Fatigue crack growth under pulsatile pressure and plaque rupture

Identification of vulnerable plaque pre-rupture is extremely important for patient risk stratification. The mechanism of plaque rupture is still not entirely clear, but it is thought to be a process involving multiple factors. From a biomechanical viewpoint, plaque rupture is usually seen as a structural failure when the plaque cannot resist the hemodynamic blood pressure and shear stress exerted on it. However, the cardiovascular system is naturally a cyclical hemodynamic environment, and myocardial infarction can be a symptomatically quiescent but potentially progressive process when plaque ruptures at stresses much lower than its strength. Therefore, fatigue accumulation is a possible mechanism for plaque rupture. In this study, a crack growth model was developed, and the previously-mentioned hypothesis was tested by conducting a comparative study between 18 symptomatic and 16 asymptomatic patients with carotid stenosis.

MRI-based fatigue analysis predicts plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

BACKGROUND: Rupture of atheromatous plaque in the carotid artery often leads to thrombosis and subsequent stroke. The mechanism of plaque rupture is not entirely clear but is thought to be a multi-factorial process involving thinning and weakening of the fibrous cap and biomechanical stress as the trigger leading to plaque rupture. As the cardiovascular system is a classic fatigue environment, the weakening of plaque leading to rupture may be a fatigue process, which is a symptomatically quiescent but potentially progressive failure process. In this study, we used a fatigue analysis based on in vivo magnetic resonance imaging (MRI) to investigate the rupture initiation location, crack propagation path and fatigue life within plaques of asymptomatic and symptomatic individuals. METHODS: Forty non-consecutive subjects (20 symptomatic and 20 asymptomatic) underwent high-resolution multi-sequence in vivo MRI of the carotid bifurcation. Fatigue analysis was performed based on the plaque geometry derived from in vivo MRI of the carotid artery at the point of maximum stenosis. Paris’ Law in fracture mechanics is adopted to determine the fatigue crack growth rate. Incremental crack propagation was dynamically simulated based on stress distributions. Plaque initiation location, crack propagation path and fatigue cycle of symptomatic and asymptomatic individuals were compared. RESULTS: Cracks were often found to begin at the lumen wall at areas of stress concentration. The preferred rupture direction was radial from the lumen center. The crack initially advanced slowly but accelerated as it developed, depending on plaque morphology. The fatigue cycles of symptomatic plaques were significantly less than those in the asymptomatic group (2.3 ± 0.9 vs 3.1 ± 0.7 (x106); p = 0.003). CONCLUSIONS: The number of cycles to rupture in symptomatic patients was higher than those predicted in asymptomatic patients by fatigue analysis, suggesting the possibility that plaques with a less fatigue life may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, fatigue analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma.

Reduction in arterial wall strain with aggressive lipid-lowering therapy in patients with carotid artery disease

Background: Inflammation and biomechanical factors have been associated with the development of vulnerable atherosclerotic plaques. Lipid-lowering therapy has been shown to be effective in stabilizing them by reducing plaque inflammation. Its effect on arterial wall strain, however, remains unknown. The aim of the present study was to investigate the role of high- and low-dose lipid-lowering therapy using an HMG-CoA reductase inhibitor, atorvastatin, on arterial wall strain. Methods and Results: Forty patients with carotid stenosis >40% were successfully followed up during the Atorvastatin Therapy: Effects on Reduction Of Macrophage Activity (ATHEROMA; ISRCTN64894118) Trial. All patients had plaque inflammation as shown by intraplaque accumulation of ultrasmall super paramagnetic particles of iron oxide on magnetic resonance imaging at baseline. Structural analysis was performed and change of strain was compared between high- and low-dose statin at 0 and 12 weeks. There was no significant difference in strain between the 2 groups at baseline (P=0.6). At 12 weeks, the maximum strain was significantly lower in the 80-mg group than in the 10-mg group (0.085±0.033 vs. 0.169±0.084; P=0.001). A significant reduction (26%) of maximum strain was observed in the 80-mg group at 12 weeks (0.018±0.02; P=0.01). Conclusions: Aggressive lipid-lowering therapy is associated with a significant reduction in arterial wall strain. The reduction in biomechanical strain may be associated with reductions in plaque inflammatory burden.

