Human Arterial Wall Research Articles

Investigating the Impact of Atherosclerotic Plaque Size on Human Arterial Wall Stress-Strain Hysteresis Loop and Deformed State Pattern

Investigating the Impact of Atherosclerotic Plaque Size on Human Arterial Wall Stress-Strain Hysteresis Loop and Deformed State Pattern

Human blood vessel microbiota in healthy adults based on common femoral arteries of brain-dead multi-organ donors.

Discovery of human microbiota is fundamentally changing our perceptions of certain diseases and their treatments. However little is known about the human blood vessel microbiota, it may have important effects on vascular pathological lesions and vascular homograft failure. In our prospective survey study fourteen femoral arteries, harvested from donors in multi-organ donations, were examined using the V3-V4 region 16S rRNA sequencing method. The most abundant phyla in the human vascular microbiota were Proteobacteria, Firmicutes and Actinobacteria. At the genus level, the most abundant taxa were Staphylococcus, Corynebacterium, Pseudomonas, Bacillus, Acinetobacter and Propionibacterium. Of the bacterial taxa that have an indirect effect on the development of atherosclerosis, we found Porphyromonas gingivalis, Prevotella nigrescens and Enterobacteriaceae spp. with different abundances in our samples. Of the bacteria that are more common in the intestinal flora of healthy than of atherosclerosis patients, Roseburia and Ruminococcus occurred in the majority of samples. The human arterial wall has a unique microbiota that is significantly different in composition from that of other areas of the body. Our present study provides a basis for ensuing research that investigates the direct role of the microbiota in vascular wall abnormalities and the success of vascular allograft transplantations.

Abstract 13560: System Gene Regulatory Network-Based Drug Repurposing Combined With Preclinical Molecular Imaging Identifies Anti-Atherosclerotic Properties of Auranofin

Introduction: The identification of new treatments for atherosclerosis (ACVD), a common complex disease, is a daunting task because sets of genes, rather than individual genes, control cell functions. Using systems genetics, our team identified gene regulatory network (GRN42) that is active in the human atherosclerotic arterial wall and is involved in the regulation of foam cell formation. Hypothesis: A network-driven drug repurposing approach combined with rigorous preclinical validation will identify new uses for existing drugs to treat ACVD. Methods: We developed a GRN42-based computational drug repurposing pipeline to infer new uses for existing drugs. Selected compounds were screened by measuring their ability to inhibit foam cell formation in vitro using THP-1-derived macrophages. The in vivo efficacy was validated in ApoE-/- mice fed a western diet by histology and in atherosclerotic rabbits using histology and non-invasive 18 F-FDG PET-MR imaging. Results: 30 candidate compounds were predicted to influence the function of GRN42 and 5 were selected for in vitro screening based on their prediction scores (Figure 1A). As expected, vitamin D reduced cholesteryl esters accumulation in foam cells. Auranofin, and FDA-approved drug for rheumatoid arthritis reduced foam cell formation. As predicted methyl-fasudil had no effect, while nicardipine and flutamide increased foam cell formation (Figure 1B). Auranofin reduced plaque burden in ApoE-/- mice (Figure 1C) and in rabbits reduced lipid accumulation (Figure 1D) and inflammation shown as reduced 18 F-FDG uptake in the arterial wall (Figure 1E). Conclusions: Our results provide robust evidence that a GRN-based computational drug repurposing approach, when combined with robust preclinical validation using translational molecular imaging, can successfully identify new uses of existing drugs for the treatment of ACVD.

Nondestructive Method for Testing Elasticity of Walls of Human Veins and Arteries

Methods of testing the elasticity of walls of human veins and arteries are considered. The problems that arise when using them are noted. The necessity of developing nondestructive methods for testing the elasticity of the walls of human veins and arteries is substantiated. A technique for monitoring changes in their elasticity using noninvasive methods of pulse wave recording is proposed. The results of comparing data on changes in the elasticity of the walls of veins and arteries obtained using various methods of pulse wave recording and invasive methods are presented. The advantages and disadvantages of the proposed technique using various pulse waves are noted.

