Sensitive three-dimensional ultrasound assessment of carotid atherosclerosis by weighted average of local vessel wall and plaque thickness change

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Vitamin B deficiency has been identified as a risk factor for vascular events. However, the reduction of vascular events was not shown in large randomized controlled trials evaluating B-Vitamin therapy. There is an important requirement to develop sensitive biomarkers to be used as efficacy targets for B-Vitamin therapy as well as other dietary treatments and lifestyle regimes that are being developed. Carotid vessel-wall-plus-plaque thickness change (VWT-Change) measured from 3D ultrasound has been shown to be sensitive to atorvastatin therapies in previous studies. However, B-Vitamin treatment is expected to confer a smaller beneficial effect in carotid atherosclerosis than the strong dose of atorvastatin. This paper introduces a sensitive atherosclerosis biomarker based on the weighted mean VWT-Change measurement from 3D ultrasound with a purpose to detect statistically significant effect of B-Vitamin therapy.


Of the 56 subjects analyzed in this study, 27 were randomized to receive a B-Vitamin tablet daily and 29 received a placebo tablet daily. Participants were scanned at baseline and 1.9 ± 0.8 yr later. The 3D VWT map at each scanning session was computed by matching the outer wall and lumen surfaces on a point-by-point basis. The 3D annual VWT-Change maps were obtained by first registering the 3D VWT maps obtained at the baseline and follow-up scanning sessions, and then taking the point-wise difference in VWT and dividing the result by the years elapsed from the baseline to the follow-up scanning session. The 3D VWT-Change maps constructed for all patients were mapped to a 2D carotid template to adjust for the anatomic variability of the arteries. A weight at each point of the carotid template was assigned based on the degree of correlation between the VWT-Change measurements exhibited at that point and the treatment received (i.e., B-Vitamin or placebo) quantified by mutual information. The weighted mean of VWT-Change for each patient, denoted by Symbol, was computed according to this weight. T-tests were performed to compare the sensitivity of Symbol with existing biomarkers in detecting treatment effects. These biomarkers included changes in intima-media thickness (IMT), total plaque area (TPA), vessel wall volume (VWV), unweighted average of VWT-Change (Symbol) and a previously described biomarker, denoted by Symbol, that quantifies the mean VWT-Change specific to regions of interest identified by a feature selection algorithm.


Among the six biomarkers evaluated, the effect of B Vitamins was detected only by Symbol in this cohort (Symbol). The sample sizes per treatment group required to detect an effect as large as exhibited in this study were 139, 178, 41 for ΔVWV, Symbol and Symbol respectively.


The proposed weighted mean of VWT-Change is more sensitive than existing biomarkers in detecting treatment effects. This measurement tool will allow for many proof-of-principal studies to be performed for various novel treatments before a more costly study involving a larger population is held to validate the results.

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