Study of carotid arterial plaque stress for symptomatic and asymptomatic patients

Stroke is one of the leading causes of death in the world, resulting mostly from the sudden ruptures of atherosclerosis carotid plaques. Until now, the exact plaque rupture mechanism has not been fully understood, and also the plaque rupture risk stratification. The advanced multi-spectral magnetic resonance imaging (MRI) has allowed the plaque components to be visualized in-vivo and reconstructed by computational modeling. In the study, plaque stress analysis using fully coupled fluid structure interaction was applied to 20 patients (12 symptomatic and 8 asymptomatic) reconstructed from in-vivo MRI, followed by a detailed biomechanics analysis, and morphological feature study. The locally extreme stress conditions can be found in the fibrous cap region, 85% at the plaque shoulder based on the present study cases. Local maximum stress values predicted in the plaque region were found to be significantly higher in symptomatic patients than that in asymptomatic patients (200±43. kPa vs. 127±37. kPa, p=0.001). Plaque stress level, defined by excluding 5% highest stress nodes in the fibrous cap region based on the accumulative histogram of stress experienced on the computational nodes in the fibrous cap, was also significantly higher in symptomatic patients than that in asymptomatic patients (154±32. kPa vs. 111±23. kPa, p<0.05). Although there was no significant difference in lipid core size between the two patient groups, symptomatic group normally had a larger lipid core and a significantly thinner fibrous cap based on the reconstructed plaques using 3D interpolation from stacks of 2D contours. Plaques with a higher stenosis were more likely to have extreme stress conditions upstream of plaque throat. The combined analyses of plaque MR image and plaque stress will advance our understanding of plaque rupture, and provide a useful tool on assessing plaque rupture risk.

Stress analysis of carotid atheroma in transient ischemic attack patients: Evidence for extreme stress-induced plaque rupture

Plaque rupture has been considered to be the result of its structural failure. The aim of this study is to suggest a possible link between higher stresses and rupture sites observed from in vivo magnetic resonance imaging (MRI) of transient ischemic attack (TIA) patients, by using stress analysis methods. Three patients, who had recently suffered a TIA, underwent in vivo multi-spectral MR imaging. Based on plaque geometries reconstructed from the post-rupture status, six pre-rupture plaque models were generated for each patient dataset with different reconstructions of rupture sites to bridge the gap of fibrous cap from original MRI images. Stress analysis by fluid structure interaction simulation was performed on the models, followed by analysis of local stress concentration distribution and plaque rupture sites. Furthermore, the sensitivity of stress analysis to the pre-rupture plaque geometry reconstruction was examined. Local stress concentrations were found to be located at the plaque rupture sites for the three subjects studied. In the total of 18 models created, the locations of the stress concentration regions were similar in 17 models in which rupture sites were always associated with high stresses. The local stress concentration region moved from circumferential center to the shoulder region (slightly away from the rupture site) for a case with a thick fibrous cap. Plaque wall stress level in the rupture locations was found to be much higher than the value in non-rupture locations. The good correlation between local stress concentrations and plaque rupture sites, and generally higher plaque wall stress level in rupture locations in the subjects studied could provide indirect evidence for the extreme stress-induced plaque rupture hypothesis. Local stress concentration in the plaque region could be one of the factors contributing to plaque rupture.

Stress analysis of carotid plaque based on in vivo MRI of acute symptomatic and asymptomatic patients