Spatially-dependent material uncertainties in anisotropic nonlinear elasticity: Stochastic modeling, identification, and propagation

This paper develops a stochastic model for the spatially-dependent material parameters parameterizing anisotropic strain energy density functions. The construction is cast within the framework of information theory, which is invoked to derive a least-informative model while ensuring consistency with theoretical requirements in finite elasticity. Specifically, almost sure polyconvexity and uniform growth conditions are enforced through proper repulsion constraints and regularization, hence making the forward problem of uncertainty propagation well posed. In addition, transformations arising from the linearization procedure are introduced for consistency and induce statistical dependencies in the primary variables. The latter include material moduli, a weight balancing between the isotropic and anisotropic contributions, and the angle defining the structural tensors. The identification of the model is subsequently performed, using an existing database on human arterial walls. Maximum likelihood estimators are obtained and provided for the adventitia, media, and intima layers, which enables the use of the proposed model as a generative surrogate for, e.g., training and classification in data-driven approaches integrating inter-patient variability. Finally, uncertainty propagation on a realistic, patient-specific geometry is conducted to demonstrate the efficiency of the stochastic modeling framework.

Evaluation of the effect of tofogliflozin on the tissue characteristics of the carotid wall\u2014a sub-analysis of the UTOPIA trial

BackgroundSince sodium-glucose cotransporter 2 (SGLT2) inhibitors have a pleiotropic antiatherogenic effect, they are expected to attenuate the progression of atherosclerosis. However, whether SGLT2 inhibitors affect the tissue characteristics of the human arterial wall remains unclear. This study aimed to evaluate the effects of tofogliflozin, a selective SGLT2 inhibitor, on the tissue characteristics of the human arterial wall in type 2 diabetes (T2DM) patients without apparent cardiovascular disease (CVD).MethodsThe present study was a post hoc analysis based on data obtained from the Using Tofogliflozin for Possible Better Intervention against Atherosclerosis for Type 2 Diabetes Patients (UTOPIA) trial, which was a multicenter prospective, randomized, open-label, blinded-endpoint study conducted to evaluate the efficacy of tofogliflozin in preventing the progression of atherosclerosis in patients with T2DM. We evaluated the longitudinal change in the ultrasonic tissue characteristics of the carotid wall using gray-scale median (GSM), an established index of ultrasonic tissue characteristics. The right and left intima-medial areas were delineated, and the GSM values were evaluated (right GSM-CCA and left GSM-CCA). The average values of the right and left carotid arteries were defined as “mean GSM-CCA value.”ResultsIn a mixed-effects model for repeated measures, mean GSM-CCA, along with the right and left GSM-CCA values, did not significantly change in either the tofogliflozin (n = 168) or conventional treatment group (n = 169). In addition, the tofogliflozin and conventional treatment groups did not significantly differ regarding the change of the mean GSM-CCA (mean difference [95% CI] − 1.24[− 3.87, 1.38], P = 0.35), along with the right (mean difference [95% CI] − 2.33[− 5.70, 1.05], P = 0.18) and the left GSM-CCA (mean difference [95% CI] − 0.29 [− 3.53, 2.95], P = 0.86) values. Similar findings were obtained even after adjusting for traditional cardiovascular risk factors and/or the administration of drugs at baseline.ConclusionsThe tissue characteristics of the carotid arterial wall did not change in either the tofogliflozin or conventional treatment group during the 104-week treatment period, and there was no significant difference between the treatment groups.Clinical trial registration UMIN000017607 (https://www.umin.ac.jp/icdr/index.html)

Hypoxia of human endothelial artery wall cells affects arterial extracellular matrix remodelling and contributes to atherosclerosis development

Hypoxia of human endothelial artery wall cells affects arterial extracellular matrix remodelling and contributes to atherosclerosis development

Abstract 12000: A Novel Human Arterial Transcriptomic Signature Associated With Major Adverse Cardiovascular Events and Oxidative Stress

