A systematic literature review of the effect of carotid atherosclerosis on local vessel stiffness and elasticity

Atherosclerosis 243 (2015) 211e222

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Atherosclerosis journal homepage: www.elsevier.com/locate/atherosclerosis

Review article

A systematic literature review of the effect of carotid atherosclerosis on local vessel stiffness and elasticity Mari E. Boesen a, b, c, d, Dilip Singh b, c, d, e, Bijoy K. Menon b, c, d, e, f, Richard Frayne a, b, c, d, * a

Biomedical Engineering Graduate Program, University of Calgary, Calgary, Canada Seaman Family Centre, Foothills Medical Centre, Alberta Health Services, Calgary, Canada c Hotchkiss Brain Institute, University of Calgary, Calgary, Canada d Departments of Radiology and Clinical Neurosciences, University of Calgary, Calgary, Canada e Calgary Stroke Program, Foothills Medical Centre, Alberta Health Services, Calgary, Canada f Department of Community Health Sciences, University of Calgary, Calgary, Canada b

a r t i c l e i n f o

a b s t r a c t

Article history: Received 11 June 2015 Received in revised form 14 August 2015 Accepted 2 September 2015 Available online 8 September 2015

Objective: This systematic literature review sought to determine the effects of carotid atherosclerotic plaque on local arterial stiffness. Methods: MedLine, EMBASE, and grey literature were searched with the following term: (“atherosclerosis” or “carotid atherosclerosis” or “carotid artery disease” or “carotid plaque”) AND (“distensibility” or “elasticity” or “stiffness” or “compliance”) NOT (“pulse wave velocity” or “PWV” or “carotid-ankle” or “ankle-brachial” or “augmentation index” or “cardio-ankle” or “CAVI” or “flow mediated dilation” or “FMD”). Results were restricted to English language articles reporting local arterial stiffness in human subjects with carotid atherosclerosis. Results: Of the 1466 search results, 1085 abstracts were screened and 191 full-text articles were reviewed for relevance. The results of the 50 studies that assessed some measure of carotid arterial elasticity or stiffness in patients with carotid plaque were synthesized and reviewed. Discussion: A number of different measures of carotid elasticity were found in the literature. Regardless of which metric was used, the majority of studies found increased carotid stiffness (or decreased distensibility) to be associated with carotid plaque presence, the degree of atherosclerosis, and incident stroke. Conclusion: Carotid artery mechanics are influenced by the presence of atherosclerotic plaque. The clinical applicability of carotid elasticity measures may be limited by the lack of reference values and standardized techniques. © 2015 Elsevier Ireland Ltd. All rights reserved.

Keywords: Carotid artery Vessel Atherosclerosis Plaque Distensibility Elasticity Stiffness Review

1. Introduction The elastic nature of large- and medium-sized arteries is a critical factor in determining overall cardiovascular health [1e4]. These arteries dampen flow pulsatility and generate a steady flow of blood at the capillary level by reflecting the pulsed waves of blood from the heart [5,6]. Diminished arterial elasticity results in reduced pulse wave reflection and can have adverse effects on cardiovascular health, such as increased pulse pressure and left ventricular hypertrophy [6,7]. Arteries are known to stiffen in healthy aging [8,9] and with atherosclerosis, diabetes, hypertension

* Corresponding author. Seaman Family Centre, Foothills Medical Centre, 1403 29th St NW, Calgary, AB, T2N 2T9, Canada. E-mail address: [email protected] (R. Frayne). http://dx.doi.org/10.1016/j.atherosclerosis.2015.09.008 0021-9150/© 2015 Elsevier Ireland Ltd. All rights reserved.

and obesity [10e13]. In addition, decreases in arterial distensibility near the carotid bifurcation, are associated with carotid atherosclerosis [14] and increased incidence of cerebrovascular events [15]. Atherosclerosis, characterized by the accumulation of plaque within vessel wall, alters both the structure and function of arteries, increasing vessel wall stiffness. It has also been proposed that changes in carotid elasticity further promote both plaque development and rupture [16]. While some imaging studies have employed carotid elasticity as a primary outcome [17], their clinical applicability is limited by a lack of standardized techniques and reference values in atherosclerotic arteries. We undertook a systematic literature review to determine the reported effects of carotid atherosclerosis on local vessel wall elasticity and stiffness measures derived from ultrasound (US) and magnetic resonance (MR) imaging.

