stable Angina-2) randomized placebo-controlled trial of angioplasty for stable angina, patients underwent prerandomization nonhyperemic pressure wire pullback assessments. Seven blinded interventional cardiologists independently reviewed each pullback trace to categorize disease patterns as focal, diffuse, or mixed. These were assigned numerical values of 1, 0, and 0.5, respectively. Overall disease pattern score was determined by the mean. A score >0.5 was considered focal and ≤0.5 was considered diffuse. Bayesian proportional odds modeling was used. A total of 245 patients with 300 target vessel pullbacks were analyzed. With adjustment for prerandomization nonhyperemic pressure ratio, PCI in focal compared with diffuse disease resulted in greater improvement in angina symptom score (OR: 1.80; 95% credible interval [CrI]: 1.48-2.18; Pr[Benefit] > 99.9%) and daily episodes of angina (OR: 1.55; 95% CrI: 1.26-1.89; Pr[Benefit] > 99.9%). Focal disease also predicted greater placebo-controlled benefit in exercise treadmill time (Pr[Interaction] > 99.9%), Canadian Cardiovascular Society class (Pr[Interaction] = 99.0%), EuroQol Group 5-Dimensions 5-Level questionnaire (Pr[Interaction] = 95.1%), and Seattle Angina Questionnaire angina frequency (Pr[Interaction] = 99.5%). There was weaker evidence of interaction between disease pattern and the placebo-controlled impact of PCI on improvement in dobutamine stress echocardiography score (Pr[Interaction] = 83%). In focal disease, PCI resulted in greater placebo-controlled improvement of symptoms compared with diffuse disease. Physiological patterns of disease may be useful to guide treatment decision making with PCI for symptom relief.

Lipoprotein(a) [Lp(a)] levels are genetically determined and causal in the development of atherosclerotic cardiovascular disease. Whether first-degree relatives (FDRs) of individuals with elevated Lp(a) levels (≥80th percentile) have an increased cardiovascular disease risk is unknown. Based on 41 304 indexes with a routine plasma Lp(a) measurement, 61 715 FDRs without a measured Lp(a) aged 35-69 years (49% women) were identified in the Swedish STRIREG cohort. First-degree relatives were stratified according to index Lp(a) percentile level: <50th, 50-<80th, 80-<95th, and ≥95th. In competing risk-adjusted cumulative incidence and adjusted Cox proportional hazards regressions, the association between Lp(a) strata and major adverse cardiovascular events (MACE; cardiovascular death, myocardial infarction, ischaemic stroke, coronary revascularization) was investigated. In a nested analysis of 4243 indexes with a first-degree relationship with another index, the concordance of plasma Lp(a) levels was assessed. During a median follow-up of 19 (11-26) years, 2043 FDRs had a MACE. The cumulative incidences of MACE in FDR until age of 65 were 6.2%, 7.0%, 7.5%, and 8.1% by increasing index Lp(a) level strata (P < .001). Compared with FDR in the lowest Lp(a) stratum, there was a higher hazard ratio for MACE by increasing Lp(a) stratum: 1.08 (95% confidence interval, 0.97-1.19), 1.30 (1.15-1.47), and 1.28 (1.06-1.55; Ptrend < .001). The Lp(a) concordance was 86% (<80th percentile) and 53% (≥80th percentile). First-degree relatives of individuals with elevated Lp(a) levels have a higher incidence of MACE. Cascade screening could be a feasible strategy to identify FDR at heightened risk.

Peripheral cannabinoid CB1 receptor antagonists that lack central nervous system effects are emerging as promising therapies for metabolic disease, yet the role of endothelial CB1 signaling in atherosclerosis remains unclear. Here, we show that endothelial CB1 is expressed in human atherosclerotic plaques, is induced by oscillatory shear stress in atheroprone flow regions, and promotes vascular inflammation, permeability and lipid uptake. Endothelial-specific Cnr1 deletion or peripheral CB1 antagonism in mice attenuates atherosclerosis, reduces endothelial caveolae-dependent low-density lipoprotein uptake by downregulating caveolin-1 and ALK1 expression, and improves metabolic parameters in brown and white adipose tissue and the liver. The anti-atherogenic and metabolic effects are more pronounced in females, which is possibly linked to estrogen signaling. These findings identify endothelial CB1 as a proatherogenic, sex-biased regulator of vascular lipid transport and plaque development and associated metabolic dysfunction.

The clinical benefit of intensive LDL cholesterol (LDL-C) lowering with evolocumab in patients with prior percutaneous coronary intervention (PCI) but without a prior myocardial infarction (MI) is not established. VESALIUS-CV (The Effect of Evolocumabin Patients at High Cardiovascular Risk Without Prior Myocardial Infarction or Stroke) randomized patients with atherosclerosis or high-risk diabetes but without prior MI or stroke and with LDL-C ≥90 mg/dL to evolocumab versus placebo. The median follow-up was 4.6 years. The dual primary end points were coronary heart disease death, MI, or ischemic stroke (3-point major adverse cardiovascular event [MACE]) and the same composite plus ischemia-driven revascularization (4-point MACE). For this prespecified subgroup analysis, patients were categorized by whether they had undergone PCI at any time before trial enrollment. Among 12 257 randomized patients, 3627 (29.6%) had undergone prior PCI with a median time between PCI and enrollment of 4 years. Their median age was 66 years, and 30.7% were women. The median LDL-C in a lipid substudy at 48 weeks was 41.5 (26.0-67.0) mg/dL versus 107.0 (84.0-135.0) mg/dL in the evolocumab versus placebo arms (P<0.0001). Evolocumab reduced the relative rate of 3-point MACE by 30% (5-year Kaplan-Meier rates 7.0% versus 9.5%; hazard ratio [HR], 0.70 [95% CI, 0.56-0.89]; P=0.004) and 4-point MACE by 18% (17.9% versus 21.7%; HR, 0.82 [95% CI, 0.71-0.96]; P=0.012) as well as both MI by 50% (3.0% versus 6.1%; HR, 0.50 [95% CI, 0.36-0.70]; P<0.001), with the effect apparent as soon as 6 months after randomization, and urgent coronary revascularization by 39% (HR, 0.61 [95% CI, 0.46-0.80]; P<0.001). There were nominally lower rates of cardiovascular death (2.6% versus 3.7%; HR, 0.66 [95% CI, 0.45-0.96]; P=0.030) and all-cause death (8.2% versus 10.2%; HR, 0.76 [95% CI, 0.60-0.95]; P=0.016) with evolocumab. Evolocumab reduced the risk of major cardiovascular events in stable patients with prior PCI but no MI. These findings support intensive LDL-C lowering in patients who have undergone PCI even in the absence of prior MI. URL: https://www.clinicaltrials.gov; Unique identifier: NCT03872401.

Drug-eluting stents (DESs) are recommended treatment for coronary in-stent restenosis (ISR) but are not used in >20% of cases. The aim of the SELUTION4ISR (SELUTION SLR 014 In-stent Restenosis) trial was to assess the safety and effectiveness of a novel sirolimus drug-eluting balloon (DEB). After successful lesion predilation, patients with ISR were randomly assigned to the SELUTION Sustained Limus Release (MedAlliance) DEB or a control strategy of usual care, including any approved DES or balloon angioplasty (BA) on the basis of operator selection prerandomization. Randomization to selected BA control treatment was limited to 20% of patients. The primary outcome was target lesion failure (TLF) (cardiac death, target vessel myocardial infarction, or clinically driven target lesion revascularization) assessed at 1 year in the per protocol group (all treated eligible patients with complete primary endpoint follow-up). Noninferiority was established if the upper limit of the 2-sided 95% credible interval was smaller than 10%. A sequential secondary hypothesis test was performed comparing DEB with DES in patients with single-layer ISR. From July 2020 to July 2024, 418 patients were randomly assigned to the DEB group (n = 210) or the control group (n = 208), with 390 patients per protocol (DEB, 197; control, 193 [154 DES; 39 BA]). TLF occurred in 32 (16.2%) of 197 patients in the DEB group and in 28 (14.5%) of 193 patients in the control group (difference: 1.7%; 95% credible interval: -5.5% to 8.9%; posterior probability of noninferiority: 98.80%). In the secondary hypothesis test, TLF occurred in 22 (14.2%) of 155 patients in the DEB group and in 9 (6.5%) of 138 patients in the DES control group (difference: 7.7%; 95% credible interval: 0.6%-14.6%, posterior probability for noninferiority: 76.07%). TLF according to operator selected control was higher for DEB compared with DES (15.3% vs 7.1%; difference: 8.1%; 95% credible interval: 1.4%-15.0%) and lower for DEB compared with BA (23.6% vs 43.6%; difference: 23.7%; 95% credible interval: -41.4% to -1.5%; Pforinteraction = 0.0026). The sirolimus DEB was noninferior to a usual care control strategy including 80% repeat DES but not noninferior to DES for single-layer ISR for TLF at 12 months. There was significant interaction on the basis of operator selection of DES vs BA. (SELUTION SLR 014 In-stent Restenosis [SELUTION4ISR]; NCT04280029).