Introduction: The biology of human vascular wall is implicated in cardiovascular pathology. We applied discovery transcriptomics to internal mammary arteries (IMAs) obtained from cardiac surgery patients, to identify pathways that can be treated therapeutically. Methods: Weighted correlation network analysis was conducted in sequencing data from IMAs RNA in 205 patients (Arm 1). Association with future incidence of major adverse cardiovascular events [MACE: cardiovascular death (CVD), non-fatal myocardial infarction or stroke, or new-onset heart failure] was assessed with Cox regression models (adjusted for age, sex, hypertension, dyslipidaemia, diabetes mellitus, and plasma TNFa). Arm 2 included 497 patients in whom segments of IMA were used for ex-vivo quantification of NADPH-stimulated superoxide by lucigenin chemiluminescence. Results: We identified 10 coexpressed gene ‘modules’ in the human arterial wall, through unsupervised transcriptomic analysis. The “red” module was found to cluster with arterial NADPH oxidase activity, while its eigengene values had the most significant correlation ( a ). Patients with high eigengene values for the “red” module showed a 3-fold higher risk of MACE ( b ), and enrichment analysis revealed top pathways ( c ). The Study Arm 2 population was followed up for a median of 6.35 years [IQR: 3.97-8.38], with 50 CVD and 101 MACE. High NADPH oxidases activity was independently predictive of cardiovascular mortality ( d ) and MACE (adj. hazard ratio 1.58 [1.07-2.36], p=0.02). Conclusion: We demonstrate that arterial oxidative stress leads to high risk of MACE in patients with atherosclerosis. We also identify a novel, redox-related arterial transcriptomic signature that predicts long-term cardiovascular risk. Pathways related with oxidative stress, or glucose metabolism or Hypoxia-Inducible Factor-1 in the human arterial wall, may be rational therapeutic targets to reduce cardiovascular risk in secondary prevention.

Feasibility of InVivo Imaging of Fibroblast Activation Protein in Human Arterial Walls.

Increased expression of fibroblast-activating protein (FAP) in fibrous caps may contribute to progression of atherosclerotic plaques. Methods: Forty-one patients who underwent 68Ga-conjugated quinoline-based FAP inhibitor (68Ga-FAPI-04) PET/CT for noncardiovascular indications were retrospectively analyzed. Correlations were assessed between the uptake of 68Ga-FAPI-04 in large arterial walls (SUVmax and target-to-background ratio, TBR) and degree of calcification and cardiovascular risk factors. Results: Focal arterial uptake of 68Ga-FAPI-04 or calcification was detected in 1,177 arterial segments in all 41 patients. TBR was negatively correlated with the degree of calcification (Hounsfield units) (r = -0.27, P < 0.01). Mean TBR in higher-risk patients was greater than in lower-risk patients (2.2 ± 0.3 vs. 1.8 ± 0.3, P < 0.01). Immunohistochemical labeling of carotid plaques exhibited prominent FAP expression in a thin fibrous cap and moderate FAP expression in a thick cap. Conclusion:68Ga-FAPI-04 PET/CT might have potential for imaging fibroblastic activation in the arterial wall.

MiR-210 regulates vascular endothelial cell apoptosis in arteriosclerosis obliterans through the JAK1-STAT3 pathway

IntroductionAtherosclerosis is a continuously worsening chronic condition that starts in the arteries and may then affect other blood vessels. There is increasing evidence linking microRNAs to the development of arteriosclerosis obliterans (ASO). Quantitative reverse transcription polymerase chain reaction (qRT-PCR) was applied in this study to detect miR-210-5p (miR-210) expression, and significant upregulation was observed in human arterial walls where ASO was prevalent.Material and methodsThe proliferation of human umbilical vascular endothelial cells (HUVECs) with various levels of miR-210 expression was assessed via MTT and colony-formation assays. Cell proliferation was significantly promoted in HUVECs with upregulated miR-210 levels and reduced in HUVECs with downregulated miR-210 levels.ResultsFlow cytometric analysis of cells stained with annexin V-FITC and propidium iodide data demonstrated that miR-210 inhibited apoptosis, while miR-210 inhibition promoted apoptosis by mediating pro-apoptotic protein expression levels. These results were verified using a dual-luciferase reporter gene assay system, which showed that Janus kinase 1 (JAK1) was directly targeted by miR-210, while an miR-210 mimic significantly decreased downstream JAK1 and signal transducer and activator of transcription 3 (STAT3) activation at a post-transcriptional level in HUVECs, as detected by western blotting and qRT-PCR. Further inhibition of either JAK1 or STAT3 counteracted the effect of miR-210 on HUVEC proliferation and apoptosis. These findings suggest that miR-210 promotes HUVEC proliferation, at least in part, by targeting the JAK1-STAT3 signaling axis.ConclusionsThis study provides insights into the contribution of the miR-210-JAK1-STAT3 axis and its underlying mechanisms to ASO pathology.