Stress analysis within carotid plaques based on in vivo MR imaging has shown to be useful for the identification of vulnerable atheroma. This study is to investigate whether magnetic resonance imaging (MRI) based-biomechanical stress analysis of carotid plaques can differentiate acute symptomatic and asymptomatic patients. 54 asymptomatic and 45 acute symptomatic patients underwent in vivo multi-contrast MRI of the carotid arteries. Plaque geometry used for finite element analysis was derived from in vivo MR images at the site of maximum and minimum plaque burden. In total 198 slices were used for the computational simulations. A pre shrink technique was used to refine the simulation. Maximum principle stress at the vulnerable plaque sites (i.e. critical stress) was extracted for the selected slices and a comparison was performed between the two groups. Critical stress at the site of maximum plaque burden is significantly higher in acute symptomatic patients as compared to asymptomatic patients [median: 198.0kPa (inter quartile range (IQR) = (119.8 - 359.0) vs. 138.4kPa (83.8, 242.6), p=0.04]. No significant difference was found at the minimum plaque burden site between the two groups [196.7kPa (133.3- 282.7) vs. 182.4kPa (117.2 - 310. 6), p=0.82). Stress analysis at the site of maximal plaque burden can be effectively used for differentiating acute symptomatic carotid plaques from asymptomatic plaques. This maybe potentially used for development of biomechanical risk stratification criteria based on plaque burden in future studies.

Curvedness study on atherosclerosis plaques and its implications to plaque stress

Atherosclerosis plaque rupture has been considered to be a mechanical failure of the thin fibrous cap, resulted from extreme plaque stress. Plaque stress was affected by many factors from morphological features to biological abnormalities. In this study, geometrical factors (curvedness, fibrous cap thickness) were studied on assessing plaque vulnerability in comparison with stress analysis results obtained by fluid structure interaction from 20 human carotid atherosclerosis plaques. The results show that plaque surface curvedness could contribute to extreme stress level, especially in plaque shoulder region. General plaque stress distribution could be predicted by fibrous cap thickness and curvedness with multi-regression model. With more features included in the regression model, plaque stress could be easily calculated and used to assess plaque vulnerability.

Invasive and non-invasive modalities of imaging carotid stenosis

Despite recent therapeutic advances, acute ischemic complications of atherosclerosis remain the primary cause of morbidity and mortality in Western countries, with carotid atherosclerotic disease one of the major preventable causes of stroke. As the impact of this disease challenges our healthcare systems, we are becoming aware that factors influencing this disease are more complex than previously realized. In current clinical practice, risk stratification relies primarily on evaluation of the degree of luminal stenosis and patient symptomatology. Adequate investigation and optimal imaging are important factors that affect the quality of a carotid endarterectomy (CEA) service and are fundamental to patient selection. Digital subtraction angiography is still perceived as the most accurate imaging modality for carotid stenosis and historically has been the cornerstone of most of the major CEA trials but concerns regarding potential neurological complications have generated substantial interest in non-invasive modalities, such as contrast-enhanced magnetic resonance angiography. The purpose of this review is to give an overview to the vascular specialist of the current imaging modalities in clinical practice to identify patients with carotid stenosis. Advantages and disadvantages of each technique are outlined. Finally, limitations of assessing luminal stenosis in general are discussed. This article will not cover imaging of carotid atheroma morphology, function and other emerging imaging modalities of assessing plaque risk, which look beyond simple luminal measurements.

The ATHEROMA (Atorvastatin Therapy: Effects on Reduction of Macrophage Activity) Study. Evaluation using ultrasmall superparamagnetic iron oxide-enhanced magnetic resonance imaging in carotid disease

Objectives: The aim of this study was to evaluate the effects of low-dose (10 mg) and high-dose (80 mg) atorvastatin on carotid plaque inflammation as determined by ultrasmall superparamagnetic iron oxide (USPIO)-enhanced carotid magnetic resonance imaging (MRI). The hypothesis was that treatment with 80 mg atorvastatin would demonstrate quantifiable changes in USPIO-enhanced MRI-defined inflammation within the first 3 months of therapy. Background: Preliminary studies indicate that USPIO-enhanced MRI can identify macrophage infiltration in human carotid atheroma in vivo and hence may be a surrogate marker of plaque inflammation. Methods: Forty-seven patients with carotid stenosis >40% on duplex ultrasonography and who demonstrated intraplaque accumulation of USPIO on MRI at baseline were randomly assigned in a balanced, double-blind manner to either 10 or 80 mg atorvastatin daily for 12 weeks. Baseline statin therapy was equivalent to 10 mg of atorvastatin or less. The primary end point was change from baseline in signal intensity (ΔSI) on USPIO-enhanced MRI in carotid plaque at 6 and 12 weeks. Results: Twenty patients completed 12 weeks of treatment in each group. A significant reduction from baseline in USPIO-defined inflammation was observed in the 80-mg group at both 6 weeks (ΔSI 0.13; p = 0.0003) and at 12 weeks (ΔSI 0.20; p < 0.0001). No difference was observed with the low-dose regimen. The 80-mg atorvastatin dose significantly reduced total cholesterol by 15% (p = 0.0003) and low-density lipoprotein cholesterol by 29% (p = 0.0001) at 12 weeks. Conclusions: Aggressive lipid-lowering therapy over a 3-month period is associated with significant reduction in USPIO-defined inflammation. USPIO-enhanced MRI methodology may be a useful imaging biomarker for the screening and assessment of therapeutic response to "anti-inflammatory" interventions in patients with atherosclerotic lesions. (Effects of Atorvastatin on Macrophage Activity and Plaque Inflammation Using Magnetic Resonance Imaging [ATHEROMA]; NCT00368589).