The benefit of percutaneous coronary intervention (PCI) for chronic total coronary occlusions (CTOs) to improve clinical symptoms and quality of life (QoL) as compared with optimal medical therapy (OMT) is still under debate because of the scarcity of available randomized trials (RCTs). We evaluated the effect of PCI vs OMT in patients with a CTO and no concomitant coronary lesions in a post-hoc pooled analysis of 2 RCTs. A total of 518 patients with a single CTO and no other significant coronary lesion were extracted from 2 RCTs, EUROCTO and DECISION-CTO, which had compared PCI vs OMT. Randomization to PCI or OMT was 1:1 in DECISION and 2:1 in EUROCTO. The clinical status was assessed by the Seattle Angina Questionnaire (SAQ) at baseline and after 12 months, and clinical events were monitored for 3 years. PCI was successful in 92.2%. On an intention-to-treat analysis, PCI appeared to be superior to OMT for the change of angina frequency scores between baseline and follow-up (12.2 vs 8.6; P = 0.009), QoL (19.5 vs 11.3; P < 0.001), and the SAQ summary score (13.8 vs 8.5; P < 0.001). For physical limitation, the difference was just at the level of the Bonferroni correction for multiple tests (P = 0.01). There was a wide variability of changes in SAQ scores. For QoL, the major determinant for a significant improvement was a low baseline score and the assignment to PCI, whereas gender, diabetes, or lesion complexity had no influence. During a mean follow-up of 3.1 years, the clinical endpoints of cardiac death or nonfatal myocardial infarction were similar in both groups (OMT vs PCI: 2.7% vs 5.1%; P = 0.17). The rates of stroke or hospitalization for bleeding were similar, and only target lesion revascularizations were more frequent with OMT (18.8% vs 10.6%; P = 0.005). In this post-hoc analysis from 2 RCTs of patients with a single CTO and no significant concomitant lesion, PCI achieved better improvement in QoL, angina frequency, and the SAQ summary score than OMT with no signal of excess harm regarding clinical endpoints. (EUROCTO [Evaluate the Utilization of Revascularization or Optimal Medical Therapy for the Treatment of Chronic Total Coronary Occlusions; NCT01760083] and DECISION-CTO [Drug-Eluting Stent Implantation Versus Optimal Medical Treatment in Patients With Chronic Total Occlusion; NCT01078051]).

Chronological age is central to cardiovascular disease (CVD) risk estimation but poorly reflects interindividual heterogeneity in cardiovascular aging. This study developed a peri-aortic adipose tissue (PAAT) radiomic cardiovascular age (CV-Age) biomarker from routine chest CT and tested whether the PAAT age gap (ΔAge = CV-Age - chronological age) stratifies major adverse cardiovascular events (MACE) and improves risk classification. Four chest CT cohorts with different protocols were utilized to train (n = 4451) and externally validate (n = 44 214) a CV-Age model. Associations between ΔAge decile groups (resilient ≤10th; accelerated ≥90th) and incident 5-point MACE (myocardial infarction, stroke, revascularization, heart failure, and death) were assessed using survival models. Clinical utility was evaluated by substituting CV-Age for chronological age in PREVENT to quantify risk reclassification. A 31-feature radiomic signature capturing PAAT volume, attenuation, and texture heterogeneity predicted age with good accuracy (training MAE 2.2 years; primary external validation MAE 2.7 years). In a separate higher-risk cohort, predictions showed a positive ΔAge (median +5.4 years), reflecting elevated baseline cardiovascular burden. ΔAge-stratified event-free survival differed across groups (log-rank P < .001); compared with normative agers, accelerated agers had higher MACE risk (HR 1.51, 95% CI 1.37-1.66), and resilient agers had lower risk (HR 0.70, 0.63-0.77). Substituting CV-Age into PREVENT improved risk reclassification (categorical NRI +0.03, P < .01, continuous NRI +0.04, P < .05). Radiomic profiling of PAAT on routine chest CT yields a scalable imaging biomarker of cardiovascular aging. CV-Age can help improve identification of higher-risk individuals missed by age-driven risk estimation, supporting its role as a risk-enrichment tool.

Interferon (IFN) alpha (IFNα) and lambda3 (IFNλ3) constitute first-line responses of immunity against severe acute respiratory syndrome coronavirus 2 (SARS-CoV-2) infection by increasing interferon-stimulated genes (ISGs). Prolonged IFN production may exacerbate inflammation, contributing to endotheliitis and vascular dysfunction in coronavirus disease 2019 (COVID-19). We investigated whether spike protein S1 (SP1) of SARS-CoV-2 via IFN influences inflammation in human vascular and lymphatic endothelial cells (ECs) and whether these processes contribute to vascular dysfunction in the context of hypertension. We focused on ISG15, a crucial immune protein that is also implicated in hypertension-associated vascular injury. Exposure of microvascular ECs to SP1 of SARS-CoV-2-induced expression of ISGs: ISG15, MX1, and IFIT1. These effects were potentiated by IFNs and reduced by ADAM17 and STAT1 inhibition and genetic inhibition of IFNα and beta receptor subunit 1 (IFNAR1). In microvascular ECs IFNλ3 and IFNα increased expression of ISGs, TMPRSS2, ADAM17, production of pro-inflammatory mediators (tumor necrosis factor [TNF]α, interleukin [IL]-6, plasminogen activator inhibitor [PAI]-1) and reduced phosphorylation of eNOS (Ser1177). In pulmonary, lymphatic, and aortic ECs, IFNα, but not IFNλ3, increased expression of ISGs and IL-6. To explore the relevance in intact vessels, effects of IFNs were studied in isolated micro-vessels from wildtype (WT), hypertensive and ISG15-/- mice. IFNα, IFNλ3, and SP1 reduced endothelium-dependent relaxation in WT vessels, whereas IFNα increased contraction in vessels from hypertensive mice. Vascular dysfunction induced by IFNα, IFNλ3 or spike protein was abrogated in vessels from ISG15-/- mice. SP1 and IFNs synergically increase EC expression of ISGs through ADAM17. IFNλ3 and IFNα promote endothelial inflammation and vascular dysfunction through ISG15. These processes may play a role in the endotheliopathy and vascular damage associated with SP1 and might contribute to cardiovascular sequelae, including hypertension, of SARS-CoV-2 infection.

Long QT syndrome (LQTS) is a life-threatening genetic disorder characterized by prolonged QT intervals on electrocardiograms. Congenital forms are mostly associated with variants in the KCNQ1 and KCNH2 genes. Among pathogenic or likely pathogenic (P/LP) variants, some are associated with a significantly higher incidence of cardiac events compared to others. While therapies have significantly reduced mortality, some patients are unresponsive or intolerant to therapy, perpetuating their arrhythmic risk, including sudden cardiac death. Current approaches for risk stratification are insufficient, highlighting the critical need for more accurate identification and management of patients carrying high-risk genetic variants. Here, we aimed to develop a refined risk stratification model for P/LP variants by applying machine learning classification to electrophysiological data measured in patient-specific human-induced pluripotent stem cell-derived cardiomyocytes (hiPSC-CMs). Ten patient-specific hiPSC lines, each carrying one of six pathogenic or likely pathogenic (P/LP) variants in the KCNQ1 or KCNH2 genes, along with two healthy control hiPSC lines, were differentiated into hiPSC-CMs. Electrophysiological responses from multielectrode array recordings at baseline and after application of selective ion channel blockers or pro-arrhythmic compounds were used to train a machine learning model to classify variant-specific risk levels based on in vitro electrophysiological readouts. An independent validation cohort of two additional KCNH2 hiPSC lines was used to test the model's performance in predicting single-variant risk. Our findings revealed a correlation between variant risk level, hiPSC-CM electrophysiological profiles, and drug responses. The machine learning classifier, trained on multielectrode array recordings, achieved 89% accuracy in the classification of P/LP genetic variants according to the associated risk levels. This study demonstrates that integrating hiPSC-CM electrophysiological profiling with machine learning provides a robust method for granular variant-specific risk stratification of LQTS patients.

Lymphocyte activation gene 3 (LAG-3) is an immune checkpoint implicated in T cell exhaustion and a potential therapeutic target in glioblastoma (GBM). We conducted a multicenter, open-label, phase 1 study with sequential allocation to evaluate the safety and preliminary activity of the anti-LAG-3 antibody relatlimab, administered alone or with the anti-programmed cell death protein 1 (PD-1) antibody nivolumab, in patients with recurrent GBM. Forty-six patients were treated (23 per cohort). The primary endpoint of safety was met, with maximum tolerated doses of 800 mg relatlimab for monotherapy and 160 mg relatlimab/240 mg nivolumab for combination therapy. Treatment-related grade 3-4 adverse events occurred in 6 of 23 patients receiving combination therapy and were not observed with monotherapy. Neoadjuvant administration was associated with increased intratumoral CD8+ T cell infiltration for both monotherapy and combination therapy. Exploratory analyses suggested that tumors with elevated baseline interferon signaling and increased T cell clonality were enriched among patients with durable responses to combination therapy. Twelve-month overall survival was 34.8% with relatlimab alone and 52.2% with combination therapy; however, this study was not designed to assess efficacy. These findings demonstrate an acceptable safety profile and provide preliminary immunologic and clinical signals supporting further evaluation of LAG-3 blockade in GBM. ClinicalTrials.gov identifier: NCT02658981 .