Single-Cell Transcriptomic Atlas of Different Human Cardiac Arteries Identifies Cell Types Associated With Vascular Physiology.

[Figure: see text].

Study of the Influence of Plaque Growth and Hydrostatic Properties in an Atherosclerotic Artery, for the Prevention of Arterial Wall Damage: Application to Vascular Diseases

The objective of this work is to prevent damage of the arterial wall, using a theoretical model of hyperelastic, anisotropic, and dynamic behavior of the human arterial. This work is mainly focused on the properties of the hydrostatic stress and the evolution of stenosis. This work is mainly focused on the properties of the hydrostatic stress and the evolution of stenosis in order to understand the effect of the size of the plaque deposit, the loss of elasticity of the wall, and the increase in the density of the blood on the mechanical behavior of the human arterial wall. The great contribution of this work shows us that increasing the size of the plaque also increases arterial stress, and the radial growth of the plaque is very dangerous compared to the longitudinal growth. Furthermore, atherosclerosis promotes the loss of elasticity of the arterial wall and increases the density of blood mass. Indeed, all these subsequent phenomena increase arterial stress. All the results are in good agreement with the expected result of the literature and could play an important role in the diagnosis of the patient with an arterial injury. It will also help the doctor and the surgeon to make a good clinical decision and good treatment planning.

Improved numerical model of the arterial wall applied for simulations of stent deployment within patient-specific coronary arteries

Arterial stenosis is the obstruction of normal blood flow that is caused by atherosclerosis. One of the endovascular treatment procedures in this case is the implantation of a stent to restore the blood flow. This study presented an improved numerical model that can precisely simulate the deformation of human arterial wall in coronary arteries, during the stent deployment process. The new model considered the arterial wall as an incompressible, isotropic and hyperrelastic material. The material coefficients were defined according to experimental values presented in literature. The accuracy of the numerical model was investigated by comparing the results with follow up data obtained in clinical examination. The small relative and standard deviation error prove that this numerical model can be used to assist clinicians in decision making and treatment planning with reliable predictions of the outcome of the stent deployment procedure.

Fat-Soluble Vitamins Affect Composition of Extracellular Matrix Deposited by Human Aortic Smooth Muscle and Endothelial Cells In Vitro

Atherosclerotic cardiovascular disease is accompanied by changes in arterial connective tissue. We evaluated the effects of fat-soluble vitamins A, D, and E individually and in combinations on the composition of extracellular matrix produced and deposited by arterial wall cells, human aortic smooth muscle cells, and endothelial cells. Individually, vitamins D and E stimulated collagen type I extracellular matrix deposition in human aortic smooth muscle cell cultures. However, vitamins A, D, and E reduced collagen type IV deposition by human aortic smooth muscle cell, counteracting the stimulatory effects of vitamin C. The extracellular matrix deposition of heparan sulfate by human aortic smooth muscle cells increased by vitamin C and its combination (C+D+E). β-carotene + D + C induced the extracellular matrix deposition of collagen I by endothelial cells. Vitamin E with other vitamins resulted in either induction (E+C+A) or inhibition (E+D). The extracellular matrix deposition of type IV collagen and elastin by human aortic endothelial cells was not affected by test vitamins, except the extracellular matrix type IV collagen decrease by combinations (A+E), (A+D+E), and (C+D+E). The extracellular matrix deposition of all tested glycosaminoglycans was reduced by vitamin A and its combination (A+C+D+E). Therefore, the fat-soluble vitamins applied individually or in combination—both with each other or with ascorbic acid—can affect extracellular matrix deposition of type I and IV collagens, and key glycosaminoglycans by cultured human aortic arterial wall cells.