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1.1. Structure and mechanics of blood vessels Larger blood vessels are made up of three concentric layers: the intima, media, and adventitia (Fig. 1 inset). The innermost layer of a vessel wall, the intima, is comprised of a single layer of endothelial cells and is bounded on the outside by a layer of elastic tissue called the internal elastic lamina. The medial layer of an artery is made up of smooth muscle cells, collagen, small elastic fibers, and is bounded on the outside by the outer elastic lamina. The intima-media connection provides both stretch and strength to the artery through the presence of elastin and collagen. A fatty streak, the first visible manifestation of an atherosclerotic lesion (Fig. 1), consists of isolated macrophage foam cells containing lipid droplets. As extracellular lipids accumulate, they form lipid pools within the intima, disrupting the cellular structure of the artery, breaking elastic fibers and causing thickening of the vessel wall. In response to this intimal disorganization, some lesions develop new connective fibrous tissue e the so-called ‘fibrous cap’ of an atherosclerotic plaque. Local wall thickening has been associated with altered hemodynamic and mechanical conditions of the artery, in that intimal thickening may represent an adaptive response to maintain normal values of both shear and tensile stresses [18]. The most common locations for such adaptive thickening are regions of disrupted blood flow and/or decreasing vessel diameter [19]. As such, the carotid bifurcation is a common site of atherosclerosis and poses a significant risk for incident cerebrovascular events. Though the degree of stenosis has long been regarded as defining plaque severity, the notion of a vulnerable plaque based on its composition has recently gained clinical traction. Lesions with large lipid pools and thin fibrous caps are regarded as likely to rupture, resulting in clot-promoting materials being exposed to the lumen [20]. In addition to the morphological evaluation of plaques, the effects of arterial wall mechanics have also been studied with respect to lesion vulnerability and stroke risk [16]. Computational

models of plaque within an elastic artery emphasize that stress concentrations occur in regions of mismatched elasticity, for example, where the fibrous cap meets a normal vessel wall [21]. Histological [21,22] and MR-based 3D fluidestructure interaction models [23] confirm that the majority of plaques rupture in these regions of high structural stresses. While global measures of arterial resistance, such as pulse wave velocity and ankle-brachial index, are popular methods for determining vessel stiffness, there are a number of measures to indicate the local elasticity of an artery [24,25]. Specifically, the local elasticity of the carotid artery, particularly in association with cardiovascular risk factors, has been investigated using a variety of modalities and measurements. 1.2. Measures of local carotid elasticity The elasticity, distensibility or stiffness of the carotid artery can be quantified using many different parameters, all employing some measure of the systolic-diastolic diameter or area change (by either US or MR). The most common measures found in the literature are summarized in Table 1, with an indication of their interrelation [26]. Fig. 2 defines the key relevant carotid measurements employed in the calculation of the stiffness and elasticity parameters listed in Table 1. The most basic of these measures is absolute distension e simply systolic minus diastolic diameter. Normalizing this value to the diastolic diameter produces the oft-reported strain (typically reported as a percentage of diastolic diameter). One factor affecting vessel compliance that this normalized value does not account for, is the blood pressure exerted on the artery. Peterson's pressure-strain elastic modulus (Ep), Young's elastic modulus (YEM), distensibility (D) and distensibility coefficient (DC) all normalize the change in carotid cross-sectional area or diameter by pulse pressure (DP ¼ Ps  Pd, where Ps and Pd are systolic and diastolic blood pressure, respectively). The unit-less beta stiffness index, for which increasing values indicate stiffer arteries, accounts for the effect of blood pressure by taking the natural logarithm of the systolic to diastolic blood pressure ratio and dividing by the strain. All of the parameters summarized in Table 1 have been used to report carotid elasticity or stiffness in healthy, aging and diseased populations. This range of modalities, parameters and units used to express carotid elasticity or stiffness makes it challenging, if not impossible, to compare results between these studies. If any of these parameters are to be truly useful in a clinical environment for the evaluation of cardiovascular and stroke risk, a standardization of methods and measures is needed. We undertook a systematic literature review to (a) explore the effect of carotid plaque on local vessel stiffness and elasticity, and (b) describe the reported values for each elastic index. Given the wide range of indices used to report vessel elasticity, we did not attempt to synthesize the data or perform a meta-analysis of the literature. 2. Methods

