Arterial luminal curvature and fibrous-cap thickness affect critical stress conditions within atherosclerotic plaque: An in vivo MRI-based 2D finite-element study

High mechanical stress in atherosclerotic plaques at vulnerable sites, called critical stress, contributes to plaque rupture. The site of minimum fibrous cap (FC) thickness (FCMIN) and plaque shoulder are well-documented vulnerable sites. The inherent weakness of the FC material at the thinnest point increases the stress, making it vulnerable, and it is the big curvature of the lumen contour over FC which may result in increased plaque stress. We aimed to assess critical stresses at FCMIN and the maximum lumen curvature over FC (LCMAX) and quantify the difference to see which vulnerable site had the highest critical stress and was, therefore, at highest risk of rupture. One hundred patients underwent high resolution carotid magnetic resonance (MR) imaging. We used 352 MR slices with delineated atherosclerotic components for the simulation study. Stresses at all the integral nodes along the lumen surface were calculated using the finite-element method. FCMIN and LCMAX were identified, and critical stresses at these sites were assessed and compared. Critical stress at FC MIN was significantly lower than that at LCMAX (median: 121.55 kPa; inter quartile range (IQR) = [60.70-180.32] kPa vs. 150.80 kPa; IQR = [91.39-235.75] kPa, p < 0.0001). If critical stress at FCMIN was only used, then the stress condition of 238 of 352 MR slices would be underestimated, while if the critical stress at LCMAX only was used, then 112 out of 352 would be underestimated. Stress analysis at FCMIN and LCMAX should be used for a refined mechanical risk assessment of atherosclerotic plaques, since material failure at either site may result in rupture.

The impact of wall shear stress and pressure drop on the stability of the atherosclerotic plaque

Rupture of vulnerable atheromatous plaque in the carotid and coronary arteries often leads to stroke and heart attack respectively. The mechanism of blood flow and plaque rupture in stenotic arteries is still not fully understood. A three dimensional rigid wall model was solved under steady state conditions and unsteady conditions by assuming a time-varying inlet velocity profile to investigate the relative importance of axial forces and pressure drops in arteries with asymmetric stenosis. Flow-structure interactions were investigated for the same geometry and the results were compared with those retrieved with the corresponding 2D cross-section structural models. The Navier-Stokes equations were used as the governing equations for the fluid. The tube wall was assumed hyperelastic, homogeneous, isotropic and incompressible. The analysis showed that the three dimensional behavior of velocity, pressure and wall shear stress is in general very different from that predicted by cross-section models. Pressure drop across the stenosis was found to be much higher than shear stress. Therefore, pressure may be the more important mechanical trigger for plaque rupture other than shear stress, although shear stress is closely related to plaque formation and progression.

Simulation of the interaction between blood flow and atherosclerotic plaque

It has been well accepted that over 50% of cerebral ischemic events are the result of rupture of vulnerable carotid atheroma and subsequent thrombosis. Such strokes are potentially preventable by carotid interventions. Selection of patients for intervention is currently based on the severity of carotid luminal stenosis. It has been, however, widely accepted that luminal stenosis alone may not be an adequate predictor of risk. To evaluate the effects of degree of luminal stenosis and plaque morphology on plaque stability, we used a coupled nonlinear time-dependent model with flow-plaque interaction simulation to perform flow and stress/strain analysis for stenotic artery with a plaque. The Navier-Stokes equations in the Arbitrary Lagrangian-Eulerian (ALE) formulation were used as the governing equations for the fluid. The Ogden strain energy function was used for both the fibrous cap and the lipid pool. The plaque Principal stresses and flow conditions were calculated for every case when varying the fibrous cap thickness from 0.1 to 2mm and the degree of luminal stenosis from 10% to 90%. Severe stenosis led to high flow velocities and high shear stresses, but a low or even negative pressure at the throat of the stenosis. Higher degree of stenosis and thinner fibrous cap led to larger plaque stresses, and a 50% decrease of fibrous cap thickness resulted in a 200% increase of maximum stress. This model suggests that fibrous cap thickness is critically related to plaque vulnerability and that, even within presence of moderate stenosis, may play an important role in the future risk stratification of those patients when identified in vivo using high resolution MR imaging.

