Atherosclerotic Vessel Wall Changes Research Articles

Target identification for the diagnosis and intervention of vulnerable atherosclerotic plaques beyond 18F-fluorodeoxyglucose positron emission tomography imaging: promising tracers on the horizon

Cardiovascular disease is the major cause of morbidity and mortality in developed countries and atherosclerosis is the major cause of cardiovascular disease. Atherosclerotic lesions obstruct blood flow in the arterial vessel wall and can rupture leading to the formation of occlusive thrombi. Conventional diagnostic tools are still of limited value for identifying the vulnerable arterial plaque and for predicting its risk of rupture and of releasing thromboembolic material. Knowledge of the molecular and biological processes implicated in the process of atherosclerosis will advance the development of imaging probes to differentiate the vulnerable plaque. The development of imaging probes with high sensitivity and specificity in identifying high-risk atherosclerotic vessel wall changes and plaques is crucial for improving knowledge-based decisions and tailored individual interventions. Arterial PET imaging with 18F-FDG has shown promising results in identifying inflammatory vessel wall changes in numerous studies and clinical trials. However, due to its limited specificity in general and its intense physiological uptake in the left ventricular myocardium that impair imaging of the coronary arteries, different PET tracers for the molecular imaging of atherosclerosis have been evaluated. This review describes biological, chemical and medical expertise supporting a translational approach that will enable the development of new or the evaluation of existing PET tracers for the identification of vulnerable atherosclerotic plaques for better risk prediction and benefit to patients.

Extra-medial thickness of carotid artery in patients with Behçet's disease: evaluation of atherosclerotic vessel wall changes with a novel carotid artery ultrasound index.

Chronic inflammation and endothelial dysfunction are the characteristic features of Behçet's disease (BD). We researched carotid extra-medial thickness (cEMT), a novel ultrasound parameter for atherosclerotic vessel wall changes, and carotid intima media thickness (cIMT), a widely accepted marker of subclinical atherosclerosis, in patients with BD, and we evaluated the relationship between these two parameters. In total, 31 patients with BD were matched to 26 control subjects based on age, gender, and major cardiovascular risk factors. Laboratory parameters, including lipid profile, were measured for both patients and controls. B-mode ultrasonography was used to assess the cEMT and cIMT. There was no significant difference in the cEMT values between the patients with BD and the control group (P = 0.90). cIMT in the BD group was significantly higher compared with the control group (P = 0.021). There was a significant positive correlation between cIMT and cEMT (r = 0.585, P = 0.001). Both cEMT and cIMT were positively correlated with age and the presence of arthritis. There was linear correlation with sedimentation, C-reactive protein, and cEMT. To the best of our knowledge, this is the first study to evaluate both cEMT and cIMT in BD. This study presents morphological evidence of subclinical atherosclerosis in terms of cIMT. Although there was no significant increment in cEMT, it has the potential to assess endothelial dysfunction in BD. Further studies are required to confirm this finding.

The Great Migration: How MRI Replaces Traditional Imaging Techniques for the Characterization of Atherosclerosis

In the Western world and developing countries, cardiovascular diseases remain the primary cause of morbidity and mortality. The incidence of cardiovascular diseases is thought to be on the rise, due to an increase in risk factors (e.g. diabetes) and aging of the population. Currently, there is no established clinical method for the in vivo characterization of atherosclerotic plaques and the prediction of ischemic stroke, myocardial infarction and other clinical complications. In this article, we will introduce novel magnetic resonance imaging (MRI) techniques and discuss how these techniques are starting to replace currently established clinical imaging methods for the detection and characterization of atherosclerotic vessel wall changes.

