Atherosclerotic plaque instability in symptomatic non-significant carotid stenoses.

Objective: Carotid endarterectomy for symptomatic carotid stenosis is recommended for patients with >70% stenosis, but not in those with <50%. Because non-significant, low-degree stenoses may still cause strokes, refined risk stratification is necessary, which could be improved by assessing biological features of plaque instability. To challenge risk-stratification based on luminal narrowing, we compared biological features of carotid plaques from symptomatic patients with low-degree (<50%) vs high-degree (>70%) stenosis and explored potential mechanisms behind plaque instability in low-degree stenoses.

Atheroma transcriptomics identifies ARNTL as a smooth muscle cell regulator and with clinical and genetic data improves risk stratification.

Background And Aims: The role of vascular smooth muscle cells (SMCs) in atherosclerosis has evolved to indicate causal genetic links with the disease. Single cell RNA sequencing (scRNAseq) studies have identified multiple cell populations of mesenchymal origin within atherosclerotic lesions, including various SMC sub-phenotypes, but it is unknown how they relate to patient clinical parameters and genetics. Here, mesenchymal cell populations in atherosclerotic plaques were correlated with major coronary artery disease (CAD) genetic variants and functional analyses performed to identify SMC markers involved in the disease.

Personalized decision-making for vascular access creation in hemodialysis.

Selecting the appropriate kidney replacement therapy (KRT) is crucial in order to secure optimal care for chronic kidney disease (CKD) patients with end-stage renal disease (ESRD). Next to renal transplantation, the choice of dialysis modality directly affects patient well-being, treatment effectiveness, and long-term outcomes. Therefore, clinical decision-making must take into account a range of factors to tailor decisions to each patient's unique needs.

Lipoproteins and lipoprotein lipid composition are associated with stages of dysglycemia and subclinical coronary atherosclerosis.

Background: Dyslipidaemia in patients with diabetes contributes to the risk of atherosclerotic cardiovascular disease. We aimed to identify a dyslipidemic profile associated with both dysglycemia and subclinical coronary atherosclerosis.

Methods: Study participants (n = 5050) were classified in three groups: normoglycemia, pre-diabetes, and diabetes.

PIEZO1 targeting in macrophages boosts phagocytic activity and foam cell apoptosis in atherosclerosis.

The rising incidences of atherosclerosis have necessitated efforts to identify novel targets for therapeutic interventions. In the present study, we observed increased expression of the mechanosensitive calcium channel Piezo1 transcript in mouse and human atherosclerotic plaques, correlating with infiltration of PIEZO1-expressing macrophages. In vitro administration of Yoda1, a specific agonist for PIEZO1, led to increased foam cell apoptosis and enhanced phagocytosis by macrophages.

Multiomics unveils extracellular vesicle-driven mechanisms of endothelial communication in human carotid atherosclerosis.

Carotid atherosclerosis is orchestrated by cell-cell communication that drives progression along a clinical continuum (asymptomatic to symptomatic). Extracellular vesicles (EVs) are cell-derived nanoparticles representing a new paradigm in cellular communication. Little is known about their biological cargo, cellular origin/destination, and functional roles in human atherosclerotic plaque.

Clinical impact of the Kidney Failure Risk Equation for vascular access planning.

Background: Risk-based thresholds for arteriovenous (AV) access creation has been proposed to aid vascular access planning. We aimed to assess the clinical impact of implementing the Kidney Failure Risk Equation (KFRE) for vascular access referral.

Methods: A total of 16 102 nephrology-referred chronic kidney disease (CKD) patients from the Swedish Renal Registry 2008-18 were included.

On the Impact of Residual Strains in the Stress Analysis of Patient-Specific Atherosclerotic Carotid Vessels: Predictions Based on the Homogenous Stress Hypothesis.

The identification of carotid atherosclerotic lesion at risk for plaque rupture, eventually resulting in cerebral embolism and stroke, is of paramount clinical importance. High stress in the fibrous plaque cap has been proposed as risk factor. However, among others, residual strains influence said stress predictions, but quantitative and qualitative implications of residual strains in this context are not well explored.

Validating human and mouse tissues commonly used in atherosclerosis research with coronary and aortic reference tissue: similarities but profound differences in disease initiation and plaque stability.

Objective: Characterization of the atherosclerotic process fully relies on histological evaluation and staging through a consensus grading system. So far, a head-to-head comparison of atherosclerotic process in experimental models and tissue resources commonly applied in atherosclerosis research with the actual human atherosclerotic process is missing.

Material And Methods: Aspects of the atherosclerotic process present in established murine atherosclerosis models and human carotid endarterectomy specimen were systematically graded using the modified American Heart Association histological classification (Virmani classification).

The VE-cadherin/AmotL2 mechanosensory pathway suppresses aortic inflammation and the formation of abdominal aortic aneurysms.

