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As disease-specific interventions for dementia are being developed, the ability to identify the underlying pathology and dementia subtypes is increasingly important. Vascular cognitive impairment and dementia (VCID) is the second most common cause of dementia after Alzheimer disease, but progress in identifying molecular biomarkers for accurate diagnosis of VCID has been relatively limited. In this Review, we examine the roles of large and small vessel disease in VCID, considering the underlying pathophysiological processes that lead to vascular brain injury, including atherosclerosis, arteriolosclerosis, ischaemic injury, haemorrhage, hypoperfusion, endothelial dysfunction, blood–brain barrier breakdown, inflammation, oxidative stress, hypoxia, and neuronal and glial degeneration. We consider the key molecules in these processes, including proteins and peptides, metabolites, lipids and circulating RNA, and consider their potential as molecular biomarkers alone and in combination. We also discuss the challenges in translating the promise of these biomarkers into clinical application.Vascular cognitive impairment and dementia is the second most common cause of dementia after Alzheimer disease. In this Review, the authors examine the potential of key molecules in the pathophysiology as biomarkers of vascular cognitive impairment and dementia and consider the challenges of clinical translation.

Endothelial to mesenchymal transition (EndMT) plays a major role during development, and also contributes to several adult cardiovascular diseases. Importantly, mesenchymal cells including fibroblasts are prominent in atherosclerosis, with key functions including regulation of: inflammation, matrix and collagen production, and plaque structural integrity. However, little is known about the origins of atherosclerosis-associated fibroblasts. Here we show using endothelial-specific lineage-tracking that EndMT-derived fibroblast-like cells are common in atherosclerotic lesions, with EndMT-derived cells expressing a range of fibroblast-specific markers. In vitro modelling confirms that EndMT is driven by TGF-β signalling, oxidative stress and hypoxia; all hallmarks of atherosclerosis. ‘Transitioning’ cells are readily detected in human plaques co-expressing endothelial and fibroblast/mesenchymal proteins, indicative of EndMT. The extent of EndMT correlates with an unstable plaque phenotype, which appears driven by altered collagen-MMP production in EndMT-derived cells. We conclude that EndMT contributes to atherosclerotic patho-biology and is associated with complex plaques that may be related to clinical events. Endothelial to mesenchymal transition (EndMT) is a crucial developmental process that also plays a role in the pathogenesis of some diseases. Here the authors show that EndMT contributes to the development of atherosclerosis in mice and humans, and is associated with complex human plaques that may be prone to rupture.

GWAS identified variants associated with birth weight (BW), childhood obesity (CO) and childhood BMI (CBMI), and placenta is a critical organ for fetal development and postnatal health. We examined the role of placental transcriptome and eQTLs in mediating the genetic causes for BW, CO and CBMI, and applied integrative analysis (Colocalization and MetaXcan). GWAS loci associated with BW, CO, and CBMI were substantially enriched for placenta eQTLs (6.76, 4.83 and 2.26 folds, respectively). Importantly, compared to eQTLs of adult tissues, only placental eQTLs contribute significantly to both anthropometry outcomes at birth (BW) and childhood phenotypes (CO/CBMI). Eight, six and one transcripts colocalized with BW, CO and CBMI risk loci, respectively. Our study reveals that placental transcription in utero likely plays a key role in determining postnatal body size, and as such may hold new possibilities for therapeutic interventions to prevent childhood obesity.

Arterial dissections, which involve an abrupt tear in the wall of a major artery resulting in the intramural accumulation of blood, are a family of catastrophic disorders causing major, potentially fatal sequelae. Involving diverse vascular beds, including the aorta or coronary, cervical, pulmonary, and visceral arteries, each type of dissection is devastating in its own way. Traditionally they have been studied in isolation, rather than collectively, owing largely to the distinct clinical consequences of dissections in different anatomical locations – such as stroke, myocardial infarction, and renal failure. Here, we review the shared and unique features of these arteriopathies to provide a better understanding of this family of disorders. Arterial dissections occur commonly in the young to middle-aged, and often in conjunction with hypertension and/or migraine; the latter suggesting they are part of a generalized vasculopathy. Genetic studies as well as cellular and molecular investigations of arterial dissections reveal striking similarities between dissection types, particularly their pathophysiology, which includes the presence or absence of an intimal tear and vasa vasorum dysfunction as a cause of intramural hemorrhage. Pathway perturbations common to all types of dissections include disruption of TGF-β signaling, the extracellular matrix, the cytoskeleton or metabolism, as evidenced by the finding of mutations in critical genes regulating these processes, including LRP1 , collagen genes, fibrillin and TGF-β receptors, or their coupled pathways. Perturbances in these connected signaling pathways contribute to phenotype switching in endothelial and vascular smooth muscle cells of the affected artery, in which their physiological quiescent state is lost and replaced by a proliferative activated phenotype. Of interest, dissections in various anatomical locations are associated with distinct sex and age predilections, suggesting involvement of gene and environment interactions in disease pathogenesis. Importantly, these cellular mechanisms are potentially therapeutically targetable. Consideration of arterial dissections as a collective pathology allows insight from the better characterized dissection types, such as that involving the thoracic aorta, to be leveraged to inform the less common forms of dissections, including the potential to apply known therapeutic interventions already clinically available for the former.