POEMS syndrome is a life-threatening syndrome due to an underlying plasma cell neoplasm. The major criteria for the syndrome are polyneuropathy, clonal plasma cell disorder (PCD), sclerotic bone lesions, elevated vascular endothelial growth factor, and the presence of Castleman disease. Minor features include organomegaly, endocrinopathy, characteristic skin changes, papilledema, extravascular volume overload, and thrombocytosis. The diagnosis of POEMS syndrome is made with three of the major criteria, two of which must include polyneuropathy and clonal plasma cell disorder, and at least one of the minor criteria. Because the pathogenesis of the syndrome is not well understood, risk stratification is limited to clinical phenotype rather than specific molecular markers. Risk factors include low serum albumin, age, pleural effusion, pulmonary hypertension, and reduced eGFR. For those patients with a dominant plasmacytoma, first line therapy is irradiation. Patients with diffuse sclerotic lesions or disseminated bone marrow involvement should receive systemic therapy. Corticosteroids are temporizing, but alkylators and lenalidomide are the mainstays of treatment, the former either in the form of low dose conventional therapy or as high-dose conditioning for stem cell transplantation. Thalidomide and bortezomib also have activity, but their benefit needs to be weighed against their risk of exacerbating the peripheral neuropathy. Daratumumab combinations also appear promising based on case series. Prompt recognition and institution of both supportive care measures and therapy directed against the plasma cell result in the best outcomes.

Foetal cholesterol is primarily carried by high-density lipoprotein (HDL) enriched with apolipoprotein E (apoE) and the foetus depends on a maternal-placental supply in early gestation until foetal de novo synthesis is established. We aimed to examine HDL cholesterol (HDL-C), apoE, and apolipoprotein AI (apoAI) concentrations in early life and the association with foetal growth and placental insufficiency. We used data from the Copenhagen Baby Heart and COMPARE study cohorts, including cord- (n = 13 353) and parallel child and maternal venous blood samples at birth (n = 444), 2- (n = 364), and 14-16 months (n = 156) after birth. HDL-C, apoAI, and apoE concentrations were higher in female vs. male newborns (P < 0.001). During the first 14-16 months of life, concentrations of HDL-C and apoAI increased (P < 0.02), apoE decreased (P < 0.001), and the HDL-C-apoAI correlation increased (Spearman's rho: 0.71, 0.87, 0.90), while the HDL-C-apoE correlation decreased (Spearman's rho: 0.58, 0.18). Small (SGA), appropriate (AGA), and large (LGA) for gestational age showed a stepwise increase in cord blood concentrations of HDL-C and apoE, but not apoA1, from SGA to LGA (P < 0.001). We found higher risk of low cord blood concentrations (<20th percentile) of HDL-C and apoE associated with placental insufficiency [odds ratio 1.39 (95% confidence interval 1.16-1.65) and 1.46 (1.22-1.75)], low pregnancy-associated plasma protein A (PAPP-A) [1.82 (1.47-2.25) and 1.50 (1.19-1.88)), preeclampsia (1.62 (1.28-2.04) and 1.39 (1.09-1.78)], hypertension (1.35 (1.05-1.73) and 1.28 (0.99-1.67)), body mass index (BMI) ≥ 25 kg/m2 [1.29 (1.17-1.43) and 1.13 (1.02-1.25)], and smoking [1.79 (1.43-2.23) and 1.38 (1.09-1.76)]. Only placental insufficiency [1.23 (1.03-1.48)], low PAPP-A [1.48 (1.18-1.85)], and smoking[(1.35 (1.06-1.72)] were associated with low cord blood apoAI. During the first 14-16 months of life, the apolipoprotein profile of HDL approaches that of adults. Offspring concentrations of HDL-C and apoE at birth were positively associated with foetal growth and placental insufficiency was associated with increased risk of low HDL-C and apoE, suggesting these traits as markers of placental function.

This study aimed to develop a set of quality indicators (QIs) based on the 2025 European Alliance of Associations for Rheumatology (EULAR) recommendations for systemic lupus erythematosus with kidney involvement and explore their association with disease outcomes. A modified Research and Development and University of California, Los Angeles appropriateness method was used. In 2 voting rounds, 23 experts rated candidate QIs for validity and feasibility. Median ratings and agreement were calculated, leading to a core QI set. Adherence to recommended care from healthcare providers was assessed at both QI and patient levels in a single tertiary centre contemporary lupus nephritis (LN) cohort (n = 130). High adherence was defined as ≥80%. Associations between adherence to QIs, damage accrual, and renal flares were explored. A total of 17 QIs were developed across 4 domains: diagnosis, treatment, monitoring, and pregnancy. High adherence was observed for kidney biopsy, hydroxychloroquine use, maintenance immunosuppression, therapy switching in persistent or relapsing disease, renin-angiotensin system inhibitor use, remission before kidney transplantation, and pregnancy-related QIs. Combination immunosuppressive therapy as initial treatment had low adherence (10.7%), reflecting practice patterns preceding publication of the recommendations. High per-patient adherence was associated with lower odds of damage accrual (increase in Systemic Lupus International Collaborating Clinic Damage Index; odds ratio: 0.29, 95% CI: 0.13-0.62) and fewer renal flares, although the latter association was not statistically significant. These QIs may serve as a structured framework for implementing the 2025 EULAR recommendations for LN. Higher adherence was associated with reduced damage accrual in a tertiary centre cohort, but results need validation in diverse clinical settings.

Despite recent advances, the pathophysiology of functional neurological disorder (FND) remains incompletely understood. Structural neuroimaging studies have identified grey matter alterations in somatomotor, salience, limbic, and default mode network associated areas, although findings are inconsistent. Mega-analyses, which combine individual-level data across studies, can help clarify structural alterations. We conducted a mega-analysis of brain structural morphometrics derived from T1-weighed MRI scans from fifteen international research groups. After across-site harmonisation with ComBat, we compared 493 functional motor and seizure patients with 564 healthy controls. Euler numbers were included to account for head motion. The FND cohort showed reduced cortical thickness in the bilateral superior frontal gyri (left d = 0.22, right d = 0.21) and sulci (d = 0.22 & 0.23), bilateral superior precentral sulcus (d = 0.22 & 0.26), right precentral gyrus (d = 0.25), right paracentral gyrus and sulcus (d = 0.23), right cuneus (d = 0.23), and right inferior opercular gyrus (d = 0.21); reduced left postcentral gyrus surface area (d = 0.25) and right hippocampal volume (d = 0.22). No regions were different in relative surface area. There were no associations between morphometrics and illness duration, or lifetime history of depression or anxiety. Differences between motor and seizure variants were not identified. This large mega-analysis suggests subtle morphometric differences, particularly in prefrontal and motor regions. This may represent predisposing vulnerabilities, compensatory mechanisms, or FND-specific alterations. Improved neuropsychiatric characterisation of FND research cohorts will help further contextualise the biological relevance of structural alterations.

Mosaic chromosomal alterations (mCAs) increase with age and are associated with many diseases, including autoimmune diseases. The associations between mCAs and systemic sclerosis (SSc) and its clinical subtypes have not been explored. We recruited study subjects from 2 independent datasets (set 1: 635 SSc, 4401 controls; set 2: 347 SSc, 2170 controls) and detected mCAs (loss, loss of heterozygosity [LOH], gain, and mosaic loss of the X chromosome [mLOX]) from their peripheral blood samples. Logistic regression analyses were conducted with covariates in each cohort, and the results were meta-analysed. We also conducted stratified analyses by age groups, the age at disease onset, clinical phenotypes based on the skin lesions, autoantibody profiles, and the presence of complications. We observed a trend of increased loss in SSc, especially in old age (P = .0063). The association of loss was strengthened in certain subtypes of SSc, including lcSSc (odds ratio [OR] = 2.22, P = .019) and SSc with vascular complications (digital ulcers, pulmonary hypertension, or renal crisis; OR = 3.30, P = .0054). The effect sizes of Loss increased in patients with high cell fractions (CFs). We also observed that mLOX was significantly associated with SSc, limited cutaneous systemic sclerosis (lcSSc), and anticentromere antibody-positive systemic sclerosis (ACA-SSc) only for subjects with high CFs. mLOX was significantly associated with lcSSc and ACA-SSc even compared with dcSSc and ATA-SSc, respectively. These associations were consistently observed in each of the 2 datasets. Finally, we identified majority of the associations of Loss were mainly driven by SSc with late age at onset. Loss and mLOX were significantly and differentially associated with SSc and its subtypes, underscoring potential phenotype-specific contributions of mCAs.

