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.

Finite element analysis of vulnerable atherosclerotic plaques: A comparison of mechanical stresses within carotid plaques of acute and recently symptomatic patients with carotid artery disease

Objectives: There is considerable evidence that patients with carotid artery stenosis treated immediately after the ischaemic cerebrovascular event have a better clinical outcome than those who have delayed treatment. Biomechanical assessment of carotid plaques using high-resolution MRI can help examine the relationship between the timing of carotid plaque symptomology and maximum simulated plaque stress concentration. Methods: Fifty patients underwent high-resolution multisequence in vivo MRI of their carotid arteries. Patients with acute symptoms (n=25) underwent MRI within 72 h of the onset of ischaemic cerebrovascular symptoms, whereas recently symptomatic patients (n=25) underwent MRI from 2 to 6 weeks after the onset of symptoms. Stress analysis was performed based on the geometry derived from in vivo MRI of the symptomatic carotid artery at the point of maximum stenosis. The peak stresses within the plaques of the two groups were compared. Results: Patient demographics were comparable for both groups. All the patients in the recently symptomatic group had severe carotid stenosis in contrast to patients with acute symptoms who had predominantly mild to moderate carotid stenosis. The simulated maximum stresses in patients with acute symptoms was significantly higher than in recently symptomatic patients (median (IQR): 313310 4 dynes/cm 2 (295 to 382) vs 2523104 dynes/cm 2 (236 to 311), p=0.02). Conclusions: Patients have extremely unstable, high-risk plaques, with high stresses, immediately after an acute cerebrovascular event, even at lower degrees of carotid stenoses. Biomechanical stress analysis may help us refine our risk-stratification criteria for the management of patients with carotid artery disease in future.

The hemodynamic effects of in-tandem carotid artery stenosis: Implications for carotid endarterectomy

Objectives: It remains controversial whether patients with severe disease of the internal carotid artery and a coexisting stenotic lesion downstream would benefit from a carotid endarterectomy (CEA) of the proximal lesion. The aim of this study was to simulate the hemodynamic and wall shear effects of in-tandem internal carotid artery stenosis using a computational fluid dynamic (CFD) idealized model to give insight into the possible consequences of CEA on these lesions. Methods: A CFD model of steady viscous flow in a rigid tube with two asymmetric stenoses was introduced to simulate blood flow in arteries with multiple constrictions. The effect of varying the distance between the two stenoses, and the severity of the upstream stenosis on the pressure and wall shear stress (WSS) distributions on the second plaque, was investigated. The influence of the relative positions of the two stenoses was also assessed. Results: The distance between the plaques was found to have minimal influence on the overall hemodynamic effect except for the presence of a zone of low WSS (range -20 to 30 dyne/cm2) adjacent to both lesions when the two stenoses were sufficiently close (<4 times the arterial diameter). The upstream stenosis was protective if it was larger than the downstream stenosis. The relative positions of the stenoses were found to influence the WSS but not the pressure distribution. Conclusions: The geometry and positions of the lesions need to be considered when considering the hemodynamic effects of an in-tandem stenosis. Low WSS is thought to cause endothelial dysfunction and initiate atheroma formation. The fact that there was a flow recirculation zone with low WSS in between the two stenoses may demonstrate how two closely positioned plaques may merge into one larger lesion. Decision making for CEA may need to take into account the hemodynamic situation when an in-tandem stenosis is found. CFD may aid in the risk stratification of patients with this problem.

Experimental measurement of the mechanical properties of carotid atherothrombotic plaque fibrous cap

Eleven carotid atherothrombotic plaque samples were harvested from patients. Three samples that were highly calcified were discarded, while eight yielded results. The elastic properties of the material were estimated by fitting the measured indentation response to finite element simulations. The methodology was refined and its accuracy quantified using a synthetic rubber. The neo-Hookean form of the material model gave a good fit to the measured response of the tissue. The inferred shear modulus μ was found to be in the range 7-100 kPa, with a median value of 11 kPa. A review of published materials data showed a wide range of material properties for human atherothrombotic tissue. The effects of anisotropy and time dependency in these published results were highlighted. The present measurements were comparable to the static radial compression tests of Lee et al, 1991 [Structure-dependent dynamic behaviour of fibrous caps from human atherosclerotic plaques. Circulation 83, 1764-1770].

