Local critical stress correlates better than global maximum stress with plaque morphological features linked to atherosclerotic plaque vulnerability: an in vivo multi-patient study

Background  

It is believed that mechanical stresses play an important role in atherosclerotic plaque rupture process and may be used for better plaque vulnerability assessment and rupture risk predictions. Image-based plaque models have been introduced in recent years to perform mechanical stress analysis and identify critical stress indicators which may be linked to rupture risk. However, large-scale studies based on in vivo patient data combining mechanical stress analysis, plaque morphology and composition for carotid plaque vulnerability assessment are lacking in the current literature.     

Geometry guided data averaging enables the interpretation of shear stress related plaque development in human coronary arteries

The average low shear stress (SS) is known to determine predilection sites of atherosclerotic plaques. However, as plaques encroach into the lumen and thereby increase SS, interpretation of patient-specific data obtained at one moment in time regarding the influence of SS in the generation of atherosclerosis is not straightforward. This study aims to compare two methods of data analysis for the aid of data interpretation: (a) point-wise analysis of the raw data, (b) global analysis: to assess the history related natural SS distribution in coronary arteries by averaging the data in the axial vessel direction. Normal to mildly diseased human coronary arteries were investigated applying a combination of 3-D reconstruction technique and computational fluid dynamics (CFD). Point-wise analysis relating local wall thickness to local SS showed in only 4% of the cases an inverse relationship. In contrast, averaging the data in the axial vessel direction, showed in 38% a significant inverse relation between wall thickness and SS, resulting in an average negative slope of -0.70+/-0.46 mm/Pa. These data suggest that using a geometry guided way of data averaging may reveal history related effects of SS, which in part explains localization of atherosclerotic plaques.     

Lipid peroxidation and decomposition--conflicting roles in plaque vulnerability and stability

The low density lipoprotein (LDL) oxidation hypothesis has generated considerable interest in oxidative stress and how it might affect atherosclerosis. However, the failure of antioxidants, particularly vitamin E, to affect the progression of the disease in humans has convinced even staunch supporters of the hypothesis to take a step backwards and reconsider alternatives. Preponderant evidence for the hypothesis came from animal antioxidant intervention studies. In this review we point out basic differences between animal and human atherosclerosis development and suggest that human disease starts where animal studies end. While initial oxidative steps in the generation of early fatty streak lesions might be common, the differences might be in the steps involved in the decomposition of peroxidized lipids into aldehydes and their further oxidation into carboxylic acids. We suggest that these steps may not be amenable to attenuation by antioxidants and antioxidants might actually counter the stabilization of plaque by preventing the formation of carboxylic acids which are anti-inflammatory in nature. The formation of such dicarboxylic acids may also be conducive to plaque stabilization by trapping calcium. We suggest that agents that would prevent the decomposition of lipid peroxides and promote the formation and removal of lipid hydroxides, such as paraoxonase (PON 1) or apo A1/high density lipoprotein (HDL) might be more conducive to plaque regression.     

An assessment of intra-patient variability on observed relationships between wall shear stress and plaque progression in coronary arteries

Background

Wall shear stress (WSS) has been associated with sites of plaque localization and with changes in plaque composition in human coronary arteries. Different values have been suggested for categorizing WSS as low, physiologic or high; however, uncertainties in flow rates, both across subjects and within a given individual, can affect the classification of WSS and thus influence the observed relationships between local hemodynamics and plaque changes over time. This study examines the effects of uncertainties in flow rate boundary conditions upon WSS values and investigates the influence of this variability on the observed associations of WSS with changes in VH-IVUS derived plaque components.

Methods

Three patients with coronary artery disease underwent baseline and 12 month follow-up angiography and virtual histology-intravascular ultrasound (VH-IVUS) measurements. Coronary artery models were reconstructed from the data and models with and without side-branches were created. Patient-specific Doppler ultrasound (DUS) data were employed as inflow boundary conditions and computational fluid dynamics was used to calculate the WSS in each model. Further, the influence of representative coronary artery flow waveforms upon WSS values was investigated and the concept of treating WSS using relative, rather than actual, values was explored.