Fig. 1. Cross-sectional schematic of a vessel wall showing the three concentric layers of a healthy artery: the intima (containing the endothelium and internal elastic lamina), the media (containing smooth muscle and external elastic lamina), and the adventitia. An atherosclerotic plaque with lipid core and fibrous thickening in the intimal layer is also shown.

The Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) methodology was adopted for this literature review [27]. Two databases (MedLine and EMBASE) were searched with the following search term: (“atherosclerosis” or “carotid atherosclerosis” or “carotid artery disease” or “carotid plaque”) AND (“distensibility” or “elasticity” or “stiffness” or “compliance”) NOT (“pulse wave velocity” or “PWV” or “carotidankle” or “ankle-brachial” or “augmentation index” or “cardioankle” or “CAVI (cardio-ankle vascular index)” or “flow mediated dilation” or “FMD”). This search term returned studies of atherosclerosis and carotid plaques that mention vessel wall stiffness or

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Table 1 Indices used to express local arterial elasticity and stiffness as a function of systolic (denoted by subscripted s) and diastolic (subscripted d) diameter (D) or area (A). Formulas and units are provided along with an indication of their interrelation and how they change with stiffening arteries. Key measurements are defined in Fig. 2. Stiffness or elasticity measure

Standard formula

Units

Notes

Absolute distension

DD ¼ Ds  Dd DA ¼ As  Ad Strain ¼ DD Dd or

[mm] [mm2] [%]

Decreasing values indicate stiffer arteries

Strain

DP Strain

DPDd DD

Peterson's Elastic modulus

EP ¼

Distensibility

DD D ¼ E1P ¼ DPD d

[k Pa1]

Distensibility coefficient (diameter) Distensibility coefficient (area)

2DD DC ¼ 2D ¼ DPD d

[k Pa1]

DA DC ¼ DPA

[k Pa1]

Young's Elastic modulus

b-Stiffness index

¼

DA Ad

[kPa]

d

DPD2

d d YEM ¼ hDDC ¼ 2h DD o o     ln PPs d b ¼ strain ¼ ln PPds

[kPa]

Dd DD

Unit-less

Normalizes distension to the diastolic diameter (or area) Decreasing values indicate stiffer arteries Divides pulse pressure (DP ¼ Ps  Pd) by strain Increasing values indicate stiffer arteries Inverse of EP Decreasing values indicate stiffer arteries Double of distensibility Decreasing values indicate stiffer arteries Alternate form of DC, using normalized change in cross sectional area Decreasing values indicate stiffer arteries Accounts for vessel wall thickness (ho) Increasing values indicate stiffer arteries Increasing values indicate stiffer arteries

Ds ¼ systolic diameter, Dd ¼ diastolic diameter, As ¼ systolic area, Ad ¼ diastolic area, Ps ¼ systolic blood pressure, Pd ¼ diastolic blood pressure, ho ¼ vessel wall thickness.

elasticity. The exclusion terms limit the studies to those that employed local measures of carotid elasticity by removing global measurement techniques, such as pulse wave velocity and cardioankle vascular index. The search period was all available literature up to July 2014. We also limited our search to include only in vivo human trials and literature published in the English language. In addition to searching MedLine and EMBASE, grey literature was identified by manually searching the internet and reviewing citations from included articles. Duplicate entries were manually removed. Two reviewers (MEB, DS) independently examined the titles and abstracts of all retrieved articles and categorized them as relevant (reporting in vivo local carotid elasticity measures in an atherosclerotic human population) or not relevant (studies of conditions other than atherosclerosis or non-local measures of carotid stiffness). An inclusion/exclusion form (Supplement 1) was completed for each article to determine its eligibility. Inclusion criteria were as