Testosterone therapy (TT) is increasingly initiated outside classical hypogonadism, but long-term cardiovascular safety in this context remains uncertain. We assessed whether TT initiation without evidence of hypogonadism is associated with higher long-term cardiovascular risk than TT initiation with evidence of hypogonadism. In this global retrospective real-world cohort study, men aged 30-75 years initiating TT were identified from secondary, de-identified structured EHR data from 123 healthcare organisations. A prespecified 3-year pre-index washout excluded prior TT and major cardiovascular/thromboembolic events. Men initiating TT without evidence of hypogonadism were compared with those with evidence of hypogonadism using 1:1 propensity-score matching. The primary outcome was major adverse cardiovascular events (MACE); secondary outcomes included separately all-cause mortality, myocardial infarction, ischaemic stroke, cardiac arrest, and heart failure. Acute appendicitis served as a negative-control outcome. Among 358,957 TT initiators, 127,152 (35.4%) had no evidence of hypogonadism. After matching, 113,554 pairs were followed for up to 10 years. TT without evidence of hypogonadism was associated with higher risk of MACE (16.53% vs 11.83%; HR 1.51, 1.45-1.56) and all-cause mortality (HR 1.90, 1.79-2.00), with higher risks of ischaemic stroke (HR 1.23, 1.14-1.33), cardiac arrest (HR 1.41, 1.23-1.61), and heart failure (HR 1.32, 1.26-1.39). Race-stratified estimates were directionally consistent but varied in magnitude. The cardiovascular safety of TT appears context-dependent and less favourable when treatment is initiated without evidence of hypogonadism, with clinically relevant heterogeneity across race/ethnicity, supporting biologically informed prescribing and cardiovascular risk surveillance. Deutsche Forschungsgemeinschaft, Schleswig-Holstein Excellence-Chair Program, and Region Stockholm.

UK South Asian populations are at high risk of physical and mental health multimorbidity, which means they live with multiple long-term conditions. The life course emergence of multimorbidity, its underlying aetiology, and consequences for future health and mortality have yet to be studied in this population. We studied Internalising (depression, anxiety, somatoform disorders) and Cardiometabolic (hypertension, obesity, type 2 diabetes, chronic kidney disease, dyslipidaemia) MultiMorbidity (ICM-MM): the lifetime occurrence of ≥1 internalising mental health condition AND ≥1 cardiometabolic condition in a longitudinal cohort of Genes and Health study participants with linked genetic and health data from 1st April 1997-24th November 2024. We used multi-state models to investigate trajectories in ICM-MM and risk of major cardiovascular or renal events (CVR) or non-CVR death. We used flexible parametric models to estimate baseline hazards for health state transitions, adjusting for sociodemographic factors, a polygenic risk score (PRS) for ICM-MM (ICM-MMPRS), and describe 10-year simulated health state probabilities. Over 10.2 years median follow-up of 23,554 British Bangladeshi and Pakistani participants (median baseline age 31.1 years, 12,934 [54.9%] women), 3,159 (13.4%) developed ICM-MM; 1,522 (6.5%) CVR; and there were 103 (0.4%) non-CVR deaths. Women were less likely to remain healthy, with higher probability of developing internalising conditions and subsequent ICM-MM, but lower risk of CVR than men. Younger age was associated with higher risk of developing internalising conditions. Bangladeshi ethnicity, higher deprivation, and smoking were all associated with higher probability of ICM-MM. 10-year CVR risk was highest for people who developed ICM-MM via the trajectory cardiometabolic-to-internalising (versus internalising-to-cardiometabolic) in mid-life (age 40). Higher ICM-MMPRS was associated with higher probability of ICM-MM via cardiometabolic conditions rather than internalising conditions. Our findings are based on routinely collected electronic health records from East London, which incompletely capture individual-level and time-varying risk factors, remission or recovery, and may not reflect British Bangladeshi and British Pakistani communities across the UK. The PRS was derived largely from GWAS of European ancestry populations, which may limit its transferability to this cohort. The burden of multimorbidity is high in British Bangladeshi and British Pakistani populations. Young Bangladeshi women are at high risk of ICM-MM, while men are at higher risk of CVR. Detection and intervention strategies for physical and mental health multimorbidity should be targeted early in the lifecourse, for those at highest risk.

There is broad consensus on the benefits of aerobic exercise training in patients with cardiovascular disease to improve cardiorespiratory fitness and lower the risk of adverse cardiovascular events. However, certain high-risk populations such as those with frailty, stroke, spinal cord injury, rheumatological conditions, or genetic cardiomyopathies and recipients of advanced heart failure therapies or cardiac implantable electronic devices warrant special considerations with regard to exercise training. This scientific statement summarizes the present state and future directions of exercise training for these high-risk populations, including functional deficits, responses to exercise training, modifications in training programs required to maximize safety and efficacy, and knowledge gaps in this field. Key findings common across most of these high-risk populations include (1) increased barriers to participation in exercise training at multiple levels; (2) low baseline cardiorespiratory fitness, creating heightened need for exercise interventions; (3) modifications to exercise prescription, frequently emphasizing strength, balance, and flexibility in addition to aerobic training, as well as accommodations with enhanced supervision and specialized equipment as needed; and (4) functional and quality-of-life gains in response to appropriately designed exercise programs that match or exceed those in more traditional populations. Future research is needed to further develop patient-centered training regimens designed to address the unique and heterogeneous needs of these populations, evaluate their impact on clinical and patient-centered outcomes, and advance scalable and equitable delivery of exercise therapies proven safe and effective.

Clinically significant portal hypertension (CSPH) drives decompensation and mortality in advanced chronic liver disease (ACLD). Although non-selective β-blockers (NSBB) reduce risk, accurate identification of patients with CSPH requires invasive hepatic venous pressure gradient (HVPG) measurement. The non-invasive Baveno-VII CSPH criteria based on liver stiffness measurement (LSM) and platelet count (PLT)-yield 40-50% indeterminate ("gray-zone") results and vary across etiologies and elastography techniques. Spleen stiffness measurement (SSM) has been proposed to improve the accuracy of the Baveno-VII CSPH criteria. We developed and validated a machine-learning (ML) model integrating pan-elastographic LSM and SSM results with clinical variables to improve CSPH rule-out and rule-in accuracy while minimizing indeterminate cases. We analyzed 1,435 compensated ACLD patients with paired HVPG, LSM, SSM, and clinical parameters. LSM and SSM were obtained by vibration-controlled transient elastography (VCTE), two-dimensional shear-wave elastography (2D-SWE), or point-SWE (p-SWE). Models were trained (n=943) and internally validated (n=150) using harmonized LSM/SSM from different technologies and clinical variables (PLT, Child-Pugh, age, gender, etiology). Cut-offs were selected for 100% negative predictive value (NPV) to rule-out and 100% positive predictive value (PPV) to rule-in CSPH. External validation was conducted in 342 patients across seven centers, comparing ML performance against Baveno VII, Baveno-SSM single- and dual-cut-off criteria, and, in the VCTE subgroup, ANTICIPATE and NICER scores. A Random Forest-based model based achieved the highest performance (external validation: AUC=0.91, Brier Score=0.13), with cut-offs≤0.45 (rule-out) and ≥0.60 (rule-in) yielding NPV=0.90 (95%C.I.0.84-0.94) and PPV=0.96 (95%C.I.0.92-0.98). The ML gray-zone was 12.3%, versus 47.9% (Baveno VII;p<0.001), 38.6% (Baveno-SSM-dual;p<0.001), and 19.6% (Baveno-SSM-single;p<0.05). In the VCTE external-validation subgroup (n=275), ELM achieved comparable rule-in performance to ANTICIPATE and NICER, while reducing the gray zone to 12.0% versus 41.1% and 41.8%, respectively. The ELM Score outperformed current Baveno criteria and markedly reduced gray zones across elastography modalities, supporting broader, safer, and non-invasive identification of ACLD patients with HVPG-defined CSPH who may be candidates for NSBB therapy.

Polypharmacy in patients with cardiovascular disease occurs frequently across the age spectrum and can lead to inappropriate prescribing and adverse outcomes. Despite polypharmacy being a known problem for decades, there is limited guidance describing how to manage polypharmacy in patients with cardiovascular disease, including when and how to initiate deprescribing strategies. Although polypharmacy can occur at any age, studies often focus on older adults. The prevalence and consequences of polypharmacy, coupled with current gaps in the deprescribing literature, highlight the need for a scientific statement focused on deprescribing in all patients with cardiovascular disease. Deprescribing can improve outcomes and can apply to both cardiovascular and noncardiovascular drugs because both contribute to polypharmacy and poor outcomes associated with inappropriate prescribing in patients with cardiovascular disease. This scientific statement reviews the consequences of polypharmacy in patients with cardiovascular disease and provides tailored deprescribing strategies across the life span, with an emphasis on the unique considerations in pediatric, adult, and older adult populations. These strategies include observing clinical cues and triggers, using validated deprescribing tools, engaging in shared decision-making, and leveraging the roles of all members of the health care team to address barriers to deprescribing. Last, this scientific statement highlights current challenges related to polypharmacy and deprescribing and suggests some strategies to address them.