Combined PET-FDG and USPIO-enhanced MR imaging in patients with symptomatic moderate carotid artery stenosis

Introduction: PET-FDG and USPIO-enhanced MRI are increasingly being used in depicting carotid atheroma inflammation - a risk factor for the high risk plaque. Their combined use has not been previously reported. Report: Two patients presenting with stroke and identified with 50% carotid stenosis on duplex ultrasonography, underwent PET FDG and USPIO-enhanced MR imaging. Results were concordant and complementary suggesting that both techniques reflect similar metabolic processes. Discussion: The selection of patients for carotid revascularisation has largely been based on the severity of luminal stenosis alone. The two imaging modalities, which identify inflammatory activity, may be potential surrogate risk markers in the selection of patients eligible for carotid surgery, if plaque inflammation can be correlated with risk of developing clinical symptoms.

Molecular mediators linking stroke and carotid artery disease

Carotid artery disease is the most prevalent etiologic precursor of ischemic stroke, which is a major health hazard and the second most common cause of death in the world. If a patient presents with a symptomatic high-grade (>70%) stenosis in the internal carotid artery, the treatment of choice is carotid endarterectomy. However, the natural course of radiologically equivalent carotid lesions may be clinically quite diverse, and the reason for that is unknown. It would be of utmost importance to develop molecular markers that predict the symptomatic phenotype of an atherosclerotic carotid plaque (CP) and help to differentiate vulnerable lesions from stable ones. The aim of this study was to investigate the morphologic and molecular factors that associate with stroke-prone CPs. In addition to immunohistochemistry, DNA microarrays were utilized to identify molecular markers that would differentiate between symptomatic and asymptomatic CPs. Endothelial adhesion molecule expression (ICAM-1, VCAM-1, P-selectin, and E-selectin) did not differ between symptomatic and asymptomatic patients. Denudation of endothelial cells was associated with symptom-generating carotid lesions, but in studies on the mechanism of decay of endothelial cells, markers of apoptosis (TUNEL, activated caspase 3) were found to be decreased in the endothelium of symptomatic lesions. Furthermore, markers of endothelial apoptosis were directly associated with those of cell proliferation (Ki-67) in all plaques. FasL expression was significantly increased on the endothelium of symptomatic CPs. DNA microarray analysis revealed prominent induction of specific genes in symptomatic CPs, including those subserving iron and heme metabolism, namely HO-1, and hemoglobin scavenger receptor CD163. HO-1 and CD163 proteins were also increased in symptomatic CPs and associated with intraplaque iron deposits, which, however, did not correlate with symptom status itself. ADRP, the gene for adipophilin, was also overexpressed in symptomatic CPs. Adipophilin expression was markedly increased in ulcerated CPs and colocalized with extravasated red blood cells and cholesterol crystals. Taken together, the phenotypic characteristics and the numerous possible molecular mediators of the destabilization of carotid plaques provide potential platforms for future research. The denudation of the endothelial lining observed in symptomatic CPs may lead to direct thromboembolism and maintain harmful oxidative and inflammatory processes, predispose to plaque microhemorrhages, and contribute to lipid accumulation into the plaque, thereby making it vulnerable to rupture.

The hemodynamic effects of in-tandem carotid artery stenosis: implications for carotid endarterectomy.

OBJECTIVES: It remains controversial whether patients with severe disease of the internal carotid artery and a coexisting stenotic lesion downstream would benefit from a carotid endarterectomy (CEA) of the proximal lesion. The aim of this study was to simulate the hemodynamic and wall shear effects of in-tandem internal carotid artery stenosis using a computational fluid dynamic (CFD) idealized model to give insight into the possible consequences of CEA on these lesions. METHODS: A CFD model of steady viscous flow in a rigid tube with two asymmetric stenoses was introduced to simulate blood flow in arteries with multiple constrictions. The effect of varying the distance between the two stenoses, and the severity of the upstream stenosis on the pressure and wall shear stress (WSS) distributions on the second plaque, was investigated. The influence of the relative positions of the two stenoses was also assessed. RESULTS: The distance between the plaques was found to have minimal influence on the overall hemodynamic effect except for the presence of a zone of low WSS (range -20 to 30 dyne/cm2) adjacent to both lesions when the two stenoses were sufficiently close (<4 times the arterial diameter). The upstream stenosis was protective if it was larger than the downstream stenosis. The relative positions of the stenoses were found to influence the WSS but not the pressure distribution. CONCLUSIONS: The geometry and positions of the lesions need to be considered when considering the hemodynamic effects of an in-tandem stenosis. Low WSS is thought to cause endothelial dysfunction and initiate atheroma formation. The fact that there was a flow recirculation zone with low WSS in between the two stenoses may demonstrate how two closely positioned plaques may merge into one larger lesion. Decision making for CEA may need to take into account the hemodynamic situation when an in-tandem stenosis is found. CFD may aid in the risk stratification of patients with this problem.