follows: (a) study participants are patients diagnosed with carotid atherosclerosis, (b) local carotid elasticity or stiffness was measured, and (c) study investigates the association of carotid elasticity or stiffness with plaque, stenosis, IMT, or the presence of atherosclerosis. Reasons for exclusion were recorded as: (a) no applicable carotid elasticity or stiffness measure, (b) participants not diagnosed with carotid atherosclerosis, (c) no applicable subgroup defined, (d) no relevant outcomes assessed, or (e) no data for relevant subgroup extractable. The two reviewers then read all included full text articles to confirm that inclusion criteria were met. Any disagreements regarding inclusion of an article at the full text level were resolved by consensus between the two reviewers. We used a structured data extraction form (Supplement 2) to extract the details of the study design, imaging modality and methodology, subject details and reported values of carotid compliance for all included articles. 3. Results

Fig. 2. Schematic of a carotid cross-section at systole depicting the various key measurements used for the stiffness and elasticity calculations listed in Table 1. The total luminal area (striped region) during diastole (Ad), is delineated with a dashed outline. The larger luminal area during systole (As), is delineated here with a solid outline. Systolic and diastolic diameters are also depicted (Ds and Dd, respectively). The vessel wall (shown in grey) thickness is ho.

The initial search returned 1466 publications, of which 82 were non-English language, 141 were non-human studies, and 381 were duplicate entries. The remaining 862 titles and abstracts were reviewed and 191 were selected for full text evaluation. Initial agreement between the two reviewers was 92% for the categorization of included and excluded articles at the title/abstract level. Consensus was reached on the remaining articles by jointly reviewing the full text of the 18% discordant publications. Of the 191 full text articles evaluated, 50 studies reporting local carotid elasticity in patients with carotid plaque were included. Fig. 3 summarizes the PRISMA flow diagram. A wide variety of techniques for the characterization of local carotid elasticity were found. Reported indices of elasticity (in order of decreasing frequency) were: (a) strain (24%), (b) distensibility coefficient (20%) (c) Peterson's pressure-strain elastic modulus (18%), (d) beta stiffness index (18%), (e) Young's elastic modulus (16%), (f) distensibility (10%), and (g) absolute distension (8%). While the imaging techniques and calculations varied significantly, all of these indices relied on the detection of systolic-diastolic area or diameter change in order to characterize the distension of the carotid artery over the cardiac cycle. US was employed in 43 (86%) and MR in 13 (26%) of these studies; 6 studies (12%) used both modalities. Table 2 contains a summary of reported results for the indices of carotid elasticity and stiffness described in Table 1. Absolute systolic-diastolic diameter provides a simple comparable measure

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Fig. 3. Preferred Reporting Items for Systematic Reviews and Meta-Analyses (PRISMA) flowchart of this systematic literature review on local arterial stiffness in carotid plaque. Two databases (MedLine and EMBASE) were searched with the following search term: (“atherosclerosis” or “carotid atherosclerosis” or “carotid artery disease” or “carotid plaque”) AND (“distensibility” or “elasticity” or “stiffness” or “compliance”) NOT (“pulse wave velocity” or “PWV” or “carotid-ankle” or “ankle-brachial” or “augmentation index” or “cardio-ankle” or “CAVI” or “flow mediated dilation” or “FMD”).

