In summary, we showed that measuring carotid arterial strain (CAS) was feasible and modestly reliable using a novel speckle-tracking based technique and that CAS values were lower in diabetics compared with non-diabetics. Furthermore, we found inter-visit, intra-reader, and inter-reader agreements were consistently higher for the mean CAS of all segments and the far wall segments (). The inter-visit ICC suggested moderate reliability based on criteria set forth by Fleiss (0.40 to <0.60 for moderate ICC) whereas the intra-/inter-reader ICC’s were excellent (ICC ≥0.75) (25
). CAS values were lower in diabetics versus non-diabetics, and this difference persisted even after adjustments for covariates and appropriate exclusions ().
Measurements of arterial wall characteristics have become increasingly recognized as possible cardiovascular risk markers in large epidemiologic studies. The elastic property of large arterial vessels depend greatly on the elastin content (organized as elastic lamina) of the arterial media, and to a lesser extent on the collagen content of the vessel (26
). Both components in turn are produced by the smooth muscle cell population of the same layer (i.e., arterial media) (26
As large arteries age, smooth muscle cells degenerate and decrease in number through apoptosis, and the elastin lamina also degenerate and become fragmented (28
). In contrast, the more rigid collagen component has been shown to proportionally increase (28
). These processes lead to increased arterial stiffness, a process best labeled with the term arteriosclerosis (27
). These observations have been borne out in clinical studies, which have found increased pulse pressures, a marker of arterial stiffness, to increase with age (27
). Certain pathologic states (e.g., hypertension through medial hypertrophy; atherosclerosis through foam cell infiltration and plaque deposition) have also been recognized to contribute and potentially to accelerate arterial stiffening (2
). Similarly, non-insulin dependent diabetes has been postulated to increase proliferation of smooth muscle cells through elevated insulin levels and to lead to advanced glycosylation end-products (AGEs) involving the collagen and elastin of the medial layer through hyperglycemia (32
). Therefore, several of the cardiovascular risk factors seem to be associated with arterial stiffness.
Regional stiffness measured using pulse wave velocity (tonometry) has been shown to be associated with incident coronary heart disease (7
). Although local carotid artery stiffness measures have shown strong associations with cardiovascular risk factors, their associations with incident cardiovascular events have been weaker/ non-significant (33
). Recent results from the Atherosclerosis Risk in Communities Study support a significant association between ultrasound-based measures of arterial stiffness and incident stroke events, independent of established atherosclerotic risk factors (35
). Thus, local measures of arterial stiffness may also hold potential as cardiovascular risk markers.
Local arterial stiffness can be estimated non-invasively through the measurement of arterial distension using imaging (e.g., magnetic resonance imaging, ultrasound imaging) (4
). Imaging-based distension measurements rely on the detection of changes in arterial dimensions over the cardiac cycle, which can be obtained from lumen-wall border tracking (i.e., lumen size) or from direct wall tracking (4
). For ultrasound, direct vessel wall tracking has been accomplished with echo-tracking and more recently with tissue Doppler imaging (TDI) and with speckle-tracking (8
Echo-tracking has been well studied and validated for measuring arterial distension but has its limitations (4
). Although Hoeks et al, found the echo-tracking resolution to be less than 0.001 mm in vitro
, they also noted the standard deviation of distension measured in a human test subject to be 0.043 mm (8
). They attributed this finding to arterial motion and physiological variations, which may be evidence of a threshold beyond which higher resolutions do not improve distension measurements (8
). Furthermore, the technology is fundamentally based on M-mode, or single-beam axes, limiting its ability to assess motion assessment in other axial directions (8
). Recently, Kawaski et al, used TDI to measure strain rates on longitudinal views of the common carotid artery in patients with coronary heart disease (38
). However, the TDI method is limited by angle dependence (38
We sought to evaluate the application of speckle-tracking for direct assessment of carotid arterial wall strain and are among the first groups to do so (40
). Speckle-tracking is a 2-dimensional angle-independent method of tissue-tracking that is used for assessing myocardial stiffness (10
). Speckle-tracking tracks the arterial wall, through “acoustic fingerprints,” or persistent speckles specific to a local tissue region and therefore gets direct arterial wall information rather than depending on luminal changes.
Bjallmark et al, employed speckle-tracking analysis of carotid strain in a population of younger (n=10) and older (n=10) individuals and showed increasing age to be associated with lower strain values (39
), which our models support. However, Bjallmark et al, acquired images for only the right common carotid artery, did not report on the inter-visit repeatability of their measurements, and examined a smaller population sample. Our work differs by demonstrating the reliability and repeatability of speckle-tracking for measuring CAS in arterial wall segments and furthermore examines CAS in a population known to have stiffer arteries, i.e. diabetics.