The mechanical triggers of plaque rupture: Shear stress vs pressure gradient

The aim of this study was to evaluate the mechanical triggers that may cause plaque rupture. Wall shear stress (WSS) and pressure gradient are the direct mechanical forces acting on the plaque in a stenotic artery. Their influence on plaque stability is thought to be controversial. This study used a physiologically realistic, pulsatile flow, two-dimensional, cine phase-contrast MRI sequence in a patient with a 70% carotid stenosis. Instead of considering the full patient-specific carotid bifurcation derived from MRI, only the plaque region has been modelled by means of the idealised flow model. WSS reached a local maximum just distal to the stenosis followed by a negative local minimum. A pressure drop across the stenosis was found which varied significantly during systole and diastole. The ratio of the relative importance of WSS and pressure was assessed and was found to be less than 0.07% for all time phases, even at the throat of the stenosis. In conclusion, although the local high WSS at the stenosis may damage the endothelium and fissure plaque, the magnitude of WSS is small compared with the overall loading on plaque. Therefore, pressure may be the main mechanical trigger for plaque rupture and risk stratification using stress analysis of plaque stability may only need to consider the pressure effect.

Study of reproducibility of human arterial plaque reconstruction and its effects on stress analysis based on multispectral in vivo magnetic resonance imaging

Purpose: To quantify the uncertainties of carotid plaque morphology reconstruction based on patient-specific multispectral in vivo magnetic resonance imaging (MRI) and their impacts on the plaque stress analysis. Materials and Methods: In this study, three independent investigators were invited to reconstruct the carotid bifurcation with plaque based on MR images from two subjects to study the geometry reconstruction reproducibility. Finite element stress analyses were performed on the carotid bifurcations, as well as the models with artificially modified plaque geometries to mimic the image segmentation uncertainties, to study the impacts of the uncertainties to the stress prediction. Results: Plaque reconstruction reproducibility was generally high in the study. The uncertainties among interobservers are around one or the subpixel level. It also shows that the predicted stress is relatively less sensitive to the arterial wall segmentation uncertainties, and more affected by the accuracy of lipid region definition. For a model with lipid core region artificially increased by adding one pixel on the lipid region boundary, it will significantly increase the maximum Von Mises Stress in fibrous cap (>100%) compared with the baseline model for all subjects. Conclusion: The current in vivo MRI in the carotid plaque could provide useful and reliable information for plaque morphology. The accuracy of stress analysis based on plaque geometry is subject to MRI quality. The improved resolution/quality in plaque imaging with newly developed MRI protocols would generate more realistic stress predictions.