Space flight exposes astronauts to a unique environment characterized by microgravity, ionizing radiation, and other stressors that can profoundly affect the human body. Deep-space exploration-type missions to the Moon (NASA’s Artemis and Gateway programs), Mars, and beyond will introduce prolonged exposure to health hazards, including but not limited to isolation and confinement, sleep disruption, and exposure to different types and quantities of particle radiation (i.e., high-energy and atomic number – HZE). There are also logistical implications of traveling farther from low Earth orbit (LEO), including limited access to medical help and supplies. Currently, the known effects of space travel on the cardiovascular system include dysrhythmias, altered vascular compliance, dysautonomia, and induction of a pro-inflammatory state. It is not known how these concerns, and other potentially unknown cardiovascular risks, will manifest during and/or after exploration-type missions. This manuscript comprehensively reviews the cardiovascular disease risks associated with deep space exploration. Brojakowska et al. review the synergistic cardiovascular risks of deep-space travel, from HZE radiation to microgravity-induced remodeling. By integrating murine mechanistic data with probabilistic modeling, the authors advocate for a shift toward individualized, Earth-independent medical frameworks to safeguard astronauts on multi-year missions.

BackgroundAccurate classification of aortic stenosis (AS) severity remains challenging despite detailed echocardiographic assessment. Adjudication of severity is informed by subjective interpretation of aortic leaflet motion from the first image parasternal long axis (PLAX) view, but quantitative metrics of leaflet motion currently do not exist. The objectives of the study were to echocardiographically quantify aortic leaflet motion using the PLAX view and correlate motion data with Doppler-derived hemodynamic indices of disease severity, and predict significant AS using these isolated motion data.MethodsPLAX loops from 200 patients with and without significant AS were analyzed. Linear and angular motion of the anterior (right coronary) leaflet were quantified and compared between severity grades. Three simple supervised machine learning classifiers were then trained to distinguish significant (moderate or worse) from nonsignificant AS and individual severity grades.ResultsLinear and angular displacement demonstrated strong correlation with aortic valve area (r = 0.81 and r = 0.74, respectively). Severe AS cases demonstrated global leaflet motion of 2.1 mm, compared with 3.6 mm for moderate cases (P < 0.01) and 9.2 mm for control cases (P < 0.01). Severe cases demonstrated mean global angular rotation of 11°, significantly less than moderate (18°, P < 0.01) and normal cases (47°, P < 0.01). Using these novel metrics, a simple supervised machine learning model predicted significant AS with an accuracy of 90% and area under the receiver operator characteristics curve (AUC) of 0.96. Prediction of individual severity class was achieved with an accuracy of 72.5% and AUC of 0.88.ConclusionsAdvancing severity of AS is associated with significantly reduced linear and angular leaflet displacement. Leaflet motion data can accurately classify AS using a single parasternal long axis view, without the need for hemodynamic or Doppler assessment. Our model, grounded in biological plausibility, simple linear algebra, and supervised machine learning, provides a highly explainable approach to disease identification and may hold significant clinical utility for the diagnosis and classification of AS.

Synthetic biomaterial vascular grafts perform well in large-diameter applications but remain an intractable challenge in small-diameter (less than 6 mm) applications due to an inability to support rapid endothelialization while imparting blood compatibility and regulating smooth muscle cells.Some extracellular matrix molecules have an inherent ability to bind endothelial cells but neither smooth muscle cells nor platelets, making them attractive candidates for incorporation into biomaterials for vascular graft applications.Advances to recombinant protein expression and emerging approaches to immobilize biomolecules on surfaces offer ways to overcome the barriers to the broader exploration of incorporating ECM molecules in vascular graft biomaterials. The performance of synthetic biomaterial vascular grafts for the bypass of stenotic and dysfunctional blood vessels remains an intractable challenge in small-diameter applications. The functionalization of biomaterials with extracellular matrix (ECM) molecules is a promising approach because these molecules can regulate multiple biological processes in vascular tissues. In this review, we critically examine emerging approaches to ECM-containing vascular graft biomaterials and explore opportunities for future research and development toward clinical use. The performance of synthetic biomaterial vascular grafts for the bypass of stenotic and dysfunctional blood vessels remains an intractable challenge in small-diameter applications. The functionalization of biomaterials with extracellular matrix (ECM) molecules is a promising approach because these molecules can regulate multiple biological processes in vascular tissues. In this review, we critically examine emerging approaches to ECM-containing vascular graft biomaterials and explore opportunities for future research and development toward clinical use.