of carotid distension despite the fact that it does not account for inter-subject variation due to overall vessel size. Mean systolicdiastolic carotid distension was found to be 0.360 mme0.424 mm in plaque and 0.451 mme0.507 mm in adjacent and contralateral vessel walls [28,29]. The most commonly reported measure was strain, used in 14 (28%) different studies. Of the studies reporting normalized systolic-diastolic diameter measures, mean percent strain ranged from 3.16% [30] to 5.2% [31] within carotid plaque. Some authors opted to measure strain within diseased carotid arteries, but specifically at a level without a plaque encroaching on the lumen. These studies found slightly higher mean values for carotid strain: 5.56% [32] to 11% [33]. One study [34] used velocity vector imaging to calculate a mean longitudinal strain of 4.614% in 96 carotid plaques with a lipid core. The definitions of distensibility and the distensibility coefficient varied somewhat (see Tables 1 and 2), but all represented a normalized change in diameter or area, divided by the pulse pressure and were therefore expressed in inverse units of pressure (most commonly 103/kPa). Mean values of cross-sectional DC within carotid plaque ranged from 8.8  103/kPa [35] to 39.7  103/kPa [35], compared to the adjacent normal carotid wall (DC ranged from 15.2  103/kPa [36] to 54.4  103/kPa [35]). Reported values of carotid plaque Ep, i.e., the inverse of DC, ranged from 96 kPa [37] to 224.4 kPa [38] with normal wall values ranging from 108.8 kPa [38] and 131.6 [30]. In the absence of individual subject values, a direct conversion of Ep to DC (or vice versa), is not possible. While almost a quarter of the papers reported values of YEM, few offered an example calculation or provided an operational definition. MokhtarieDizaji et al. [39], using the formula contained in Table 1, found YEM to be 577.228 kPa in severe carotid stenosis, 502.962 kPa in mild carotid stenosis, and 384.264 kPa in control subjects. All 9 studies that reported b-stiffness indices used the same formula (per Table 1). Wada et al. [40] found that a threshold of b-

stiffness index ¼ 13 discriminated between atherosclerosis grades with both sensitivity and specificity of 80%. MokhtarieDizaji et al. [39] however, reported much lower values for carotid b-stiffness: 6.12 in normal controls and 8.24 in severe carotid disease. In addition to the indices summarized in Table 1, a number of computational modeling methods were employed to generate alternative measures of plaque stiffness. High-resolution MR plaque composition was used (without measured blood pressure) as the input for fluidestructure interaction analyses [41e44] that created plaque-wall stress maps. The overall conclusion of these reports was that greater plaque-wall stresses are observed in ruptured plaques and these stress concentrations often correlate with the location of rupture. Various techniques for advanced processing of US images were also used to calculate motion of intraplaque contents [45], plaque surface velocities [46], and displacement vector maps [47]. Carotid distensibility was found to be significantly associated with the presence [48] and degree of atherosclerosis [49]. Studies of multiple carotid elasticity measures found increased stiffness associated with incident stroke [15,50e53] and symptomatic carotid artery disease [34,35,54] but not cardiovascular mortality [55] or coronary heart disease [15]. Studies comparing elasticity measures to plaque features found significant differences between lipid present and lipid absent plaques [56], as well as echogenic and echolucent plaques [57]. Stiffness was reported to increase with the degree of atherosclerosis [14,28,31,39,40,48,58]. Comparisons of elasticity between carotid plaque and adjacent common carotid artery wall found two different patterns of longitudinal strain gradients: (a) plaque stiffer than the adjacent wall [32,38,59] and (b) plaque more elastic than the adjacent wall [32]; either way, the mismatch in elasticity at a plaque shoulder could result in stress concentrations that promote plaque rupture. Finally, comparing carotid atherosclerosis patients to control subjects, the common carotid arteries of the patients were found to be less distensible than those without plaques [30,31,33,36,39,48,49,52,58,60e63]. A few studies found no significant difference between their test groups or subsamples of their datasets. For example, Beaussier et al. [28] found that strain was not significantly different between simple plaques and the adjacent vessel wall. Canton et al. [60] found that the distensibility coefficient was not statistically different between 5 normal subjects and 17 patients with >15% carotid stenosis. Kanber et al. [64] found that strain did not differ significantly between symptomatic and asymptomatic carotid arteries, both measured before the proximal shoulder of a plaque. Similarly, Sadat et al. [35] found no significant difference between symptomatic and contralateral asymptomatic carotids when measuring DC at the point of maximum stenosis. While Hosomi et al. [51] found the b-stiffness index to differ between those with stroke and those with no cardiovascular disease, though YEM failed to be significantly different between the two groups. 4. Discussion The variety and range of elasticity and stiffness indices reported in the literature make it difficult to determine the absolute change that can be expected with the presence of carotid artery disease. Despite the fact that carotid stiffness has already been employed as an indicator of atherosclerosis and a primary outcome in clinical trials, the literature reflects a lack of standardized reference values and measurements techniques. Nevertheless, the vast majority of published studies regarding carotid elasticity or stiffness found significant decreases in elasticity (or increases in stiffness) with the presence of plaque and incident stroke, regardless of which index was used.