To quantify the hospital burden of short-term wildfire-specific fine particulate matter (PM2.5), we linked 184.5 million patient-level hospitalizations across 449 Brazilian regions from 2000-2019 with daily wildfire-specific and non-wildfire PM2.5 estimates at 0.25° resolution. Using wind-driven variation in wildfire-specific PM2.5 within a space-time-stratified case-crossover framework, we estimated the effects of exposure on hospitalization costs and length of stay. Each 1 µg/m3 increase in wildfire-specific PM2.5 was associated with higher hospitalization costs for all-cause, respiratory, and cardiovascular diseases by 0.36%, 1.59%, and 0.25%, respectively, and longer stays by 0.63%, 1.72%, and 0.68%. Asthma and heart failure showed the largest cost increases, while asthma and pneumonia showed the largest increases in length of stay. Overall, wildfire-specific PM2.5 accounted for US$755.6 million in hospitalization costs and 30.8 million hospital days, with stronger relative effects among individuals aged 0-19 years and higher burdens in central-west Brazil.

Weight loss and weight loss maintenance are prominent topics of discussion for clinicians and health professionals involved in treatment to reduce obesity and the risk of cardiovascular disease. Because physical activity is a key component of comprehensive obesity treatment, this scientific statement summarizes the role of physical activity in promoting weight loss, weight loss maintenance, and cardiometabolic health, complementing lifestyle, pharmacological, and surgical-based weight loss intervention strategies. Independently of weight loss, physical activity and exercise programs improve major cardiometabolic risk factors, including hypertension, insulin resistance, and dyslipidemia, which are highly prevalent in patients with overweight or obesity. As a single treatment modality, physical activity and exercise programs are unlikely to result in clinically meaningful weight loss (ie, at least 5% loss of initial body weight) unless aerobic physical activity levels are exceptionally high. When combined with diet-induced negative energy balance, obesity medication, or surgical treatment, increased physical activity can augment total weight loss and improve cardiometabolic outcomes. Because clinicians and health professionals play a pivotal role in fostering and sustaining patients' health goals, this scientific statement also provides an overview of evidence-based strategies for targeted weight loss counseling and for leveraging digital technology, particularly to engage patients and achieve realistic physical activity goals.

Telehealth may help maintain access to care for individuals with chronic conditions, particularly during periods of disruption. This study examined the association between telehealth use and health care utilization, continuity, and quality in primary care. We used a difference-in-differences design (2019-2021) to compare outcomes for patients attributed to practices with high versus low telehealth uptake before and after the onset of the COVID-19 pandemic across three clinical research networks. Outcomes included evaluation and management visits, preventable emergency department visits, avoidable hospitalizations, Bice-Boxerman and Usual Provider of Care continuity indices, and disease-specific quality measures. Among 383,570 Medicare fee-for-service patient-quarters with chronic conditions, telehealth use was not associated with changes in preventable emergency department visits or hospitalizations. Continuity of care, measured by the Bice-Boxerman Index, increased by 0.01 (95% CI, 0.002 to 0.017), corresponding to an 8.3% greater increase relative to the pre-period mean in high versus low telehealth practices. However, telehealth use was associated with declines in selected disease-specific quality measures, including beta-blocker use among patients with heart failure (-0.04; 95% CI, -0.08 to -0.002) and controlled blood pressure among patients with hypertension (-0.10; 95% CI, -0.14 to -0.06). These findings suggest that telehealth may support continuity of care without increasing acute care utilization, although its implications for chronic disease management quality remain uncertain.

AI-enabled electrocardiogram (ECG) models trained on 12-lead recordings may underperform on home single-lead devices due to device and context domain shift. We trained Lead-I models using 676,192 ECGs from 246,874 patients and externally validated them in 219,231 ECGs from 65,338 patients. We evaluated two methodological control indicators (gender and age) and seven clinical phenotypes [90-day mortality, left ventricular ejection fraction (EF), pulmonary artery systolic pressure (PASP), left atrial diameter, N-terminal pro-B-type natriuretic peptide (NT-proBNP), hemoglobin, and estimated glomerular filtration rate]. Cross-hospital validation showed minimal overall degradation (AUC decline <0.03). In contrast, direct deployment to consumer ECGs from Apple Watch (n = 9835) and QOCA ECG102D (n = 31,517) produced substantial accuracy losses. After fine-tuning, AUCs across eight classification tasks for the Apple Watch and QOCA ECG102D were significantly improved, with high performance for low EF (0.85/0.86) and more modest performance for elevated PASP (0.73/0.68) and anemia (0.73/0.69). Performance was higher in sinus rhythm than atrial fibrillation. Learning curves indicated that approximately 500-1000 labeled ECGs are required for reliable fine-tuning; smaller sets can be harmful. We release an evaluation-only HOME dataset to facilitate reproducible benchmarking of cross-device generalization. Models should be interpreted as screening or triage tools, not standalone diagnostic tests.

To compare five-year systemic complication risks in non-infectious uveitis (NIU) patients treated with systemic biologic versus conventional therapy. Multicenter retrospective clinical cohort study. Adult patients (≥18 years old) with NIU from the TriNetX Collaborative Network. We identified patients with NIU using International Classification of Diseases, Ninth and Tenth Revision, Clinical Modification codes. We assembled propensity score-matched comparisons: biologic therapy versus no systemic therapy (n=6,896 each), biologic versus conventional therapy with corticosteroids matched (n=5,994 each), between January 1, 2005, and January 1, 2024. A pre-specified subgroup analysis of Analysis 2 restricted to patients receiving combination biologic + conventional therapy versus conventional therapy alone (n=3,653 each) was also conducted. We employed time-to-event analyses to identify incidence of systemic complications. Incidence of serious infections, hematologic cytopenias, heart failure, thromboembolic events, diabetes mellitus, malignancy, psychiatric illness, all-cause hospitalization, and all-cause mortality. After propensity score matching, cohorts were balanced on all measured covariates (all standardized mean differences <0.1). Compared with no systemic therapy, biologic treatment was associated with higher five-year risks of serious infections, including pneumonia (hazard ratio [HR]: 1.41, 95% confidence interval [95% CI]: 1.20-1.67), sepsis (HR: 1.43, 95% CI: 1.16-1.77), and hematologic cytopenias (HR: 1.58, 95% CI: 1.44-1.74), representing 5-year Kaplan-Meier-estimated cumulative incidences of 6.43%, 3.87%, and 30.12%, respectively, in biologic-treated patients. Risks of heart failure, thromboembolic events, psychiatric illness, diabetes, and all-cause mortality did not significantly differ between groups. When compared with conventional immunomodulatory therapy, biologic treatment demonstrated a largely comparable five-year safety profile, with the primary exceptions of higher rates of hematologic cytopenias (HR: 1.28, 95% CI: 1.16-1.41), psychiatric illness (HR: 1.13, 95% CI: 1.01-1.27), and hospitalization (HR: 1.20, 95% CI: 1.07-1.35). In patients with NIU, systemic biologic therapy was associated with higher risks of serious infections and hematologic cytopenias compared with no systemic treatment, while demonstrating a broadly comparable five-year safety profile to conventional immunomodulatory therapy. These findings support guideline-concordant stepwise immunosuppression and underscore the importance of individualized risk assessment, infection surveillance, and hematologic monitoring for patients requiring systemic therapy.

Neurological disorders refer to a diverse group of conditions that affect the brain, peripheral nerves, and spinal cord and impair socioemotional, cognitive, motor, and sensory functions. Alzheimer's disease (AD), Multiple Sclerosis (MS), Parkinson's disease (PD), Huntington's disease (HD), and Amyotrophic Lateral Sclerosis (ALS) are some of the well-known neurodegenerative diseases that affect millions of people worldwide. Despite the advanced technologies and nano-drug delivery systems, the success rate of developing drugs for neurological disorders is significantly low. Among several constraints, including gastrointestinal irritation, rapid metabolism, and low stability, the blood-brain barrier (BBB) emerges as one of the key challenges in the development and application of drugs against neurological disorders. These challenges necessitate innovative approaches to develop cost-effective therapeutic strategies. Drug repurposing, the discovery of new therapeutic benefits of existing drugs, is a promising drug discovery approach for discovering potential treatment options for complex neurological disorders. This review aims to explore the advanced and significant progress in drug repurposing for major neurological disorders, including MS, AD, PD, ALS, HD, stroke, and neuropsychiatric conditions. It places an explicit emphasis on discussing the potential role of artificial intelligence (AI)-assisted drug repurposing and understanding of the biological mechanisms in discovering new drugs for these neurological conditions. This also examines current challenges in drug repurposing and provides a critical review of the available opportunities and limitations in AI-assisted drug repurposing.

