A novel 3-dimensional micro-ultrasound approach to automated measurement of carotid arterial plaque volume as a biomarker for experimental atherosclerosis.
ABSTRACT Improved methods for non-invasive in vivo assessment are needed to guide development of animal models of atherosclerosis and to evaluate target engagement and in vivo efficacy of new drugs. Using novel 3D-micro-ultrasound technology, we developed and validated a novel protocol for 3D acquisition and analysis of imaging to follow lesion progression in atherosclerotic mice. The carotid arteries of ApoE receptor knockout mice and normal control mice were imaged within the proximal 2mm from the aortic branch point. Plaque volume along that length was quantified using a semi-automated 3D segmentation algorithm. Volumes derived by this method were compared to those calculated using 3-D histology post-mortem. Bland-Altman comparison revealed close correlation between these two measures of plaque volume. Furthermore, using a segmentation technique that captures early positive and 33 week negative remodeling, we found evidence that plaque volume increases linearly over time. Each animal and each plaque served as its own control, allowing accurate comparison. The high fidelity anatomical registration of this protocol provides increased spatial resolution and therefore greater sensitivity for measurement of plaque wall size, an advance over 2-dimensional measures of intimal-medial-thickening. Further, 3-dimensional analysis ensures a point of registration that captures functional markers in addition to the standard structural markers that characterize experimental atherosclerosis. In conclusion, this novel imaging protocol provides a non-invasive, accurate surrogate marker for experimental atherosclerosis over the life of the entire lesion.
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ABSTRACT: B-mode ultrasound is a noninvasive method of examining the walls of peripheral arteries and provides measures of the intima-media thickness (IMT) at various sites (common carotid artery, bifurcation, internal carotid artery) and of plaques that may indicate early presymptomatic disease. The reported associations between cardiovascular risk factors, clinical disease, IMT, and plaques are inconsistent. We sought to clarify these relationships in a large, representative sample of men and women living in 2 British towns. The study was performed during 1996 in 2 towns (Dewsbury and Maidstone) of the British Regional Heart Study that have an approximately 2-fold difference in coronary heart disease risk. The male participants were drawn from the British Regional Heart Study and were recruited in 1978-1980 and form part of a national cohort study of 7735 men. A random sample of women of similar age to the men (55 to 77 years) was also selected from the age-sex register of the general practices used in the original survey. A wide range of data on social, lifestyle, and physiological factors, cardiovascular disease symptoms, and diagnoses was collected. Measures of right and left common carotid IMT (IMTcca) and bifurcation IMT (IMTbif) were made, and the arteries were examined for plaques 1.5 cm above and below the flow divider. Totals of 425 men and 375 women were surveyed (mean age, 66 years; range, 56 to 77 years). The mean (SD) IMTcca observed were 0. 84 (0.21) and 0.75 (0.16) mm for men and women, respectively. The mean (SD) IMTbif were 1.69 (0.61) and 1.50 (0.77) mm for men and women, respectively. The correlation between IMTcca and IMTbif was similar in men (r=0.36) and women (r=0.38). There were no differences in mean IMTcca or IMTbif between the 2 towns. Carotid plaques were very common, affecting 57% (n=239) of men and 58% (n=211) of women. Severe carotid plaques with flow disturbance were rare, affecting 9 men (2%) and 6 women (1.6%). Plaques increased in prevalence with age, affecting 49% men and 39% of women aged <60 years and 65% and 75% of men and women, respectively, aged >70 years. Plaques were most common among men in Dewsbury (79% affected) and least common among men in Maidstone (34% affected). IMTcca showed a different pattern of association with cardiovascular risk factors from IMTbif and was associated with age, SBP, and FEV1 but not with social, lifestyle, or other physiological risk factors. IMTbif and carotid plaques were associated with smoking, manual social class, and plasma fibrinogen. IMTbif and carotid plaques were associated with symptoms and diagnoses of cardiovascular diseases. IMTbif associations with cardiovascular risk factors and prevalent cardiovascular disease appeared to be explained by the presence of plaques in regression models and in analyses stratified by plaque status. IMTcca, IMTbif, and plaque are correlated with each other but show differing patterns of association with risk factors and prevalent disease. IMTcca is strongly associated with risk factors for stroke and with prevalent stroke, whereas IMTbif and plaque are more directly associated with ischemic heart disease risk factors and prevalent ischemic heart disease. Our analyses suggest that presence of plaque, rather than the thickness of IMTbif, appears to be the major criterion of high risk of disease, but confirmation of these findings in other populations and in prospective studies is required. The association of fibrinogen with plaque appears to be similar to its association with incident cardiovascular disease. Further work elucidating the composition of plaques using ultrasound imaging would be helpful, and more data, analyzed to distinguish plaque from IMTbif and IMTcca, are required to understand the significance of thicker IMT in the absence of plaque.Stroke 04/1999; 30(4):841-50. · 6.16 Impact Factor
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ABSTRACT: Noninvasive assessment of vascular dysfunction in the pediatric population has taken advantage of the development of high-resolution ultrasound techniques. The most frequently used methods are the quantification of flow-mediated endothelium-dependent dilation of the brachial artery and measurement of the intima-media thickening of the carotid artery. Both reduced flow-mediated dilation and increased intima-media thickness have been proven to correlate with late cardiovascular events and/or mortality in adults. As these noninvasive methods can easily be applied in children, there have been recent investigations in high-risk pediatric patients harboring classical cardiovascular risk factors. Endothelial dysfunction and increased thickness of the intima media are currently observed in children with familial hypercholesterolemia, obesity, and type 1 diabetes mellitus. The association of early vascular dysfunction with a known risk factor is an important issue as these anomalies precede the formation of atherosclerotic plaques. Therefore, they may help in stratification of the risk for cardiovascular event and to better tailor therapeutic interventions in at risk children. Finally, these methods have been applied in specific pediatric populations, such as children with end-stage renal disease, chronic parenteral nutrition, HIV infection, and coarctation of the aorta. In these conditions, endothelial dysfunction and vascular remodeling are also present early in life and these data raise new possibilities in the understanding of the pathogenesis of atherosclerosis in these populations.Pediatric Research 09/2005; 58(2):173-8. · 2.67 Impact Factor
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ABSTRACT: Transesophageal echocardiography (TEE) has been used to visualize aortic arch plaques. TEE is moderately invasive. We employed a new non-invasive method for visualization of the aortic arch to assess the correlation of the extent of plaque in the aortic arch as visualized by non-invasive ultrasound with the prevalence of coronary artery disease (CAD). The aortic arch was examined with B-mode sonography using a right supraclavicular approach in 517 consecutive patients referred for carotid duplex sonography. CAD was defined as previous myocardial infarction, previous coronary revascularization or typical angina pectoris requiring treatment. Cardiovascular risk factors were documented. The aortic arch could be visualized to measure intima-media thickness (IMT) in 97% of the 517 patients. The IMT was a strong predictor for the presence of CAD. Only 14% (37 out of 256) of patients with an IMT of <1.1 mm had overt CAD. The prevalence increased consistently with increase of IMT to 86% among the patients with IMT over 5 mm (chi2, p<0.0000001) (R=0.97, p<0.001). The average IMT increased also with age, diabetes mellitus, arterial hypertension, hypercholesterolemia and tobacco smoking. Aortic arch IMT can be measured in the majority of patients using the right supraclavicular window. The method is non-invasive, allowing sequential examinations applicable to prospective studies of the risk of CAD.Atherosclerosis 03/2006; 185(1):159-64. · 3.71 Impact Factor