Results

Models that included side-branch outflows and subject-specific DUS velocities were considered to be the reference cases. Hemodynamic differences were caused by the exclusion of side-branches and by imposing alternative velocity waveforms. One patient with fewer side-branches and a scaled generic waveform had little deviation from the reference case, while another patient with several side-branches excluded showed much larger departures from the reference situation. Differences between models and the respective reference cases were reduced when data were analyzed using relative, rather than actual, WSS.

Conclusions

When considering individual subjects, large variations in patient-specific flow rates and exclusion of multiple side-branches in computational models can cause significant differences in observed associations between plaque evolution and ranges of computed WSS. These differences may contribute to the large variability typically found among subjects in pooled populations. Relative WSS may be more useful than actual WSS as a correlative variable when there is a large degree of uncertainty in flow rate data.

     

Neural mechanisms of stress resilience and vulnerability

Exposure to stressful events can be differently perceived by individuals and can have persistent sequelae depending on the level of stress resilience or vulnerability of each person. The neural processes that underlie such clinically and socially important differences reside in the anatomical, functional, and molecular connectivity of the brain. Recent work has provided novel insight into some of the involved biological mechanisms that promises to help prevent and treat stress-related disorders. In this review, we focus on causal and mechanistic evidence implicating altered functions and connectivity of the neuroendocrine system, and of hippocampal, cortical, reward, and serotonergic circuits in the establishment and the maintenance of stress resilience and vulnerability. We also touch upon recent findings suggesting a role for epigenetic mechanisms and neurogenesis in these processes and briefly discuss promising avenues of future investigation.     

In vivo shear stress response

EC (endothelial cell) responses to shear stress generated by vascular perfusion play an important role in circulatory homoeostasis, whereas abnormal responses are implicated in vascular diseases such as hypertension and atherosclerosis. ECs subjected to high shear stress in vitro alter their morphology, function and gene expression. The molecular basis for mechanotransduction of a shear stress signal, and the identity of the sensing mechanisms, remain unclear with many candidates under investigation. Translating these findings in vivo has proved difficult. The role of VEGF (vascular endothelial growth factor) flow-dependent nitric oxide release in remodelling skeletal muscle microcirculation is established for elevated (activity, dilatation) and reduced (overload, ischaemia) shear stress, although their temporal relationship to angiogenesis varies. It is clear that growth factor levels may offer only a permissive environment, and alteration of receptor levels may be a viable therapeutic target. Angiogenesis in vivo appears to be a graded phenomenon, and capillary regression on withdrawal of stimulus may be rapid. Combinations of physiological angiogenic stimuli appear not to be additive.     

A new imaging technique to study 3-D plaque and shear stress distribution in human coronary artery bifurcations in vivo

OBJECTIVE: Bifurcations of coronary arteries are predilection sites for atherosclerosis and expansive remodeling, the latter being associated with plaque vulnerability. Both are related to blood flow-induced shear stress (SS). We present a new approach to generate 3-D reconstructions of coronary artery bifurcations in vivo and investigate the relationship between SS, wall thickness (WT) and remodeling. METHODS: The patient specific 3-D reconstruction of the main branch of the bifurcation was obtained by combining intravascular ultrasound and biplane angiography, and the 3-D lumen of the side branch was based on biplane angiography only. The two data sets were fused and computational methods were applied to determine the SS distribution, using patient derived flow and viscosity data. The intravascular ultrasound data allowed us to measure local WT and remodeling in the main branch. RESULTS: The lumen reconstruction procedure was successful and it was shown that the impact of the side branch on SS distribution in the main branch diminished within 3mm. Distal to the bifurcation, two continuous regions in the main branch were identified. In the proximal region, we observed lumen preservation, and expansive remodeling. Although a plaque was observed in the low SS region at the non-divider wall, no relationship between SS and WT was found. In the distal region, we observed lumen narrowing and a significant positive relationship between SS and WT. CONCLUSIONS: A new imaging technique was applied to generate a 3-D reconstruction of a human coronary artery bifurcation in vivo. The observed relationship between SS, WT and remodeling in this specific patient illustrates the spatial heterogeneity of the atherosclerosis in the vicinity of arterial bifurcations.     