Irritable bowel syndrome (IBS) is a complex disorder of gut-brain interaction, with heterogeneous symptoms, no available biomarkers and limited pathogenetic insight. To identify genetic risk factors and actionable mechanisms for future clinical translation in IBS. We conducted a genome-wide association study (GWAS) meta-analysis of IBS in 2 775 539 individuals from 22 biobanks. IBS genetics was studied across multiple ancestries, different case definitions and symptom-related subtypes. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS data were functionally annotated and fine-mapped to prioritise tissues, cell types, pathways, candidate genes, specific mechanisms and druggable targets. Significant heritability was only detected in individuals of European ancestry, with near-identical genetic architecture across case definitions. Genetic correlations with GI, psychiatric and cardiometabolic traits were observed, including causal relationships with triglyceride (TG) levels. Functional annotation of IBS risk loci highlighted cell types and pathways relevant to brain, enteric neuro-glial and cardiometabolic domains, as well as actionable targets like GCKR, a regulator of TG metabolism. Druggability analyses converged on cardiometabolic mechanisms, including TG modulation. IBS polygenic risk scores were derived and showed a significant association with case status in an independent case-control dataset, supporting further evaluation in external population-based and clinically ascertained cohorts. This study provides the most comprehensive assessment of IBS genetics to date, demonstrating reproducible polygenic inheritance. We link IBS risk to convergent neurogastrointestinal and novel cardiometabolic mechanisms, highlight specific biological pathways and actionable mechanisms and outline translational opportunities emerging from integrated computational analyses.

Genetic studies of stool frequency (SF), an indirect proxy for gastrointestinal transit, may reveal therapeutically tractable pathways relevant to IBS and other dysmotility disorders. To identify genes and mechanisms involved in gut motility, providing a foundation for clinical translation. We performed a multiancestry genome-wide association study (GWAS) meta-analysis of SF in 268 606 European and East Asian individuals. Heritability and genetic correlations with other traits were estimated, and Mendelian randomisation was used to test causal relationships. GWAS signals were fine-mapped and functionally annotated to prioritise candidate genes and pathways. Findings implicating thiamine metabolism were followed-up with dietary interaction analyses in UK Biobank (UKB). SF heritability was comparable in Europeans (7.0%) and East Asians (5.6%). We observed strong genetic correlations with gastrointestinal and psychiatric disorders (rg=0.18-0.47), and causal effects on IBS. Novel correlations with cardiovascular traits (rg=0.12-0.14) were supported by drug signature enrichment analyses. We identified 21 independent loci, including 10 novel signals implicating bile acid synthesis (KLB) and cholinergic signalling (COLQ). Fine-mapping converged on vitamin B1 metabolism, highlighting single-variant causal effects at SLC35F3 (a thiamine transporter) and XPR1 (phosphate exporter essential for thiamine activation). In 98 449 UKB participants, thiamine intake was positively associated with SF (p<0.0001), and a combined SLC35F3/XPR1 genotype score significantly modulated this effect (p<0.0001). We identify therapeutically tractable mechanisms involved in the control of gut motility, including a previously unrecognised role for vitamin B1. These findings warrant mechanistic and clinical studies to evaluate their translational potential in IBS and other dysmotility syndromes.

Clinical trial design (CTD) is a time-consuming process that requires substantial domain expertise. Large-scale real-world data (RWD), such as electronic health records (EHR), encodes practice-based evidence that is of tremendous value to CTD. In recent years, many machine learning methods have been developed to extract such real-world evidence (RWE) from the RWD to inform CTD, but they still need to be communicated with the domain experts extensively in an iterative manner to be further refined and ultimately useful. In this paper, we introduce EmulatRx, an agentic framework that derives RWE for helping with CTD. Through the iterative conversation and analysis across agents with different roles, EmulatRx can autonomously refine trial protocols and finally generate a robust report containing insights that inform better CTD. We applied EmulatRx on the CTD process for both acute diseases (e.g., septic shock, acute heart failure, acute pulmonary edema, and acute kidney injury) using the MIMIC-IV data and chronic diseases (e.g., Alzheimer's disease and Parkinson's disease) using the INSIGHT Network across five New York City health systems. The results demonstrate EmulatRx's capabilities in facilitating and accelerating the CTD process.

Drugs targeting genes supported by human genetic evidence are more likely to succeed in clinical trials. While previous approaches have benchmarked individual methods such as genome-wide association studies (GWAS), rare variant burden testing, and quantitative trait locus (QTL)-informed Mendelian randomization, it remains unclear how best to integrate these signals for drug target discovery. We compared gene-prioritization strategies across 30 complex traits, evaluating their ability to recover approved drug targets compiled into lenient and moderate gold-standard sets from six curated databases. Gene-level association scores from GWAS, expression QTL, protein QTL, and exome-based analyses were integrated using five unsupervised approaches. Predictive performance was assessed with area under the receiver operating characteristic curve (AUROC) and enrichment-based statistics. Across traits, GWAS alone ranked known drug targets on average ∼652 ranks (3.42%) above random expectation, and the minimum-rank-based integration strategy further improved performance by approximately ∼558 positions (2.93%), achieving the best AUROC in 23 of 30 traits. Genetic correlation and drug target overlap across trait pairs showed a significant positive association ([Formula: see text]). Cross-trait analyses further revealed that prioritization scores derived from related diseases could at times equal or even surpass a trait's own performance. For instance, coronary artery disease data improved the prediction of stroke targets ([Formula: see text]), while inflammatory bowel disease data enhanced the prioritization of chronic kidney disease targets ([Formula: see text]). These results demonstrate that using the strongest signal from complementary genetic prioritization methods, combined with information from genetically related traits, systematically strengthens drug target identification across complex diseases.

Pulmonary arterial hypertension (PAH) is characterized by excessive remodeling of the distal arterioles and arteries, driven by endothelial cell (EC) apoptosis and uncontrolled mural cell proliferation. Increasing evidence suggests immune dysregulation in PAH, but one crucial part of the immune system, the pulmonary lymphatics, has been largely overlooked. Patients with idiopathic PAH (IPAH) often develop abnormal tertiary lymphoid structures adjacent to remodeled arteries, yet the role of lymphatics in PAH pathogenesis and vascular remodeling remains unclear. Mice with lymphatic EC-specific fluorescent label (Prox1-CreERT2::Rosa26-LSL-tdT) or lymphatic EC-specific deletion of Vegfr3 (vascular endothelial growth factor receptor 3; Prox1-CreERT2::Vegfr3fl/fl) were used. Pulmonary hypertension (PH) was induced in mice via exposure to hypoxia (10% FiO2) for 1, 2, 3, or 6 weeks and in Sprague-Dawley rats via a single monocrotaline injection. MAZ51 was administered to inhibit Vegfr3. Right ventricular systolic pressure, right ventricular hypertrophy, and echocardiography were assessed. Immunofluorescent staining was performed in rodent and in IPAH lung sections for lymphatic EC analysis. Publicly available single-cell RNA sequencing data sets from human IPAH and mouse PH were reanalyzed to identify differentially expressed genes in lymphatic ECs. Pulmonary lymphatic vessels proliferated, branched, and dilated in response to hypoxia. Vegfr3 inhibition using MAZ51 or lymphatic EC-specific Vegfr3 deletion reduced hypoxia-induced lymphangiogenesis and was associated with worsened PH, right ventricular hypertrophy, and impaired drainage. Comparative single-cell RNA sequencing analysis revealed upregulation of CD74/Cd74 in lymphatic EC clusters from human IPAH and hypoxia-induced PH mouse lungs. In IPAH lymphatic ECs, increased CD74 expression was associated with increased FLT4 and activation of the VEGFR3-downstream MEK (mitogen-activated protein kinase)/ERK (extracellular signal-regulated kinase) signaling pathways. Consistently, increased CD74 expression was found in lymphatic ECs from IPAH tissues, whereas CD74 overexpression in human lymphatic ECs enhanced VEGFR3 expression and was associated with impaired barrier permeability. These findings identify adaptive lymphangiogenesis as a protective response in experimental PH and reveal a previously unrecognized CD74-VEGFR3 signaling axis in lymphatic ECs. Targeting lymphatic dysfunction may represent a novel therapeutic strategy to improve outcomes in PAH.