Fluid-structure interaction study on human arterial plaque with patient specific geometry and boundary conditions

Atherosclerotic plaque rupture has been extensively considered as the leading cause of death in western countries. It is believed that high stresses within plaque can be an important factor on triggering the rupture of the plaque. Stress analysis in the coronary and carotid arteries with plaque have been developed by many researchers from 2D to 3-D models, from structure analysis only to the Fluid-Structure Interaction (FSI) models[1].

Correlation of carotid atheromatous plaque inflammation using USPIO-enhanced MR imaging with degree of luminal Stenosis

BACKGROUND AND PURPOSE Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The study explores the relationship between the degree of Magnetic Resonance (MR)"defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles and the severity of luminal stenosis in asymptomatic carotid plaques. METHODS Seventy-one patients with an asymptomatic carotid stenosis of ĝ‰¥40% underwent multi-sequence USPIO-enhanced MR imaging. Stenosis severity was measured according to the NASCET and ECST methods. RESULTS No demonstrable relationship between inflammation as measured by USPIO-enhanced signal change and the degree of luminal stenosis was found. CONCLUSIONS Inflammation and stenosis are likely to be independent risk factors, although this needs to be further validated.

Comparison of the inflammatory burden of truly asymptomatic carotid atheroma with atherosclerotic plaques in patients with asymptomatic carotid stenosis undergoing coronary artery bypass grafting: An ultrasmall superparamagnetic iron oxide enhanced magnetic resonance study

Introduction: Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. The aim of this study was to explore whether there is a difference in the degree of Magnetic Resonance (MR) defined inflammation using Ultra Small Super-Paramagnetic Iron Oxide (USPIO) particles, within carotid atheroma in completely asymptomatic individuals and the asymptomatic carotid stenosis in a cohort of patients undergoing coronary artery bypass grafting (CABG). Methods: 10 patients awaiting CABG with asymptomatic carotid disease and 10 completely asymptomatic individuals with no documented coronary artery disease underwent multi-sequence MR imaging before and 36 hours post USPIO infusion. Images were manually segmented into quadrants and signal change in each quadrant, normalised to adjacent muscle signal, was calculated following USPIO administration. Results: The mean percentage of quadrants showing signal loss was 94% in the CABG group, compared to 24% in the completely asymptomatic individuals (p < 0.001). The carotid plaques from the CABG patients showed a significant mean signal intensity decrease of 16.4% after USPIO infusion (95% CI 10.6% to 22.2%; p < 0.001). The truly asymptomatic plaques showed a mean signal intensity increase (i.e. enhancement) after USPIO infusion of 8.4% (95% CI 2.6% to 14.2%; p = 0.007). The mean signal difference between the two groups was 24.9% (95% CI 16.7% to 33.0%; p < 0.001). Conclusions: These findings are consistent with the hypothesis that inflammatory atheroma is a systemic disease. The carotid territory is more likely to take up USPIO if another vascular territory is symptomatic.

Correlation of macrophage location and plaque stress distribution using USPIO-enhanced MRI in a patient with symptomatic severe carotid stenosis: A new insight into risk stratification

High resolution, USPIO-enhanced MR imaging can be used to identify inflamed atherosclerotic plaque. We report a case of a 79-year-old man with a symptomatic carotid stenosis of 82%. The plaque was retrieved for histology and finite element analysis (FEA) based on the preoperative MR imaging was used to predict maximal Von Mises stress on the plaque. Macrophage location correlated with maximal predicted stresses on the plaque. This supports the hypothesis that macrophages thin the fibrous cap at points of highest stress, leading to an increased risk of plaque rupture and subsequent stroke.

Is adiponectin implicated in venous thromboembolism?