Furthermore, we examined CAS measures using a lumen based assessment of distension and found no significant differences between the two groups suggesting that speckle tracking may be more sensitive. Although our lumen-based distension measure was not obtained with echo-tracking, studies by others have shown the reliability of distension measured using echo-tracking and of that using B-mode ultrasound imaging to be comparable (9
). Furthermore, our lumen based distensibility measurement evaluates a larger segment of the artery compared with echo tracking.
Finally, we found arterial strain measurements to be significantly higher in the right than in the left carotid artery for the two of the three far wall segments, the average of all three far wall segments, and the net average of all arterial wall segments. Differences in right versus left measurements have been reported in common carotid intima-media thickness measurements, with the right having lesser values than the left (43
). In fact, in one study of participants with and without migraine headaches, arterial distension was also found to be significantly greater in the right than in the left for both groups of individuals. These findings are consistent with the findings in our study. These observations suggest that there may be differences in blood pressure, shear forces, and vascular anatomy specific in the same individual between the right and the left carotid arteries and merits further investigation.
Ultrasound imaging offers a non-invasive and safe method of evaluating the arterial wall. Carotid artery measures of atherosclerosis (namely carotid intima-media thickness and plaque presence) has already been shown to be useful in coronary heart disease risk prediction and as a surrogate marker to test efficacy of anti-atherosclerotic therapy (46
). Ultrasound based stiffness measures provide potentially yet another measure to improve our assessment of vascular health. Pulse pressure is often considered a good marker of arterial stiffness (48
); and in general, when the arterial stiffness increases, in order to maintain a similar arterial distensibility (strain), the pulse pressure should also proportionally increase.
However, as noted in our analysis, there is a very poor correlation between pulse pressure and CAS as measured by speckle-tracking. The poor correlation between these two measures of stiffness may be explained by the fact that CAS measures only local carotid stiffness while pulse pressure reflects the stiffness of the entire vascular tree. Furthermore, given that the association between CAS and diabetes persisted after adjustment for pulse pressure, one could hypothesize that a simple pulse pressure measurement may not be an adequate surrogate for CAS, and perhaps both provide complementary information on vascular health. Whether local arterial strain reflects the advanced sequelae of pathologic processes or remodeling due to various medical interventions remains a potential area for further clinical investigation. Clearly, much further work will be required before this technology will have any use in routine clinical practice.
Our study had limitations. Brachial blood pressures were used instead of local carotid pressures, both of which have been shown to differ from each other and to differ in local remodeling effects within an individual (49
). However, it must be noted that in individuals with cardiovascular risk factors such as diabetes, the peripheral pulse pressure tends to be similar to the central pulse pressure while in healthy individuals the central pulse pressure tends to be lower (51
). Despite this (i.e. likely greater central pulse pressures which in turn could increase arterial distension/ strain) diabetics in our study had lower arterial strain, suggesting that the arterial strain we measured by speckle tracking also reflects a stiffer arterial wall. The inter-visit intraclass correlation coefficients were modest and may have been due to variations in time from last meal, use of vasoactive substances (e.g., caffeine or alcohol), and diurnal variations. Additionally we used a system intended for myocardial analysis and used DICOM images instead of raw US data. Dedicated strain platforms for arterial wall imaging may further improve the repeatability and reproducibility of arterial strain measurements. We also acquired at higher frame rates than those used for myocardial analyses; however, the effects of higher frame rates on reproducibility (by potentially affecting spatial resolution) of strain measurements are unclear. Strain measurements were not compared with phantom or animal models using sonomicrometry crystals. Still, we tested the technique with a common clinical disease entity known to lead to increased arterial strain to lay the groundwork for the potential clinical vascular applications of the speckle-tracking technique.
The diabetic sample size was small, and we did not examine the association of strain values with the severity or duration of diabetes. We were also unable to adjust for glomerular filtration rates, as serum creatinine levels were not available on all subjects. Acoustic shadowing of the medial-lateral wall segments was observed and may have limited the reliability of strain measures in these segments. We analyzed strain measurements in only the distal common carotid artery, and differences in these measures may be present along the different carotid artery segments. We examined the carotid artery for only circumferential strain; other strain measures including longitudinal and radial strain should also be examined. Lastly, we adapted an ultrasound system and analysis package originally optimized for cardiac use to vascular applications.
The results of this study point to several potential avenues of investigation. Different scanning approaches need to be investigated to see if probe pressure does indeed influence strain measurements. Differences in strain values at different levels of the carotid vasculature should also be examined. Additional data on differences between left versus right sides for not only distensibility measures but also carotid intima-media thickness measures are still needed. Optimization of speckle-tracking systems for use with vascular applications will also be required.