Statin therapy influences endothelial cell morphology and F-actin cytoskeleton structure when exposed to static and laminar shear stress conditions

AimsTo determine how statin drugs (3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitors) affect endothelial cell (EC) shape and F-actin cytoskeleton arrangement in the presence of physiologically relevant wall shear stress (WSS) of 12.5 dyn/cm².Main methodsHuman abdominal aortic endothelial cells (HAAECs) were cultured to a confluent monolayer within three dimensional tissue culture models and presheared for 6 h at 12.5 dyn/cm² within a continuous flow loop. Statins were added to the perfusion media and the perfusion was continued for a further 24 h. ECs were then analyzed for morphology and F-actin cytoskeleton arrangement using light microscopy and laser scanning confocal microscopy.Key findingsECs became rounded with a significantly higher shape index with the addition of 10 μM simvastatin under both static and flow conditions. F-actin cytoskeleton structure was disorganized and fragmented with statin treatment under static and flow conditions. Neither of these findings were observed with the addition of both simvastatin and 200 μM mevalonate, confirming regulation through the cholesterol biosynthesis pathway.SignificanceEC morphology and F-actin cytoskeleton arrangement are regulated through the cholesterol biosynthesis pathway and are therefore impacted by statin treatment. ECs treated with statins became rounded, which is usually associated with unhealthy cells in regions of the vasculature prone to developing atherosclerotic plaques.     

Non-uniform shrinkage for obtaining computational start shape for in-vivo MRI-based plaque vulnerability assessment

BackgroundCritical mechanical conditions, such as stress within the structure and shear stress due to blood flow, predicted from in-vivo magnetic resonance image (MRI)-based computational simulations have shown to be potential in assessing carotid plaque vulnerability. Plaque contours obtained from in-vivo MRI are a result of a pressurized configuration due to physiological loading. However, in order to make accurate predictions, the computational model must be based on the loading-free geometry. A shrinkage procedure can be used to obtain the computational start shape.MethodIn this study, electrocardiograph (ECG)-gated MR-images of carotid plaques were obtained from 28 patients. The contours of each plaque were segmented manually. Additional to a uniform shrinkage procedure, a non-uniform shrinkage refinement procedure was used. This procedure was repeated until the pressurized lumen contour and fibrous cap thickness had the best match with the in-vivo image.ResultsCompared to the uniform shrinkage procedure, the non-uniform shrinkage significantly reduced the difference in lumen shape and in cap thickness at the thinnest site. Results indicate that uniform shrinkage would underestimate the critical stress in the structure by 20.5±10.7%.ConclusionFor slices with an irregular lumen shape (the ratio of the maximum width to the minimum width is more than 1.05), the non-uniform shrinkage procedure is needed to get an accurate stress profile for mechanics and MRI-based carotid plaque vulnerability assessment.     