Proliferative lupus nephritis (LN) is triggered by deposition of autoantibodies in glomeruli and paralleled by a T cell-rich kidney infiltrate. Although these T cells have been attributed to the propagation of tissue injury, it is unclear how they are activated and whether T cell autoreactivity drives local inflammation. Kidney-infiltrating T cells are also observed in urine, where they have high resemblance to interstitial T cells. Therefore, urinary T cells are a proxy for investigating tissue pathogenesis. Here, we analyzed urinary T cells to elucidate whether a kidney-specific T cell autoimmune reaction contributes to tubulointerstitial inflammation in LN. Using single-cell RNA sequencing, we compared transcriptomes and clonotypes of T cells from the blood and urine of patients with active LN and showed that urinary T cells were mostly activated CD8 effector memory cells recruited from a circulating CX3CR1+ subset. Several urinary CD8 T cell clones were expanded. However, upon in vitro testing of their T cell receptors, we did not observe autoreactivity against autologous tubular epithelial cells. Instead, ~20% of expanded clonotypes were Epstein-Barr virus-specific or cytomegalovirus-specific, but respective viral antigens were undetectable in kidney biopsies or urine. Conversely, kidney-infiltrating T cells had access to interleukin-15 and interferon-β (IFN-β), and stimulation with these cytokines was sufficient to trigger degranulation and production of tumor necrosis factor, IFN-γ, and granzyme K. Together, these results show that CD8+CX3CR1+ T cells are recruited into the kidney in LN, where they are activated by cytokines, enabling them to contribute to local inflammation.

Although pulmonary arterial hypertension (PAH) is a rare and fatal disease that is well-characterized, vasodilator-responsive PAH accounts for a minority of cases, with little mechanistic knowledge, but with dramatically improved survival. By assembling national cohorts, we evaluated genetic influences on acute vasodilator drug response, a key determinant of the presence of vasodilator-responsive PAH. Differences between hemodynamics at rest and after a PAH-specific vasodilator were tested in a genome-wide association study. Validated loci were functionally tested in cell culture and in a hypoxic mouse model of pulmonary hypertension. Rs8057488 in the sorting nexin 29 (SNX29) gene reached genome-wide significance in the discovery cohort (P=4.00×10-8) and was nominally replicated (P=0.027). Consistent with its predicted function, SNX29 demonstrated an endosomal distribution in PA smooth muscle cells. Silencing SNX29 redistributed stromal interaction molecule proteins to the cell membrane and enhanced store-operated calcium entry. Over-expression of SNX29, in vivo, attenuated hypoxic vasoconstriction in isolated perfused murine lung models. The data cumulatively suggest SNX29 may contribute to vasodilation partly through reduced store-operated calcium entry and endosomal trafficking of store-operated calcium entry proteins, advancing our understanding of vasodilator-responsive PAH.

Biallelic mutations in EIF2AK4, encoding Eukaryotic Translation Initiation Factor 2α kinase 4 or General Control Nonderepressible 2 (GCN2), cause pulmonary veno-occlusive disease (PVOD), a fatal form of pulmonary hypertension. The mechanisms linking GCN2 deficiency with pulmonary vascular pathology are poorly understood. To investigate this, we developed two mouse models: genetic ablation of Gcn2, to mirror GCN2-mutation positive PVOD, and a pharmacological model using mitomycin C, a drug which can cause PVOD as an idiosyncratic drug reaction. Both models were phenotyped, and lungs from wild-type and Gcn2-deficient mice were analyzed using single-cell RNA sequencing. We show that homozygous loss of Gcn2 is sufficient to induce mild pulmonary hypertension in mice. Single-cell transcriptomic profiling identified adventitial fibroblasts as the cell population exhibiting the most Gcn2-dependent transcriptional changes. Pathway analysis revealed upregulation of inflammatory signaling in Gcn2-/- adventitial fibroblasts. Consistent with this, we demonstrate a proinflammatory phenotype in Gcn2-/- mouse fibroblasts and in Gcn2-/- mice. Using a mitomycin C-induced murine model, genetic deletion of interleukin-6 (Il6) rescued the pulmonary vascular phenotype. Furthermore, chronic lipopolysaccharide exposure exaggerated pulmonary hypertension in Gcn2-/- mice, and Il6 ablation rescued both baseline and lipopolysaccharide-exacerbated disease. Pharmacological inhibition or genetic ablation of the Integrated Stress Response, which can be driven by GCN2-activation, phenocopies Gcn2 deficiency. Therefore, we establish a regulatory effect of an intact GCN2-Integrated Stress Response on IL-6 signaling. Together, we show that interleukin-6 is a critical mediator of both Gcn2 deficiency-associated and mitomycin C-triggered pulmonary vascular disease in mice and highlight IL-6-dependent pathways as potential therapeutic targets.

Artificial intelligence (AI) algorithms are currently executed using silicon-based hardware, resulting in excessively high energy demand for data centers. Edge computing AI for healthcare, robotics, and autonomous vehicles presents even stricter power and latency constraints, which are unmet by incumbent computing architectures. With vastly superior energy efficiency, biological neuronal networks provide hints towards alternative computational approaches including memory-logic colocation, asynchronous parallelism, and spike-triggered computation. Here, we draw inspiration from the cerebellum to demonstrate asymmetric-contact-gated MoS2 memtransistors that exhibit bias-polarity-dependent excitatory/inhibitory short-term plasticity. Arrays of these cerebellum-inspired memtransistors exploit the evolving interplay between excitatory and inhibitory responses to emulate the emergent synaptic differentiation of the cerebellum, enabling rapid identification of novel events. When applied to electrocardiogram data, arrhythmias are detected within a single heartbeat with 10,000-fold fewer operations than existing silicon-based approaches. In this manner, cerebellum-inspired neuromorphic hardware provides a pathway to computationally efficient, high-speed novelty detection for edge intelligence.

Chronic neuroinflammation is a defining feature of brain ageing and neurodegenerative disorders, yet the molecular mechanisms responsible for its persistence remain incompletely understood. Although autophagy dysfunction, glial senescence, and inflammasome activation are well-established contributors to progressive neurodegeneration, these processes are often analysed independently or through pairwise interactions, leaving their collective contribution to persistent neuroinflammation and disease progression insufficiently defined. Here, we synthesise emerging evidence supporting an integrated 'Autophagy-Senescence-Inflammasome (ASI) axis', in which reciprocal interactions among impaired autophagy, senescent glia, and inflammasome signalling establish a self-sustaining cycle of neuroinflammation. We discuss how defective autophagy promotes mitochondrial dysfunction, oxidative stress, and danger signalling, while senescent astrocytes and microglia amplify inflammatory responses through the senescence-associated secretory phenotype (SASP). These intertwined processes converge on chronic inflammasome activation, with mitochondrial dysfunction emerging as a central mechanistic hub. Evidence across Alzheimer's disease, Parkinson's disease, amyotrophic lateral sclerosis, multiple sclerosis, stroke, and chronic neuropathic pain highlight the broad relevance of this pathological network. We further analyse current therapeutic strategies targeting autophagy, senescence, and inflammasome pathways, emphasising the limitations of single-target approaches and the potential of multi-target interventions. By integrating these processes into a unified framework, this review provides new insights into the possible molecular mechanisms underlying neuroinflammaging and identifies the 'ASI axis' as a promising target for neurodegenerative disease-modifying therapies.

Cardiovascular disease (CVD) is the leading cause of mortality in chronic kidney disease (CKD). While CKD is known to give rise to systemic inflammation, its inciting factors remain poorly defined. Oxalate, long implicated in rare genetic kidney disorders, accumulates with decreased kidney function and has emerged as a driver of inflammation and independent risk factor for CVD. Here, we investigate the immunological mechanisms linking oxalate nephropathy to systemic inflammation, cardiac damage and kidney injury. Oxalate nephropathy was induced in C57Bl6/N mice through an oxalate-enriched diet. Oxalate induced systemic immune activation, renal fibrosis, and adverse cardiac remodeling, including pulmonary congestion with systolic and diastolic dysfunction. Flow cytometry analysis identified interleukin (IL)-17A as a dominant inflammatory effector, with expansion of Th17 and Th17-like Treg in the kidney, intestine, and spleen. Bulk mRNA sequencing confirmed these findings in kidney and heart. In line, plasma IL-17A was increased in oxalate-fed mice. Confirming the oxalate-IL-17A relationship, plasma IL-17A was elevated in patients with primary hyperoxaluria. Gut microbiome analysis by 16S amplicon sequencing showed only mild oxalate-induced alterations in mice. However, soluble oxalate directly enhanced Th17 polarization and disrupted mitochondrial respiration in vitro. In vivo, antibody-mediated IL-17A blockade improved kidney function, cardiac fibrosis, reduced neutrophil infiltration, and partially restored cardiac function in oxalate-fed mice. Our study identifies oxalate as a systemic immunometabolic stressor and IL-17A as a central mediator of oxalate-induced cardiorenal injury. These findings establish the oxalate-IL-17A axis as a mechanistic link between CKD and CVD and suggest IL-17A inhibition as a potential therapeutic strategy to reduce cardiovascular damage in CKD.