In summary, these results imply that the relationship of adiponectin with lipoproteins is more complex than previously predicted using other methods of lipoprotein fractionation. Higher correlation of adiponectin was shown with large lipoprotein particle size, independent of the apolipoprotein content. Given the small population studied, we could not assess the influence of mild risk factors for venous thrombosis, such as obesity, on the analysis of the results. Thus, we can only state that adiponectin levels appear not to be a strong risk factor for VTE. It is possible that adiponectin deficiency may contribute indirectly to the etiology of VTE by enhancing the inflammatory state. © 2006 International Society on Thrombosis and Haemostasis.

Corticosterone accelerates atherosclerosis in the apolipoprotein E-deficient mouse

Chronic stress is an important risk factor for atherosclerosis, which is a chief process in the development of cardiovascular disease. Increased circulating levels of corticosterone have been documented in several animal models of chronic stress. However, it remains to be established whether corticosterone is sufficient to exacerbate atherosclerosis. To test this hypothesis, apolipoprotein E (ApoE)-deficient mice were fed a high-fat diet for 13 weeks with exposure to either corticosterone or vehicle in the drinking water (CORT and Con). Corticosterone treatment significantly increased atherosclerotic plaque area at the aortic root. Such exacerbation of atherosclerosis was accompanied by significantly lower levels of circulating white blood cells and serum interleukin-1β (IL-1β), and significantly elevated serum concentrations of total cholesterol, low-density lipoprotein (LDL), very-low-density lipoprotein (VLDL) and small dense low-density lipoprotein (sd-LDL) in CORT mice when compared to Con mice. These findings demonstrate that corticosterone is sufficient to exacerbate atherosclerosis in vivo despite its anti-inflammatory properties and that this marked pro-atherogenic phenotype is primarily associated with increased dyslipidaemia.

Cardiovascular diseases and vulnerable plaques: data, modeling, predictions and clinical applications PREFACE

Introduction Two symposia on “cardiovascular diseases and vulnerable plaques” Cardiovascular disease (CVD) is the leading cause of death worldwide. Huge effort has been made in many disciplines including medical imaging, computational modeling, bio- mechanics, bioengineering, medical devices, animal and clinical studies, population studies as well as genomic, molecular, cellular and organ-level studies seeking improved methods for early detection, diagnosis, prevention and treatment of these diseases [1-14]. However, the mechanisms governing the initiation, progression and the occurrence of final acute clinical CVD events are still poorly understood. A large number of victims of these dis- eases who are apparently healthy die suddenly without prior symptoms. Available screening and diagnostic methods are insufficient to identify the victims before the event occurs [8,9]. Most cardiovascular diseases are associated with vulnerable plaques. A grand challenge here is to develop new imaging techniques, predictive methods and patient screening tools to identify vulnerable plaques and patients who are more vulnerable to plaque rupture and associated clinical events such as stroke and heart attack, and recommend proper treatment plans to prevent those clinical events from happening. Articles in this special issue came from two symposia held recently focusing on “Cardio-vascular Diseases and Vulnerable Plaques: Data, Modeling, Predictions and Clinical Applications.” One was held at Worcester Polytechnic Institute (WPI), Worcester, MA, USA, July 13-14, 2014, right after the 7th World Congress of Biomechanics. This symposium was endorsed by the World Council of Biomechanics, and partially supported by a grant from NIH-National Institute of Biomedical Image and Bioengineering. The other was held at Southeast University (SEU), Nanjing, China, April 18-20, 2014.

Temporal dependence of in vivo USPIO-enhanced MRI signal changes in human carotid atheromatous plaques