In vivo assessment of intraplaque and endothelial fibrin in ApoE−/− mice by molecular MRI

ObjectiveMolecular magnetic resonance imaging (MRI) has emerged as a promising non-invasive modality to characterize atherosclerotic vessel wall changes on a morphological and molecular level. Intraplaque and endothelial fibrin has recently been recognized to play an important role in the progression of atherosclerosis. This study aimed to investigate the feasibility of intraplaque and endothelial fibrin detection using a fibrin-targeted contrast-agent, FTCA (EPIX Pharmaceuticals, Lexington, MA), in a mouse model of atherosclerosis. MethodsMale apolipoproteinE-knockout mice (ApoE−/−) were fed a high fat diet (HFD) for one to three months. MRI of the brachiocephalic artery was performed prior to and 90min after the administration of FTCA (n=8 per group). Contrast to noise ratios (CNR) and longitudinal relaxation rates (R1) of plaques were determined and compared to ex vivo fibrin density measurements on immunohistological sections stained with a fibrin-specific antibody and gadolinium concentrations measured by inductively coupled mass spectroscopy (ICP-MS). ResultsMolecular MRI after FTCA administration demonstrated a significant increase (p<0.05) in contrast agent uptake in brachiocephalic artery plaques. In vivo CNR measurements were in good agreement with ex vivo fibrin density measurements on immunohistochemistry (y=2.4x+11.3, R2=0.82) and ICP-MS (y=0.95x+7.1, R2=0.70). Late stage atherosclerotic plaques displayed the strongest increase in CNR, R1, ex vivo fibrin staining and gadolinium concentration (p<0.05). ConclusionThis study demonstrated the feasibility of intraplaque and endothelial fibrin imaging using FTCA. Direct in vivo fibrin detection and quantification could be useful for characterization and staging of coronary and carotid atherosclerotic lesions, which may aid diagnosis and intervention.

Fibrinogen Promotes Early Atherosclerotic Changes of the Carotid Artery in Young, Healthy Adults

To determine whether high plasma levels or activities of different hemostatic proteins contribute to the development of early atherosclerotic vessel wall changes. Elevated levels of various hemostatic proteins and markers of inflammation have been linked to an increased risk of ischemic cardiovascular events; however, the mechanisms by which these molecules might contribute to this increased risk is not clear. The intima-media thickness of the common carotid arteries (CCA-IMT) of 125 healthy young volunteers without known cardiovascular risk factors was measured by high-resolution ultrasound. Plasma concentrations of fibrinogen, thrombomodulin, protein Z and CRP were quantified, and the plasma activities of protein C, plasminogen and factor VIII were measured. Other established risk factors, such as body mass index (BMI) and plasma levels of cholesterol, triglycerides and homocysteine, were also determined. Furthermore, the carotid arteries were examined for the presence of plaques and stenoses. Univariate analysis showed a significant negative correlation between CCA-IMT and HDL cholesterol, and positive correlations with age, BMI, LDL cholesterol, triglycerides, homocysteine, fibrinogen and thrombomodulin, but not with total cholesterol, lipoprotein(a) and hsCRP. CCA-IMT was also statistically independent of the activities of protein C, factor VIII and plasminogen. Multivariate analysis revealed a significant correlation of CCA-IMT with age, BMI and fibrinogen. Our data suggest that fibrinogen levels correlate with early atherosclerotic changes of the carotid artery in a population with very low cardiovascular risk.

Ganzkörper-MR-Angiografie

Cardiovascular diseases still rank number one in terms of morbidity and mortality statistics in the western industrialized world. The majority of these diseases are due to atherosclerotic vessel wall changes. Atherosclerosis gets symptomatic in an advanced stage where vessel wall changes are apparent. Thus an early diagnosis of this disease is desirable. Especially atherosclerosis but also most of the inflammatory vessel diseases are known as systemic in nature. Magnetic resonance angiography offers an excellent and ethically justifiable method for non invasive imaging of the entire arterial vasculature without ionizing radiation. DSA comparable imaging results can be achieved nowadays. Possibilities to perform a whole body MR angiography and concerning imaging protocols are very dependent on the configuration of the available MR scanner.