Spatial context modifies visual perception by enhancing novel and salient features over spatially redundant features in the underlying neural code of the primary visual cortex (V1). Although multiple intracortical pathways contribute to contextual modulation, their specific contributions to different types of contextual modulation are not fully understood. Leveraging the distinct laminar connectivity patterns of feedforward, feedback, and lateral pathways, we used ultra-high-resolution fMRI (7T T2*-weighted, 0.6 mm isotropic resolution) to infer their relative contributions to contextual modulation in V1 by analyzing blood-oxygenation-level-dependent (BOLD) signal across cortical depth. Participants viewed sine-wave grating disks embedded in large surround gratings. Segmentation cues were introduced or removed by manipulating the relative phase and orientation of the surround gratings, yielding three contextual conditions and a surround-only condition to measure the effects of context in the absence of feedforward input. Our analysis isolated the effects of orientation-tuned surround suppression (OTSS) from orientation-independent border-induced modulation (BIM). The results show that BOLD laminar profiles differ by modulation type: OTSS was absent from deep layers, whereas BIM was more broadly distributed. We also find that voxels at all depths are driven by spatial context in the absence of feedforward input, which accords with the finding of contextually driven neural responses in mammalian V1. These laminar differences likely reflect different proportional contributions of feedback from higher-order visual areas and long-range lateral connections within V1. Our findings help to explicate the contributions of recurrent processing to visual contextual modulation and its impacts on laminar-dependent BOLD fMRI.

Limb dominance is a human behavioral characteristic with many cultural, practical, scientific, and clinical implications. Yet why the dominant limb performs better across a range of motor skill-requiring tasks remains unanswered. Is it because of an intrinsic hemispheric advantage or instead is it the result of life-long practice with the dominant side? We tested these alternatives using two tasks either cross sectionally or after training. The first was 3D reaching with either an inertial challenge or the need to use a stick-like tool. The second required participants to write with their dominant and nondominant elbows. We applied a geometric analysis to quantify movement-trajectory shape. We show that 1) tool-use unmasks markedly inferior control in the nondominant arm, and this is because tools impose the need to generate unfamiliarly shaped movement trajectories; and 2) there is no general dominant limb motor control advantage, only task-specific experience or practice riding on top of an initial preference. These results reframe dominance as predominantly about learned control of tool kinematics rather than baseline asymmetry in control of limb dynamics.

Proteostasis, or protein homeostasis, is a tightly regulated network of cellular pathways essential for maintaining proper protein folding, trafficking, and degradation. Neurons are particularly vulnerable to proteostasis collapse due to their postmitotic and long-lived nature and thus represent a unique cell type to understand the dynamics of proteostasis throughout development and maturation. Here, we utilized a dual-species co-culture model of human excitatory neurons and mouse glia to recapitulate and investigate cell type-specific, maturation-related changes in the proteostasis network using data-independent acquisition LC-MS/MS proteomics. We quantified branch-specific unfolded protein response (UPR) activation by monitoring curated effector proteins downstream of the ATF6, IRE1/XBP1s, and PERK pathways, enabling a comprehensive, unbiased evaluation of UPR dynamics during in vitro neuronal maturation between 30 d and 60 d. Species-specific analysis revealed that mature neurons largely preserved proteostasis, although they showed some signs of collapse, primarily in endoplasmic reticulum (ER)-to-Golgi transport mechanisms. However, these changes were accompanied by upregulation of proteostasis-related machinery and activation of the ATF6 branch, as well as maintenance of the XBP1s and PERK branches of the UPR over time. In contrast, glia exhibited broad downregulation of proteostasis factors and UPR components, independent of neuronal presence. Furthermore, we quantified stimulus-specific modulation of select UPR branches in matured neurons exposed to pharmacologic ER stressors. These findings highlight distinct, cell-type-specific stress adaptations during in vitro maturation and provide a valuable proteomic resource for dissecting proteostasis and UPR regulation in human neurons.

Circadian rhythms play a crucial role in maintaining cardiovascular homeostasis, orchestrating fluctuations in blood pressure, heart rate variability, endothelial function, and systemic vascular tone. Disruptions of the circadian clock -arising from ageing, genetic predisposition, or environmental and lifestyle factors- can significantly elevate the risk of cardiovascular diseases, including hypertension, atherosclerosis, heart failure, and arrhythmias. This review examines the role of circadian regulation in cardiovascular physiology, from molecular clock networks and clock-controlled gene regulation to systemic cardiovascular physiology and clinical translation. We discuss how circadian disruption affects blood pressure, heart rate variability, and vascular health, through mechanisms including inflammation, mitochondrial dysfunction, and metabolic dysregulation. We further position circadian biology within the broader context of cardiovascular ageing and the molecular mechanisms that drive age-associated cardiovascular decline.Special attention is given to the role of inflamm-ageing in promoting atherosclerosis and acute cardiovascular events, as well as the impact of desynchrony between central and peripheral clocks on disease severity. Additionally, we highlight the circadian regulation of genes implicated in cardiovascular ageing and disease. Finally, we explore emerging research on the clinical implications of circadian misalignment, with a focus on therapeutic strategies such as chronotherapy, time-restricted eating, and physical activity. By integrating current evidence, this review provides a comprehensive perspective on leveraging circadian rhythms for the prevention and management of cardiovascular diseases.

SCN2A encodes the voltage-gated sodium channel NaV1.2, a central regulator of action potential initiation and propagation in glutamatergic neurons, and one of the strongest single-gene risk factors for autism spectrum disorder. Premature termination codons in SCN2A are widely considered to produce uniform haploinsufficiency through nonsense-mediated mRNA decay, an assumption that underpins current mechanistic and therapeutic models. We generated two mouse lines carrying patient-derived mutations - Scn2aY84X/+ (p.Tyr84UAA; early coding sequence) and Scn2aR1627X/+ (p.Arg1627UGA; terminal coding exon). We assessed allele-specific mRNA expression, NaV1.2 protein expression, ex vivo whole-cell recordings, and behavioral phenotypes in these mice. Allele-specific RNA handling diverged by position: mRNA carrying Y84X engaged partial nonsense-mediated decay, whereas R1627X transcripts were at allelic balance. Despite this difference in RNA fate, NaV1.2 protein was comparably reduced in both lines. Both variants slowed the action potential upstroke, with a larger decrement in Scn2aY84X/+. Spike threshold was depolarized only in Scn2aY84X/+. Mutant neurons showed reduced firing near rheobase. Both lines exhibited increased grooming, but Scn2aY84X/+ alone showed greater exploration and a male-predominant rotarod learning deficit. Locomotion, sociability, and sensorimotor gating were preserved. In maximal electroshock testing, mortality was reduced in both lines without changes in seizure threshold or severity. Our results show that SCN2A premature termination codon position determines allele-specific effects on neuronal excitability and behavior, where both NMD and phenotypes of the Scn2aY84X/+ line are more penetrant. These data challenge the assumption of uniform haploinsufficiency and directly support allele-tailored mechanistic studies and therapeutic strategies.

Neocortical spiking dynamics underlie voluntary behavior and are thought to emerge through synaptic plasticity during learning. However, the causal role of plasticity across cortical cell types in shaping population dynamics remains unclear. To address this, we manipulated Ca2+/calmodulin-dependent protein kinase II (CaMKII), a key mediator of plasticity, in mice learning a motor timing task. Transient CaMKII inactivation in the premotor cortex impaired learning without affecting execution of learned actions. Cell-type-specific manipulations revealed that CaMKII-dependent plasticity in two pyramidal tract (PT) neuron subtypes-but not intratelencephalic (IT) neurons-was required for learning. Concurrent large-scale electrophysiology showed that CaMKII activity in the two PT subtypes was necessary to shape distinct aspects of premotor cortical dynamics that jointly anticipate motor timing, whereas IT neuron plasticity was required to reduce the dimensionality of cortical activity. Together, synaptic plasticity in major cortical cell types plays specialized and complementary roles in sculpting cortical dynamics during learning.

Anthracycline chemotherapeutics are common chemotherapeutics that have substantial toxicities. There is substantial interpatient pharmacokinetic variability, though there is no method to quantify organ or tumor exposure. Here, we exposed an optical nanosensor array to detect each of four anthracyclines. We screened 12 ssDNA sequences paired with seven single-walled carbon nanotube (n,m) species against several concentrations of doxorubicin, daunorubicin, idarubicin, and epirubicin. Complex spectral responses were used to develop machine-learning-based classification models to quantify each anthracycline. The optimized extreme gradient boosting model classified high levels of each anthracycline with 100% accuracy. Principal component analysis distinguished low (≤5 μM) and high concentrations of each anthracycline. Finally, we validated selected ssDNA-(n,m) pair performance in synthetic urine and sweat. Our findings deliver a generalizable optical spectral fingerprinting methodology for hard-to-detect analytes. Their use in clinical biofluids portends the preclinical and potentially clinical pharmacokinetic measurement of anthracyclines to improve efficacy and reduce toxicities.