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Table 2 Summarized results of studies investigating local arterial stiffness in carotid atherosclerosis, sorted by index reported. Imaging modality and units are specified and results are reported by subgroup, where applicable. Index

Author, year (Ref.)

Modality Variation on formula [units]

Subgroups

DD

Beaussier, 2011 [28]

US

Plaque Simple plaques 424 (327,717) (N ¼ 32) 360 (308,462) Complex plaques (N ¼ 14) Previous stroke or TIA (N ¼ 260) 411.4 (145.7) Stenosis (N ¼ 10) 374.9 (32.8) First-ever stroke (N ¼ 193) 351 (323, 378) Univariate OR 1.41 (1.11e1.80) Lesion site (N ¼ 8) 3.16(0.43)

Dijk, 2004 [50]

DD/Dd

US

[um]

Giannattasio, US 2001 [29] US Tsivgoulis, 2006 [67]

[um]

Barth, 1988 [30]

US

Blankenhorn, US 1988 [38] Kanber, 2013 US [64]

R. Liu, 2011 [62]

US

US Mokhtari eDizaji, 2005 [39] US Mokhtari eDizaji, 2006 [31] Paini, 2007 US [32]

US RahmaniCherati, 2007 [58] Wang, 2012 US [59]

Wilt, 1997 [68]

DA/Ad DV/Vs

[um]

US

US Mokhtari eDizaji, 2006 [31] Naim, 2013 US [56]

[um]

[%]

[%]

[%]

[%]

[%]

[%]

[%]

Statistics & notes

Results CCA 507 (305, 664)

(Q1, Q3, p ¼ 0.9)

458 (388, 604)

(Q1, Q3, p < 0.03)

No stroke or TIA (N ¼ 160) 458.0 (167.6) Contralateral (N ¼ 10) 450.8 (39.8) Controls (N ¼ 106) 418 (381, 455) Proximal (N ¼ 8) 4.78(0.52)

(SD, OR ¼ 2.1 (1.1e4.1))

(SE, p < 0.05)

(Q1, Q3, p ¼ 0.005) (95% CI, p < 0.05) Controls (N ¼ 9) 4.12(0.40)

Lesion site (N ¼ 13) 4.04 (0.79) Symptomatic carotids* (N ¼ 31) 6.6

Adjacent wall (N ¼ 13) 6.52 (1.00) Asymptomatic carotids (N ¼ 30) 7.2

MetS w/AS* (N ¼ 30) 6.99 (3.31)

MetS w/out AS Controls (N ¼ 30) (N ¼ 30) 8.34 (2.34) 12.68 (6.87)

Severe stenosis (N ¼ 34) 5.8 (2.8) Severe stenosis (N ¼ 44) 5.2 (0.5) With plaque* (N ¼ 25)

Mild stenosis (N ¼ 39) 7.7 (3.2) Mild stenosis (N ¼ 41) 7.8 (0.9) Without plaque (N ¼ 37) 5.36 (2.38) Adjacent wall 4.96 (2.56)

(SE, p ¼ NS proximal vs control, p < 0.05 plaque vs proximal)

(SE, p not provided)

(SD shown in plot, p ¼ 0.16) *measured before proximal shoulder of plaque

Control (N ¼ 55) 9.4 (3.5) Control (N ¼ 60) 9.9 (0.8)