Correlation of carotid atheromatous plaque inflammation with biomechanical stress: Utility of USPIO enhanced MR imaging and finite element analysis

Objective: The aim of this study was to explore whether there is a relationship between the degree of MR-defined inflammation using ultra small super-paramagnetic iron oxide (USPIO) particles, and biomechanical stress using finite element analysis (FEA) techniques, in carotid atheromatous plaques. Methods and Results: 18 patients with angiographically proven carotid stenoses underwent multi-sequence MR imaging before and 36 h after USPIO infusion. T2 * weighted images were manually segmented into quadrants and the signal change in each quadrant normalised to adjacent muscle was calculated after USPIO administration. Plaque geometry was obtained from the rest of the multi-sequence dataset and used within a FEA model to predict maximal stress concentration within each slice. Subsequently, a new statistical model was developed to explicitly investigate the form of the relationship between biomechanical stress and signal change. The Spearman's rank correlation coefficient for USPIO enhanced signal change and maximal biomechanical stress was -0.60 (p = 0.009). Conclusions: There is an association between biomechanical stress and USPIO enhanced MR-defined inflammation within carotid atheroma, both known risk factors for plaque vulnerability. This underlines the complex interaction between physiological processes and biomechanical mechanisms in the development of carotid atheroma. However, this is preliminary data that will need validation in a larger cohort of patients.

Assessment of carotid plaque vulnerability using structural and geometrical determinants

Background Because many acute cerebral ischemic events are caused by rupture of vulnerable carotid atheroma and subsequent thrombosis, the present study used both idealized and patient-specific carotid atheromatous plaque models to evaluate the effect of structural determinants on stress distributions within plaque. Methods and Results Using a finite element method, structural analysis was performed using models derived from in vivo high-resolution magnetic resonance imaging (MRI) of carotid atheroma in 40 non-consecutive patients (20 symptomatic, 20 asymptomatic). Plaque components were modeled as hyper-elastic materials. The effects of varying fibrous cap thickness, lipid core size and lumen curvature on plaque stress distributions were examined. Lumen curvature and fibrous cap thickness were found to be major determinants of plaque stress. The size of the lipid core did not alter plaque stress significantly when the fibrous cap was relatively thick. The correlation between plaque stress and lumen curvature was significant for both symptomatic (p = 0.01; correlation coefficient: 0.689) and asymptomatic patients (p = 0.01; correlation coefficient: 0.862). Lumen curvature in plaques of symptomatic patients was significantly larger than those of asymptomatic patients (1.50±1.0mm-1 vs 1.25±0.75 mm-1; p = 0.01). Conclusion Specific plaque morphology (large lumen curvature and thin fibrous cap) is closely related to plaque vulnerability. Structural analysis using high-resolution MRI of carotid atheroma may help in detecting vulnerable atheromatous plaque and aid the risk stratification of patients with carotid disease.

Structural analysis and magnetic resonance imaging predict plaque vulnerability: A study comparing symptomatic and asymptomatic individuals

Background: More than half of all cerebral ischemic events are the result of rupture of extracranial plaques. The clinical determination of carotid plaque vulnerability is currently based solely on luminal stenosis; however, it has been increasingly suggested that plaque morphology and biomechanical stress should also be considered. We used finite element analysis based on in vivo magnetic resonance imaging (MRI) to simulate the stress distributions within plaques of asymptomatic and symptomatic individuals. Methods: Thirty nonconsecutive subjects (15 symptomatic and 15 asymptomatic) underwent high-resolution multisequence in vivo MRI of the carotid bifurcation. Stress analysis was performed based on the geometry derived from in vivo MRI of the carotid artery at the point of maximal stenosis. The finite element analysis model considered plaque components to be hyperelastic. The peak stresses within the plaques of symptomatic and asymptomatic individuals were compared. Results: High stress concentrations were found at the shoulder regions of symptomatic plaques, and the maximal stresses predicted in this group were significantly higher than those in the asymptomatic group (508.2 ± 193.1 vs 269.6 ± 107.9 kPa; P = .004). Conclusions: Maximal predicted plaque stresses in symptomatic patients were higher than those predicted in asymptomatic patients by finite element analysis, suggesting the possibility that plaques with higher stresses may be more prone to be symptomatic and rupture. If further validated by large-scale longitudinal studies, biomechanical stress analysis based on high resolution in vivo MRI could potentially act as a useful tool for risk assessment of carotid atheroma. It may help in the identification of patients with asymptomatic carotid atheroma at greatest risk of developing symptoms or mild-to-moderate symptomatic stenoses, which currently fall outside current clinical guidelines for intervention.