Statine und ihr Einfluss auf entzündliche Prozesse in arteriosklerotischen Plaques bei Patienten mit Stenose der Arteria carotis interna

Arterio-arterial emboli originating from a high-grade stenosis of the internal carotid artery are a common cause for cerebral ischemias. Inflammatory processes are not only pivotal in the development of atherosclerotic vessel wall changes, but also for their clinical destabilization. Inflammatory cells, like macrophages, can turn a chronic high-grade carotid stenosis into a high-risk area for the development of arterial thromboses by way of a complex pathogenesis involving the elevation of proinflammatory factors, biosynthesis of collagen-degrading matrix metalloproteinases and expression of prothrombotic tissue factor. This process could affect the occurrence of perioperative complications during carotid endarterectomies. Statins are potent cholesterol-lowering agents. Among other lipid-independent effects, statins appear to play a significant role in preventing cardiovascular events. A number of studies have shown that statins possess plaque-stabilizing effects and that they improve cerebral autoregulation. A growing evidence supports the preoperative administration of statins in patients with high-grade stenoses of the internal carotid artery.

Elevated Lipoprotein(a) does not promote early atherosclerotic changes of the carotid arteries in young, healthy adults

Background Elevated levels of Lipoprotein(a) [Lp(a)] have been linked to an increased risk of ischemic cardiovascular events. Yet the mechanism by which Lp(a) might contribute to this increased risk is not clear. Methods To elucidate whether high plasma levels of Lp(a) contribute to the development of early atherosclerotic vessel wall changes, the intima-media thickness of the common carotid arteries [CCA-IMT] of 151 healthy young volunteers without additional relevant cardiovascular risk factors was measured by high-resolution ultrasound. Plasma concentrations of Lp(a) were quantified and other established risk factors, such as body mass index [BMI], plasma levels of cholesterol, triglycerides and homocysteine, were determined. Furthermore, the carotid arteries were examined for the presence of plaques and stenoses. Results Univariate analysis showed a significantly negative correlation of CCA-IMT with HDL cholesterol and positive correlations with age, BMI, total and LDL cholesterol, triglycerides and even with homocysteine, but not with Lp(a). When the study population was dichotomized according to Lp(a) levels, no statistically significant differences in CCA-IMT could be detected between persons with plasma Lp(a) < 300 mg/l or ≥300 mg/l, respectively. Conclusion Our data suggest that elevated Lp(a) levels alone do not contribute to increased cardiovascular risk by promoting early atherogenesis in vivo.

Optimization of ex vivo CT- and MR- Imaging of Atherosclerotic Vessel Wall Changes

To optimize a methodology for ex vivo imaging of atherosclerotic vessel wall changes using multidetector-row computed tomography (MDCT) and multi-contrast magnetic resonance imaging (MRI). In phantom studies and studies on intact ex vivo porcine and human hearts, various filling mixtures of MDCT and MRI contrast agents have been evaluated, to enable filling and distension of the coronary arteries for optimal visualization of atherosclerotic vessel wall changes with both techniques. Various proportions of methyl cellulose, iodine-containing CT contrast agent and paramagnetic MR contrast agent containing iron-oxide particles have been tested. Imaging parameters have been optimized for high resolution plaque imaging using a four detector-row CT scanner and a 1.5 T MR system. Phantom studies and studies on ex vivo porcine and human hearts demonstrated optimal proportion of methyl cellulose and CT contrast agent to be 98% vs. 2%, and 75% vs. 25% of methyl cellulose vs. MR contrast agent, respectively. These proportions provided optimal opacification of the vessel lumen in the MDCT images with 250 Hounsfield Units, and good signal suppression within the vessel lumen in the MR images, resembling in vivo imaging techniques. After retrospective matching with histopathology, atherosclerotic lesions of the human ex vivo specimens could be identified on MRI and MDCT images. Using an optimized mixture of methyl cellulose, MDCT and MRI contrast agents, visualization of atherosclerotic vessel wall changes is feasible, and applicable to various ex vivo models.

Optimization of ex vivo CT- and MR- Imaging of Atherosclerotic Vessel Wall Changes

Optimization of ex vivo CT- and MR- Imaging of Atherosclerotic Vessel Wall Changes

Patients with type 3 severe von Willebrand disease are not protected against atherosclerosis: results from a multicenter study in 47 patients.