5.56 (2.42) Plaque Inward bending 6.5 (2.53) pattern (N ¼ 16) 4.5 (2.20) 6.74 (1.66) Outward bending pattern (N ¼ 8) [%] Severe stenosis Mild stenosis Normal (N ¼ 10) (N ¼ 15) (N ¼ 15) 4.7 (1.7) 6.4 (2.1) 11.1 (3.7) not defined, [values Circumferential strain and strain rate of plaque shoulder not reported] were significantly greater than that of fibrous cap Circumferential strain and strain rate without plaque were significantly greater than with plaque [%] Right CCA strain Left CCA strain (N ¼ 94) (N ¼ 94) 4.8 (1.4) 5.2 (1.7) [%] Severe stenosis Mild stenosis Control (N ¼ 44) (N ¼ 41) (N ¼ 60) 11.7 (1.7) 15.3 (1.9) 21.1 (1.9) Lipid present Lipid absent Mean strain plaque* (N ¼ 17) plaque* amplitude [%] (N ¼ 14) Mean strain at peak 1.101 (0.677) 1.428 (0.871)

(SE, p < 0.05 between MetS groups, p < 0.01 between MetS and controls), *measured at level w/out plaque

(1.96(SE), p not provided)

(1.96(SE), p < 0.05) *Performed in CCA proximal to plaque (SD, NS) (SD, p < 0.01) (SD, p ¼ 0.01)

(SD, p < 0.05) (p < 0.05) (p < 0.05)

(SD, p not provided)

(1.96(SE), p < 0.05) *All patients >50% stenosis

(SD, p ¼ 0.131) (continued on next page)

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Table 2 (continued ) Index

Author, year (Ref.)

Modality Variation on formula [units]

Zhang, 2009 [53]

US

systolic compression [%] Volume compression ratio [%]

Longitudinal Strain Huang, 2013 [34]

US

[%]

US

[kPa]

d Ep ¼ DPD DD

Barth, 1988 [30]

Blankenhorn, US 1988 [38] Hosomi, 2004 US [51]

Subgroups

[kPa]

[kPa] Left CCA Right CCA

Labropolous, 2000 [37] R. Liu, 2011 [62]

US

[kPa]

US

[Not specified]

US Mokhtari eDizaji, 2006 [31]

[kPa]

US Mokhtari eDizaji, 2005 [39]

[kPa]

US RahmaniCherati, 2007 [58] Wilt, 1997 US [68]

Static Ep [Pa]

Standard Ep Static Ep

D

Imanaga, 1998 [48]

US

Lin, 1999 [69]

US

Not defined, [106 N1m2]

Lind, 2009 [49] R. Liu, 2011 [62]

US/MR

[Values not reported] ðDs 2  Dd 2 Þ=ðDP  Dd 2 Þ [not specified]

Wilt, 1997 [68]

DC ¼ 2DD/DPDd

[kPa]

US

US

Canton, 2012 MR [60]

[Not specified]

Fractional increase in volume/pulse pressure [%/kPa]

[105/Pa]

Statistics & notes

Results 0.163 (0.076)

0.257 (0.144)

Incident cerebrovascular infarction (N ¼ 58) 22.19 (8.42) Symptomatic carotid (N ¼ 96)

No infarction (N ¼ 46)

(SD, p ¼ 0.032)

4.614 (1.314) Lesion site (N ¼ 8) 208.6 (32.4)

13.95 (7.86) Asymptomatic carotid (N ¼ 39) 4.001 (1.468) Proximal Control (N ¼ 8) (N ¼ 9) 131.3 (16.1) 148.8 (14.9)

Lesion site (N ¼ 13) 224.4 (47.2) Incident stroke (N ¼ 61) 142.3 (103.9) 120.6 (87.3) Carotid plaque (n ¼ 41) 96 [19] MetS w/AS (N ¼ 30) 1065.97 (449.45)

Adjacent wall (N ¼ 13) 108.8 (15.1) No CVD (N ¼ 50) 92.3 (56.0) 78.7 (26.1) Control (N ¼ 40) 52 (7.6) MetS w/out AS (N ¼ 30) 754.52 (322.70)

Controls (N ¼ 30) 448.84 (190.07)

Severe stenosis (N ¼ 44) 160.341 (45.780)

Mild stenosis (N ¼ 41) 122.342 (15.569)

Control (N ¼ 60) 79.847 (7.797)

(SD, p < 0.01)

(SE, p < 0.05)

(SE, p < 0.05 lesion vs proximal, NS proximal vs control)

(SE, p ¼ 0.036)

(SD, p < 0.005) (SD, p < 0.005)

(SD, p < 0.0001)