Aortic, common carotid and external iliac artery arterial wall stiffness parameters in horses: Inter-day and inter-observer and intra-observer measurement variability.

In human medicine, local and regional arterial wall stiffness (AWS) parameters are routinely used to assess the vascular health. In horses, information regarding reproducibility of ultrasonographically derived AWS parameters is lacking. To evaluate the inter-day and inter-observer and intra-observer measurement variability of both local and regional AWS parameters in horses. Experimental study. In 10 healthy, adult Warmblood horses, B-, M-mode and pulsed-wave Doppler ultrasound images were collected on two different days from aorta, cranial and caudal common carotid arteries and external iliac artery. Heart rate and noninvasive blood pressure were recorded simultaneously. From blinded data, diastolic and systolic vessel lumen areas and diameters were measured from B/M-mode images and the velocity of the pressure wave was determined by pulsed-wave Doppler spectra. From each horse, one examination was measured again by the same observer and by a second, independent observer. Local and regional AWS parameters were calculated and inter-day and inter-observer and intra-observer measurement coefficient of variation (CV) were assessed. Low CV was found for both arterial diameter and lumen area measurements. Moderate to high CV was found for local AWS parameters, while regional AWS parameters had low CV. The number of horses investigated was too low to obtain reference values. The inter-operator variability was not evaluated. Our results show good reproducibility of aortic, carotid and external iliac artery diameter and area measurements using both B- and M-mode ultrasonography. Nevertheless, the variability of the derived local AWS parameters was relatively high. Therefore, local AWS parameters might be less suitable for follow-up studies, although they might be useful for population studies. On the other hand, regional AWS parameters showed low CV, making them valuable for both follow-up and population studies.

A patient-specific numerical modeling of the spontaneous coronary artery dissection in relation to atherosclerosis

The spontaneous coronary artery dissection (SCAD) is a clinical complication of angioplasty leading to an initiation of a tear/crack in the intima layer of the artery. The crack can propagate to the interface of the intima-media layer following by intramural hematoma. The relation between the SCAD and atherosclerosis is a controversial issue, as some studies stated no correlation between them while others showed that a crack can initiate in the intima but cannot propagate into the atrophied media layer. To investigate the relation between the intraluminal crack propagation in the atherosclerotic artery and SCAD, this study numerically investigated the initiation and propagation of a crack in the intraluminal and radial locations of the healthy and atherosclerotic human coronary arterial walls. The energy release rate, namely J-integral, is computed as a numerical derivative of the strain energy with respect to a crack extension using a user-defined virtual crack method (VCE) of extended finite element method (XFEM). Experimental measurements were carried out to calculate the elasto-plastic mechanical properties of the healthy and atherosclerotic human coronary arteries. The experimental data were then assigned to our own established patient-specific FE model of the coronary artery. Cracks were sketched in the intraluminal and radial locations of the arterial wall and allowed to propagate to the virtual interface of the intima-media to form a false lumen. The results revealed a higher stress at the crack tip of the healthy arterial wall compared to the atherosclerotic one. Lower crack tip opening displacement (CTOD) and crack tip opening angle (CTOA) were observed in the intraluminal crack of the atherosclerotic artery. J-integral of the atherosclerotic arterial wall was also found to be higher than the healthy one at the intraluminal crack. The results revealed that although a crack can initiate in the intraluminal of an atherosclerotic artery, it cannot propagate into the media layer due to a relatively higher rate of the strain energy release in the atherosclerotic arterial wall compared to the healthy one.