The results of a number of studies in pigs and mice suggest that absence of von Willebrand factor (vWF) protects against the development of atherosclerosis. We studied whether patients with a complete deficiency of vWF (type 3 von Willebrand disease [vWD]) develop fewer atherosclerotic vessel wall changes than healthy controls. This study included 47 individuals with type 3 vWD and 84 healthy controls. Early atherosclerotic changes were assessed by measuring the thickness of the intima-media in the carotid and femoral arteries by B-mode ultrasonography. Advanced atherosclerotic changes were quantified by summing the maximal thickness of atherosclerotic plaques in the carotid and femoral arteries and were expressed as a plaque score. Established risk factors were determined to adjust for possible differences between the groups. We found no substantial difference in intima-media thickness between vWD patients and controls (adjusted difference for carotid artery 0.007 mm, 95% CI -0.022 to 0.036 mm; femoral artery 0.069 mm, 95% CI -0.056 to 0.19 mm). Similar proportions of patients and controls had atherosclerotic plaques (19% and 17%, respectively). No difference was found in the plaque score between groups (adjusted difference -0.22 mm, 95% CI -0.69 to 0.26). Among vWD patients, we found no effect of treatment with vWF concentrates on intima-media thickness or plaque score. The results of this study indicate that vWF does not play a substantial role in human atherogenesis.

Evaluating multislice computed tomography for imaging coronary atherosclerosis

The purpose of this study was the evaluation of multidetector-row computed tomography (MDCT) for the assessment of atherosclerotic coronary artery vessel wall changes. In an ex vivo study, 17 human hearts were scanned with MDCT and results were compared to histopathology. Morphologic imaging criteria of MDCT for various plaque-types were developed. In a following in vivo study, 94 coronary MDCT angiograms (MDCTA) of patients with suspected coronary artery disease (CAD) were reviewed retrospectively, assessing the diagnostic value of the coronary MDCTA, and determining the number and correlations of the various plaques types as described in the ex vivo study. Additionally, volumetry of calcified and noncalcified plaque components was performed. In the ex vivo study, MDCT showed a high sensitivity for calcified and non-calcified plaques. Comparing the results with histopathology, characteristic image criteria could be determined for lipid-rich, fibrous and calcified plaque components. Reviewing the contrastenhanced in-vivo MDCT coronary angiographies, presence of noncalcified plaques was proven in 38% of the patients. In 5 patients with a calcium score of 0, presence of coronary atherosclerosis was proven in the contrastenhanced scan. MDCT is able to differentiate various plaque components in an ex vivo setting as well as invivo. Contrastenhanced MDCT of the coronary arteries allows for the detection of noncalcified plaques. In vivo volumetry of noncalcified plaques is feasible.

Lipoprotein(a) and ultrasonographically determined early atherosclerotic changes in the carotid and femoral artery

Recent studies suggest that high lipoprotein(a) [Lp(a)] plasma levels are associated with symptomatic ischemic cardiovascular disease. We examined whether Lp(a) plasma levels are associated with early atherosclerotic vessel wall changes in a group of asymptomatic subjects. In a group of 142 asymptomatic men, the intima-media thickness (IMT) in the common carotid artery, the carotid bifurcation and the common femoral artery was determined by B-mode ultrasonography. In addition to Lp(a) levels, established risk factors, such as blood pressure and cholesterol levels were determined. Lipoprotein(a) values ranged from 2 mg L(-1) to 900 mg L(-1) (median 145 mg L(-1)). Linear regression analysis showed a clear association of IMT with the established risk factors but not with Lp(a) [regression coefficient carotid artery -0.0003, 95% confidence interval (CI) -0.002-0.001; regression coefficient femoral artery -0.0003, 95% CI -0.004-0.003]. We found no increased intima-media thickness in the carotid or femoral artery at high levels of Lp(a). Lipoprotein(a) levels are not associated with early atherosclerotic vessel wall changes in the carotid or femoral artery.