Endothelial cells respond to mechanical forces exerted by blood flow. Endothelial cell-cell junctions and the sites of endothelial adhesion to the matrix sense and transmit mechanical forces to the cellular cytoskeleton. Here we show that the scaffold protein AmotL2 connects junctional VE-cadherin and actin filaments to the nuclear lamina.

Biliverdin Reductase B Is a Plasma Biomarker for Intraplaque Hemorrhage and a Predictor of Ischemic Stroke in Patients with Symptomatic Carotid Atherosclerosis.

Background: Intraplaque hemorrhage (IPH) is a hallmark of atherosclerotic plaque instability. Biliverdin reductase B (BLVRB) is enriched in plasma and plaques from patients with symptomatic carotid atherosclerosis and functionally associated with IPH.

Objective: We explored the biomarker potential of plasma BLVRB through (1) its correlation with IPH in carotid plaques assessed by magnetic resonance imaging (MRI), and with recurrent ischemic stroke, and (2) its use for monitoring pharmacotherapy targeting IPH in a preclinical setting.

FHL5 Controls Vascular Disease-Associated Gene Programs in Smooth Muscle Cells.

Background: Genome-wide association studies have identified hundreds of loci associated with common vascular diseases, such as coronary artery disease, myocardial infarction, and hypertension. However, the lack of mechanistic insights for many GWAS loci limits their translation into the clinic. Among these loci with unknown functions is -four-and-a-half LIM (LIN-11, Isl-1, MEC-3) domain 5 (; chr6q16.

Interleukin-6 trans-signaling induced laminin switch contributes to reduced trans-endothelial migration of granulocytic cells.

Background And Aims: Laminins are essential components of the endothelial basement membrane, which predominantly contains LN421 and LN521 isoforms. Regulation of laminin expression under pathophysiological conditions is largely unknown. In this study, we aimed to investigate the role of IL-6 in regulating endothelial laminin profile and characterize the impact of altered laminin composition on the phenotype, inflammatory response, and function of endothelial cells (ECs).

Long Term Mortality Rate in Patients Treated with Carotid Endarterectomy.

Objective: Carotid endarterectomy (CEA) is an effective surgical method for stroke prevention in selected patients with carotid stenosis. Few contemporary studies report on the long term mortality rate in CEA treated patients, despite continuous changes in medication, diagnostics, and patient selection. Here, the long term mortality rate is described in a well characterised cohort of asymptomatic and symptomatic CEA patients, sex differences evaluated, and mortality ratio compared with the general population.

Pyruvate dehydrogenase kinase regulates vascular inflammation in atherosclerosis and increases cardiovascular risk.

Aims: Recent studies have revealed a close connection between cellular metabolism and the chronic inflammatory process of atherosclerosis. While the link between systemic metabolism and atherosclerosis is well established, the implications of altered metabolism in the artery wall are less understood. Pyruvate dehydrogenase kinase (PDK)-dependent inhibition of pyruvate dehydrogenase (PDH) has been identified as a major metabolic step regulating inflammation.

In silico model of atherosclerosis with individual patient calibration to enable precision medicine for cardiovascular disease.

Objective: Guidance for preventing myocardial infarction and ischemic stroke by tailoring treatment for individual patients with atherosclerosis is an unmet need. Such development may be possible with computational modeling. Given the multifactorial biology of atherosclerosis, modeling must be based on complete biological networks that capture protein-protein interactions estimated to drive disease progression.

Biomechanical Assessment of Macro-Calcification in Human Carotid Atherosclerosis and Its Impact on Smooth Muscle Cell Phenotype.

Intimal calcification and vascular stiffening are predominant features of end-stage atherosclerosis. However, their role in atherosclerotic plaque instability and how the extent and spatial distribution of calcification influence plaque biology remain unclear. We recently showed that extensive macro calcification can be a stabilizing feature of late-stage human lesions, associated with a reacquisition of more differentiated properties of plaque smooth muscle cells (SMCs) and extracellular matrix (ECM) remodeling.

Therapeutic potential of the Proprotein Convertase Subtilisin/Kexin family in vascular disease.

Proprotein convertase subtilisin/kexins (PCSKs) constitute a family of nine related proteases: PCSK1-7, MBTPS1, and PCSK9. Apart from PCSK9, little is known about PCSKs in cardiovascular disease. Here, we aimed to investigate the expression landscape and druggability potential of the entire PCSK family for CVD.

Patient-specific biomechanical analysis of atherosclerotic plaques enabled by histologically validated tissue characterization from computed tomography angiography: A case study.

Background: Rupture of unstable atherosclerotic plaques with a large lipid-rich necrotic core and a thin fibrous cap cause myocardial infarction and stroke. Yet it has not been possible to assess this for individual patients. Clinical guidelines still rely on use of luminal narrowing, a poor indicator but one that persists for lack of effective means to do better.