RNA sequencing analysis revealed the induction of CCL3 expression in human intracranial aneurysms

Intracranial aneurysm (IA) is a socially important disease as a major cause of subarachnoid hemorrhage. Recent experimental studies mainly using animal models have revealed a crucial role of macrophage-mediated chronic inflammatory responses in its pathogenesis. However, as findings from comprehensive analysis of unruptured human IAs are limited, factors regulating progression and rupture of IAs in humans remain unclear. Using surgically dissected human unruptured IA lesions and control arterial walls, gene expression profiles were obtained by RNA sequence analysis. RNA sequencing analysis was done with read count about 60~100 million which yielded 6~10 billion bases per sample. 79 over-expressed and 329 under-expressed genes in IA lesions were identified. Through Gene Ontology analysis, ‘chemokine activity’, ‘defense response’ and ‘extracellular region’ were picked up as over-represented terms which included CCL3 and CCL4 in common. Among these genes, quantitative RT-PCR analysis using another set of samples reproduced the above result. Finally, increase of CCL3 protein compared with that in control arterial walls was clarified in IA lesions. Findings of the present study again highlight importance of macrophage recruitment via CCL3 in the pathogenesis of IA progression.

Virtual Histology of Human Arterial Wall Segments Using Microcomputed Tomography for Soft Tissue Imaging

Virtual Histology of Human Arterial Wall Segments Using Microcomputed Tomography for Soft Tissue Imaging

Comparison of method using phase-sensitive motion estimator with speckle tracking method and application to measurement of arterial wall motion

At present, the speckle tracking method is widely used as a two- or three-dimensional (2D or 3D) motion estimator for the measurement of cardiovascular dynamics. However, this method requires high-level interpolation of a function, which evaluates the similarity between ultrasonic echo signals in two frames, to estimate a subsample small displacement in high-frame-rate ultrasound, which results in a high computational cost. To overcome this problem, a 2D motion estimator using the 2D Fourier transform, which does not require any interpolation process, was proposed by our group. In this study, we compared the accuracies of the speckle tracking method and our method using a 2D motion estimator, and applied the proposed method to the measurement of motion of a human carotid arterial wall. The bias error and standard deviation in the lateral velocity estimates obtained by the proposed method were 0.048 and 0.282 mm/s, respectively, which were significantly better than those (−0.366 and 1.169 mm/s) obtained by the speckle tracking method. The calculation time of the proposed phase-sensitive method was 97% shorter than the speckle tracking method. Furthermore, the in vivo experimental results showed that a characteristic change in velocity around the carotid bifurcation could be detected by the proposed method.

MicroRNA-31 promotes arterial smooth muscle cell proliferation and migration by targeting mitofusin-2 in arteriosclerosis obliterans of the lower extremitie.

MicroRNA (miR)-31 serves a key role in various biological processes, including tumor development, angiogenesis and inflammation. Whether miR-31 is involved in the pathological processes of arteriosclerosis obliterans (ASO) remains to be elucidated, as does the mechanism of miR-31 regulation of arterial smooth muscle cells (ASMCs). In the present study, miR-31 expression was detected by reverse transcription-quantitative polymerase chain reaction and in situ hybridization, and was significantly upregulated in human ASO arterial walls compared with normal arterial walls (P<0.001). In addition, miR-31 proliferation was detected by Cell Counting Kit-8 and EdU assays; proliferation was significantly promoted in platelet-derived growth factor (PDGF)-BB-induced human ASMCs (HASMCs) (P<0.001). miR-31 migration was detected by transwell and wound closure assays, and was revealed to be promoted in PDGF-BB-induced HASMCs (P<0.001). Lastly, HASMCs were transfected with miR-31 mimics and inhibitors, and negative controls. A dual-luciferase reporter assay was performed to verify that mitofusin-2 (MFN2) was a direct target of miR-31 and that MFN2 expression was significantly downregulated by miR-31 at a post-transcriptional level in HASMCs as detected by western blotting (P<0.01). These findings suggest that miR-31 is able to promote the proliferation and migration of HASMCs, at least in part, by targeting MFN2. The results of the present study provide novel insight into the underlying mechanisms and roles of miR-31/MFN2 in the pathology of ASO, which may offer a potential therapeutic target for the treatment of ASO.