Vessel wall MRI of the thoracic aorta: correlation to histology and transesophageal ultrasound. Preliminary results.

To visualise the vessel wall of the descending thoracic aorta using magnetic resonance imaging. To evaluate the diagnostic potential of tailored T1-weighted sequences with contrast enhancement to assess systemic atherosclerotic disease. This study was performed on a clinical 1.5 Tesla scanner using a gradient strength of 30 mT/m and the phased array spine coil. A cadaver was examined to optimise a magnetic resonance imaging (MRI) protocol to evaluate atherosclerotic aortic wall disease. The acquired MR images were compared to gross specimens and histology. Subsequently seven patients who had undergone transesophageal ultrasound (TEU) with detailed assessment of the descending thoracic aorta were examined with MRI. The optimised protocol included untriggered and fat suppressed T2-weighted turbo spin echo sequences and ECG-triggered and fat suppressed T1-weighted spin echo sequences before and after iv administration of Gd-DTPA. Findings of the MR images were compared to the results of TEU. Contrast enhancement measurements were performed in normal and thickened vessel wall segments. For the cadaver study a good correlation of the degree of vessel wall thickening and the extent of plaque imaged with the applied MR protocol was found. Tissue characterisation was limited due to post mortem changes. In vivo ECG-triggered T1-weighted images showed good correlation to TEU in terms of vessel wall thickness and plaque extension as verified by means of consensus reading. Differentiation of the plaque components fat, calcium and fibrous tissue was possible. In thickened aortic wall segments and fibrous caps a mean contrast enhancement of 50.4 % +/- 23.5 % was measurable while normal wall segments showed an enhancement of 6.7 % +/- 3.1 %. The difference of contrast enhancement was highly significant (p < 0.0001). Using fat suppressed T1-weighted sequences with contrast enhancement the extent of atherosclerotic vessel wall changes can be demonstrated. The suggested MR protocol contains a high potential for diagnosis and follow-up of therapy of atherosclerotic disease of the descending thoracic aorta.

Ultrasound assessment of atherosclerotic vessel wall changes: reproducibility of intima-media thickness measurements in carotid and femoral arteries.

Ultrasonography is widely used in cardiovascular research to quantify early atherosclerotic vessel wall changes. In this article, we examined the short- and long-term reproducibility of this technique in the common carotid artery, carotid bifurcation, common femoral artery, and superficial femoral artery. Furthermore, we assessed the effect of progressed atherosclerosis on reproducibility. Repeated ultrasound examinations were performed by one observer on 15 healthy individuals and 18 patients suffering from coronary heart disease. Intima-media thickness was determined by B-mode ultrasonography. The examinations were repeated by the same observer after a short time interval (short-term) and after a few weeks (long-term) and expressed as the mean difference between the measurements and the coefficient of variation (CV). The reproducibility of the intima-media thickness determination turned out to be best in the common carotid artery and the superficial femoral artery when performed in healthy controls (CV 5.6% and 5.5%, respectively). Reproducibility was less in patients with clinical atherosclerosis; this especially affected the reliability of the superficial femoral artery measurement (CV in healthy controls was 5.5%; in coronary heart disease patients, 17.5 %). The reliability of the intima-media thickness measurements in the common carotid artery (CV in healthy controls was 5.6%; in coronary heart disease patients, 9.5%) proved to be least affected by progressed atherosclerosis. A longer time interval between measurements did not affect the reproducibility of intima-media thickness measurements in healthy controls, whereas in the patients it led to some decrease of reproducibility and to a major decrease in reproducibility of the superficial femoral artery measurements (CV changed from 12.7% to 17.5%). Ultrasonography is a reliable and accurate technique to determine intima-media thickness in superficial arteries. In studies in which the intima-media thickness determination is used as a marker for generalized and coronary atherosclerosis, the common carotid artery should always be included, whereas the benefit of inclusion of other arteries depends on age and the expected extent of atherosclerosis in the individuals studied.