Genetic studies have linked PHACTR1 to a range of vascular diseases, underscoring its pivotal role in vascular biology. However, the full spectrum of PHACTR1 -mediated signaling pathways remains largely unexplored. To bridge this gap, we employ a multi-omics pipeline combining pairwise differential expression analysis, multi-omics pathway integration, and feature-level correlation analyses across four distinct omics datasets to map the global signaling networks driven by PHACTR1 . By integrating transcriptomic, proteomic, metabolic, and lipidomic profiles from human HT1080 cells with PHACTR1 overexpression or knockdown, and then validating key findings in primary human endothelial cells, here we show that PHACTR1 exerts broad control over fundamental cellular processes beyond cytoskeletal regulation. We demonstrate that PHACTR1 governs cell cycle progression, validating that increased expression alters key regulatory proteins. We also uncover a distinct function in iron metabolism, showing PHACTR1 regulates essential cellular iron-storage proteins and identify the PHACTR1 protein within the mitochondria where it directs morphology and bioenergetics through a signaling axis involving AKAP1 and Drp1. These mitochondrial changes align with observed shifts in lipid metabolism and correlations in human arterial tissue. These findings provide a systems-level blueprint of PHACTR1 function, revealing how this gene influences vascular health and offering potential targets for therapeutic intervention. Integrated multi-omics analysis uncovers the role of the vascular disease-associated gene PHACTR1 in regulating mitochondrial dynamics, iron metabolism, and cell cycle.

Patients with ST-segment elevation myocardial infarction (STEMI) admitted during nonregular working hours (off-hours) have been reported to have greater mortality than those admitted during regular working hours (on-hours), perhaps because of the lower availability of catheterization laboratory services and longer door-to-balloon times. This might not be the case, however, for hospital centers in which primary percutaneous coronary intervention (PCI) is invariably performed. We conducted a substudy using the Harmonizing Outcomes with Revascularization and Stents in Acute Myocardial Infarction study data to determine whether the STEMI arrival time was associated with differing clinical outcomes. We identified all patients with STEMI admitted to a PCI-capable hospital who underwent primary PCI. Patients presenting during on-hours were compared to those presenting during off-hours. The primary outcome of death, major adverse cardiovascular events, and net adverse clinical events was examined. We identified 2,440 patients (1,205 [49%] on-hours and 1,235 [51%] off-hours). Similar baseline characteristics were observed. The off-hour patients had a significantly longer door-to-balloon time (92 vs 75 minutes; p <0.0001) and total ischemic time (209 vs 194 minutes; p <0.0001). Despite these differences, the risk-adjusted all-cause mortality, major adverse cardiovascular events, and net adverse clinical events rates were similar for both groups during the in-hospital, 1-year, and 3-year follow-up. In conclusion, patients with STEMI presenting to primary PCI hospitals during off-hours might have slightly longer delays to revascularization; however, they experienced similar short- and long-term survival and clinical outcomes as those arriving during on-hours.

Coronary artery disease (CAD) is a complex inflammatory disease involving genetic influences across cell types. Genome-wide association studies have identified over 200 loci associated with CAD, where the majority of risk variants reside in noncoding DNA sequences impacting cis -regulatory elements. Here, we applied single-nucleus assay for transposase-accessible chromatin with sequencing to profile 28,316 nuclei across coronary artery segments from 41 patients with varying stages of CAD, which revealed 14 distinct cellular clusters. We mapped ~320,000 accessible sites across all cells, identified cell-type-specific elements and transcription factors, and prioritized functional CAD risk variants. We identified elements in smooth muscle cell transition states (for example, fibromyocytes) and functional variants predicted to alter smooth muscle cell- and macrophage-specific regulation of MRAS (3q22) and LIPA (10q23), respectively. We further nominated key driver transcription factors such as PRDM16 and TBX2. Together, this single-nucleus atlas provides a critical step towards interpreting regulatory mechanisms across the continuum of CAD risk. Single-nucleus ATAC-seq characterization of chromatin accessibility in human coronary artery disease samples identifies cell-type- and state-specific regulatory mechanisms underlying disease risk, highlighting the roles of TBX2 and PRDM16.