Introduction: Ultrasmall superparamagnetic iron oxide (USPIO)-enhanced MRI has been shown to be a useful modality to image activated macrophages in vivo, which are principally responsible for plaque inflammation. This study determined the optimum imaging time-window to detect maximal signal change post-USPIO infusion using T1-weighted (T1w), T2*- weighted (T2*w) and quantitative T2*(qT 2*) imaging. Methods: Six patients with an asymptomatic carotid stenosis underwent high resolution T1w, T2*w and qT2*MR imaging of their carotid arteries at 1.5 T. Imaging was performed before and at 24, 36, 48, 72 and 96 h after USPIO (Sinerem™, Guerbet, France) infusion. Each slice showing atherosclerotic plaque was manually segmented into quadrants and signal changes in each quadrant were fitted to an exponential power function to model the optimum time for post-infusion imaging. Results: The power function determining the mean time to convergence for all patients was 46, 41 and 39 h for the T1w, T 2*w and qT2*sequences, respectively. When modelling each patient individually, 90% of the maximum signal intensity change was observed at 36 h for three, four and six patients on T1w, T 2*w and qT2*, respectively. The rates of signal change decrease after this period but signal change was still evident up to 96 h. Conclusion: This study showed that a suitable imaging window for T 1w, T2*w and qT2*signal changes post-USPIO infusion was between 36 and 48 h. Logistically, this would be convenient in bringing patients back for one post-contrast MRI, but validation is required in a larger cohort of patients.

Iron oxide particles for atheroma imaging

The selection of patients for vascular interventions has been solely based on luminal stenosis and symptomatology. However, histological data from both the coronary and carotid vasculature suggest that other plaque features such as inflammation may be more important in predicting future thromboembolic events. Ultrasmall superparamagnetic iron oxide (USPIO) contrast agents have been used for noninvasive MRI assessment of atherosclerotic plaque inflammation in humans. It has reached the stage of development to have been recently used in an interventional drug study to not only assess inflammatory progression but also select patients at high risk. This article reviews the basic science behind the use of USPIO contrast agents in atheroma MR imaging, experimental work in animals, and how this has led to the emergence of this promising targeted imaging platform for assessment of high risk carotid atherosclerosis in humans.

Stress analysis of carotid atheroma in a transient ischaemic attack patient using the MRI-based fluid-structure interaction method

Rupture of atherosclerotic plaque is a major cause of mortality. Plaque stress analysis, based on patient-specific multisequence in vivo MRI, can provide critical information for the understanding of plaque rupture and could eventually lead to plaque rupture prediction. However, the direct link between stress and plaque rupture is not fully understood. In the present study, the plaque from a patient who recently experienced a transient ischaemic attack (TIA) was studied using a fluid-structure interaction method to quantify stress distribution in the plaque region based on in vivo MR images. The results showed that wall shear stress is generally low in the artery with a slight increase at the plaque throat owing to minor luminal narrowing. The oscillatory shear index is much higher in the proximal part of the plaque. Both local wall stress concentrations and the relative stress variation distribution during a cardiac cycle indicate that the actual plaque rupture site is collocated with the highest rupture risk region in the studied patient.

Stress analysis on human arterial plaques by fluid structure interactions - Multi-case study

Atherosclerotic plaque rupture has been extensively considered as the leading cause of death in the world. It is believed that high stress within plaque can be an important factor which can trigger the rupture of the plaque. High resolution multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components (arterial wall, lipids, and fibrous cap) to be visualized in vivo [1]. The patient specific finite element model can be generated from the image data to perform stress analysis and provide critical information on understanding plaque rupture mechanisms [2]. The present work is to apply the procedure to a total of 14 patients (S1 ∼ S14), to study the stress distributions on carotid artery plaque reconstructed from multi-spectral magnetic resonance images, and the possible relationships between stress and plaque burdens.

Non-invasive MR imaging of inflammation in a patient with both asymptomatic carotid atheroma and an abdominal aortic aneurysm: A case report

Inflammation is a recognized risk factor for the vulnerable atherosclerotic plaque. USPIO-enhanced MRI imaging is a promising non-i nvasive method to identify high-risk atheromatous plaque inflammation in vivo in humans, in which areas of focal signal loss on MR images have been shown to correspond to the location of activated macrophages, typically at the shoulder regions of the plaque. This is the first report in humans describing simultaneous USPIO uptake within atheroma in two different arterial territories and again emphasises that atherosclerosis is a truly systemic disease. With further work, USPIO-enhanced MR imaging may be useful in identifying inflamed vulnerable atheromatous plaques in vivo, so refining patient selection for intervention and allowing appropriate early aggressive pharmacotherapy to prevent plaque rupture.