Apoptosis of vascular smooth muscle cells induces features of plaque vulnerability in atherosclerosis

Vascular smooth muscle cell (VSMC) apoptosis occurs in many arterial diseases, including aneurysm formation, angioplasty restenosis and atherosclerosis. Although VSMC apoptosis promotes vessel remodeling, coagulation and inflammation, its precise contribution to these diseases is unknown, given that apoptosis frequently accompanies vessel injury or alterations to flow. To study the direct consequences of VSMC apoptosis, we generated transgenic mice expressing the human diphtheria toxin receptor (hDTR, encoded by HBEGF) from a minimal Tagln (also known as SM22alpha) promoter. Despite apoptosis inducing loss of 50-70% of VSMCs, normal arteries showed no inflammation, reactive proliferation, thrombosis, remodeling or aneurysm formation. In contrast, VSMC apoptosis in atherosclerotic plaques of SM22alpha-hDTR Apoe-/- mice induced marked thinning of fibrous cap, loss of collagen and matrix, accumulation of cell debris and intense intimal inflammation. We conclude that VSMC apoptosis is 'silent' in normal arteries, which have a large capacity to withstand cell loss. In contrast, VSMC apoptosis alone is sufficient to induce features of plaque vulnerability in atherosclerosis. SM22alpha-hDTR Apoe-/- mice may represent an important new model to test agents proposed to stabilize atherosclerotic plaques.     

Method for in-shoe shear stress measurement

A methodology is described for use of a shear transducer, based on a magneto-resistive principle, to measure stresses under the plantar surface of the foot in-shoe during walking. Particular attention is paid to a projected application for study of diabetic plantar ulceration and its management by footwear. The transducer has a disc construction, approximately 4 mm thick by 16 mm diameter, and measures two orthogonal axes of shear simultaneously; this disc is mounted into an inlay that can be inserted into any stock orthopaedic shoe of the type commonly prescribed for diabetic foot problems. The transducer is located in the metatarsal head region of the inlay; exact placement of the transducer is determined by reference to the direct pressure distribution, the common method of palpation shown to be imprecise. Pilot trials on normal subjects are presented to evaluate the method.     

血流剪切力在动脉粥样硬化形成中的作用

血管内皮位于血管壁和血液的界面,直接与血流接触而持续受血流剪切力的作用。血管内皮细胞能感受血流机械力的变化,通过激活相应的信号通路调节血管内皮和平滑肌的结构和功能。研究发现,血液流动力的形式与动脉粥样硬化的发生发展有密切的关系。本综述将就血流剪切力与动脉粥样硬化的相互关系及作用机制的最新研究进展作简要介绍。     

Advances in endothelial shear stress proteomics

The vascular endothelium lining the luminal surface of all blood vessels is constantly exposed to shear stress exerted by the flowing blood. Blood flow with high laminar shear stress confers protection by activation of antiatherogenic, antithrombotic and anti-inflammatory proteins, whereas low or oscillatory shear stress may promote endothelial dysfunction, thereby contributing to cardiovascular disease. Despite the usefulness of proteomic techniques in medical research, however, there are relatively few reports on proteome analysis of cultured vascular endothelial cells employing conditions that mimic in vivo shear stress attributes. This review focuses on the proteome studies that have utilized cultured endothelial cells to identify molecular mediators of shear stress and the roles they play in the regulation of endothelial function, and their ensuing effect on vascular function in general. It provides an overview on current strategies in shear stress-related proteomics and the key proteins mediating its effects which have been characterized so far.     

Life history influences the vulnerability of New Zealand galaxiids to invasive salmonids

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The role of shear stress in atherosclerosis

Atherosclerotic lesions preferentially localize near side branches or curved vessels. During the last few decades, research has been shown that low or low and oscillating shear stress is associated with plaque location. Despite ample evidence, the precise mechanism is unknown. This is mainly because of a lack of appropriate animal models. We describe two novel methods to study the hypothesis that shear stress acts through endothelial gene expression or shear stress acts through localizing of inflammation. Both literature evidence and own findings support a role for both mechanisms in atherosclerosis.     

Response of mammalian cells to shear stress

Summary The influence of shear forces on adherent mammalian cells was investigated by means of a developed flow chamber. The viability of the cells decreased with increasing exposure level and duration. Additional, changes in the morphology of the cells due to the shear forces were observed. Offprint requests to: G. Kretzmer