Carotid artery atherosclerotic profile as a predictor of the aorta atherosclerotic profile in patients with cerebrovascular events

Background: It is well known that the presence of atheroma of the thoracic aorta is a risk factor for cerebrovascular events. We sought to evaluate whether the presence and the morphology of atherosclerotic plaque in the carotid artery detected by duplex ultrasonography is associated with disease in the proximal aorta visualized by transesophageal echocardiogram in patients with a cerebrovascular event. Methods: We carried out a cross-sectional prospective study including 147 consecutive patients with prior stroke or transient ischemic attack (TIA). Neurological evaluations were performed by an expert neurologist using clinical and tomographic diagnostic criteria including the definition of etiology and whether the patient suffered from stroke or TIA. Transthoracic and transesophageal echocardiograms and carotid artery duplex ultrasonography were performed by the same examiner. Patients with and without plaque in the carotid artery were compared using Student's t test or the χ2 test. Regression analysis was used to determine whether the presence of plaque in the carotid artery was predictive of the presence of plaque in the proximal aorta and to analyze the relationship between the echogenicity of carotid and aortic plaques. The significance level was set at p < 0.05. Results: All 147 patients (95 men) were included in the analysis. Patients' ages ranged from 23 to 85 years (65 ± 12.4 years). Most of the patients (58.5%) were Caucasian, while 41.5% were African-Brazilian. Arterial hypertension, diabetes and tobacco use were more frequent among patients with atherosclerotic plaque in the aorta. A normal carotid intima-media thickness halved the risk of atherosclerotic plaque in the aorta [odds ratio (OR) 0.46, 95% confidence interval (CI) 0.23-0.91; p = 0.026]. The presence of carotid plaque increased the risk of aortic plaque by 70-fold (OR 73.2, 95% CI 25.6-2,018.6; p < 0.001) in univariate analysis. The absence of atherosclerotic plaque in the carotid artery reduced the risk of plaque in the aorta to almost 0 (OR 0.014, 95% CI 0.004-0.041; p < 0.001). Considering the 86 patients with both aortic and carotid plaques, the presence of hypoechoic plaque in the carotid artery was a predictor of hypoechoic plaque in the aorta (OR 10.1, 95% CI 3.3-31.2; p < 0.001). Conclusions: The carotid artery atherosclerotic profile defined by ultrasonography is a strong predictor of the atherosclerotic profile of the proximal aorta. This should be taken into consideration before referring patients with acute cerebrovascular events for transesophageal echocardiogram. © 2013 S. Karger AG, Basel.

Evaluation of cardiovascular disease markers in patients submitted to carotid artery stenting or endarterectomy

Introduction. Microembolization during the carotid artery revascularization procedure may cause cerebral lesions. Elevated C-Reactive Protein (hsCRP), Vascular endothelial growth factor (VEGF) and serum amyloid A protein (SAA) exert inflammatory activities thus promoting carotid plaque instability. Neuron specific enolase (NSE) is considered a marker of cerebral injury. Neoangiogenesis represents a crucial step in atherosclerosis, since neovessels density correlates with plaque destabilization. However their clinical significance on the outcome of revascularization is unknown. This study aims to establish the correlation between palque vulnerabilty, embolization and histological or serological markers of inflammation and neoangiogenesis. Methods. Serum hsCRP, SAA, VEGF, NSE mRNA, PAPP-A mRNA levels were evaluated in patients with symptomatic carotid stenosis who underwent filter-protected CAS or CEA procedure. Cerebral embolization, presence of neurologicals symptoms, plaque neovascularization were evaluated testing imaging, serological and histological methods. Results were compared by Fisher’s, Student T test and Mann-Whitney U test. Results. Patients with hsCRP<5 mg/l, SAA<10mg/L and VEGF<500pg/ml had a mean PO of 21.5% versus 35.3% (p<0.05). In either group, embolic material captured by the filter was identified as atherosclerotic plaque fragments. Cerebral lesions increased significantly in all patients with hsCRP>5mg/l and SAA>10mg/l (16.5 vs 2.8 mean number, 3564.6 vs 417.6 mm3 mean volume). Discussion. High hsCRP, SAA and VEGF levels are associated with significantly greater embolization during CAS and to the vulnerabiliy of the plaque. This data suggest CAS might not be indicated as a method of revascularization in this specific group of patients.

Prevalence of findings compatible with carotid artery calcifications on dental panoramic radiographs

Cerebrovascular accidents are responsible for killing or disabling more than half a million Americans every year. They are the third leading cause of death in this country. In Germany, the annual stroke incidence reaches 182 cases per 100,000 inhabitants. Stroke there is the fourth leading cause of death. There is a need of finding cost-effective means of decreasing stroke mortality and morbidity. Instruments for early diagnosis are of great humanitarian and economic importance. All possible clinical findings should be taken into account. It is not the demand of this study to present the panoramic radiograph as a screening test method for early diagnosis of atherosclerosis. The aim is to show the potential of this radiograph used in everyday clinical dental practice by the prevalence of radiopaque findings in the carotid region. This study included panoramic dental radiographs of 2,557 patients older than 30 years of age. Fifty-nine percent of the patients were women and 41% were men. The radiographs were adjudged for signs compatible with carotid arterial calcifications appearing as a radiopaque nodular mass adjacent to the cervical vertebrae at or below the intervertebral space C3-4. Of all these radiographs, 4.8% showed radiopaque findings compatible with atherosclerotic lesions. The proportion of women reached 64.8% and that of men reached 35.2%. In accordance to recent literature, the results of this study show that about 5% of the patients show radiological findings compatible with carotid arterial calcifications. Some of these patients at risk for a cerebrovascular accident may be identified in the dentist's office by appropriate review of the panoramic dental radiograph. The suspicion of carotid artery calcifications demands an impetuous referral to an appropriate practitioner who can assist in the control of risk factors and if necessary arrange surgical removal of the carotid arterial plaque. So, the dentist should be aware of this problem and able to make a contribution to stroke prevention.

Carotid plaque in Alzheimer caregivers and the role of sympathoadrenal arousal

To test the hypothesis that those who provide care for a spouse diagnosed with Alzheimer's disease would have increased prevalence of carotid artery plaque compared with noncaregiving controls and that prolonged sympathoadrenal arousal to acute stress would relate to this difference. Providing care for a spouse with Alzheimer's disease has been associated with an increased risk of coronary heart disease, potentially due to the impact of caregiving stress on the atherosclerotic disease process.

Circulating oxidized LDL is associated with the occurrence of echolucent plaques in the carotid artery in 61-year-old men.

OBJECTIVE The aim of this study was to elucidate the relationship between the echogenicity of carotid artery plaques and the following risk factors: circulating oxLDL, hsCRP, the metabolic syndrome (MetS), and several of the traditional cardiovascular (CV) risk factors. MATERIAL AND METHODS A cross-sectional population-based study of 513 sixty-one-year-old men. The levels of circulating oxLDL were determined in plasma samples by sandwich ELISA utilizing a specific murine monoclonal antibody (mAb-4E6). High-sensitivity CRP was measured in plasma by ELISA. Plaque occurrence, size and echogenicity were evaluated from B-mode ultrasound registrations in the carotid arteries. Plaque echogenicity was assessed based on a four-graded classification scale. RESULTS A higher frequency of echolucent carotid plaques was observed with increasing levels of oxLDL and systolic blood pressure (p = 0.008 and p = 0.041, respectively). Subjects with the MetS had a significantly higher frequency of echogenic plaques than subjects without the MetS (p = 0.009). In a multiple logistic regression analysis, oxLDL turned out to be independently associated with echolucent carotid plaques. CONCLUSIONS The occurrence of echolucent carotid plaques was associated with oxLDL and systolic blood pressure, and oxLDL was associated with echolucent carotid plaques independently of systolic blood pressure.

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.