Severe stenosis Mild stenosis Normal (N ¼ 34) (N ¼ 39) (N ¼ 55) Values reported in graphical form Values reported in graphical form Severe stenosis Mild stenosis Normal (N ¼ 10) (N ¼ 15) (N ¼ 15) 6168 (1026) 3829 (1501) 1772 (566) Right CCA Left CCA (N ¼ 94) (N ¼ 94) 157.7 (70.0) 141.9 (50.9) There was an association between arterial IMT and stiffness as assessed by Ep (r2 ¼ 0.12, p < 0.001) Severe AS Mild AS No AS (N ¼ 28) (N ¼ 39) (N ¼ 15) 1.023 (0.090) 1.408 (0.088) 3.681 (0.270) CHD þ carotid CHD only Control AS (N ¼ 12) (N ¼ 13) (N ¼ 13) 14.8 (1.7) 21.8 (1.2) 25.6 (1.5) Regression w/IMT (N ¼ 954) Regression with Total AS (N ¼ 306) MetS w/AS MetS w/out AS Controls (N ¼ 30) (N ¼ 30) (N ¼ 30) 0.25 (0.15) 0.34 (0.15) 0.59 (0.34)

Right CCA Left CCA (N ¼ 94) (N ¼ 94) 1.5 (0.5) 1.6 (0.5) There was an association between arterial IMT and stiffness as assessed by distensibility Stenosis >15% Normal (N ¼ 5) (N ¼ 12) 3.52 (1.84) 4.56 (1.02)

(SE, p < 0.01 between MetS groups, p < 0.01 between MetS and controls)

(1.96(SE), p not provided, significance only between severe stenosis and controls)

(NS between mild and normal groups) (p < 0.05, all groups)

(SD, p < 0.05)

(SD)

(SE, p < 0.01 all comparisons)

(NS, p < 0.05, p < 0.01) (0.25, p ¼ 0.021) (0.21, p ¼ 0.0006)

(SE, p < 0.05 between MetS groups, p < 0.01 between MetS and controls)

(SD, p not provided) (r2 ¼ 0.05, p ¼ 0.02)

(SD, p ¼ 0.162)

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Table 2 (continued ) Index

Author, year (Ref.)

Modality Variation on formula [units]

Harloff, 2009 US/MR [36]

Subgroups

Results

Statistics & notes *Performed in CCA at plaque free site

MR

High grade ICA Healthy stenosis* (N ¼ 7) volunteer (N ¼ 31) 26.4 (6.5) 41.6 (9.0)

[103/kPa]

US Odink, 2008 [70]

US

[Values not reported] Quartile 1 (Reference) Quartile 2 Quartile 3 Quartile 4

Van Popele, 2001 [14]

DC ¼ DA/AdDP

Beaussier, 2011 [28]

US

US/MR

Beaussier, 2008 [71]

US

Li, 2008 [72]

MR

[103/kPa], values estimated from plot

[1/MPa]

[103/kPa]

[Values not reported] Previous endarterectomy

US Mokhtari eDizaji, 2006 [31] Paini, 2007 US [32]

Sadat, 2014 [35]

MR

[100/kPa]

[103/kPa]

[103/kPa]

(SD, p only reported between US and MRI)

15.2 (5.7) 41.3 (7.4) OR w/Carotid Calcification (by Quartile) 1 1.9 (1.0e3.5) 2.3 (1.2e4.3) 3.6 (1.7e7.1) Cross sectional DC independently associated with carotid calcification Severe (2.5% of Moderate Mild plaque None subjects) (30.7% of (21% of (30.8% of subjects) subjects) subjects) ~8.7 ~10.1 ~10.8 ~10.9 0.80 0.25 (0.56, 0.22 (1.49,0.11) 0.06) (0.55,0.11) DC decreased significantly with increasing plaques of the CCA Complex plaque CCA (N ¼ 14) (N ¼ 14) 16.3 (13.3,17.8) 21.1 (15.6,24.6) Simple PLAQUE CCA (N ¼ 32) (N ¼ 32) 20.4 (15.2, 27.5) 19.7 (14.5, 29.6) Reduced strain, associated with an outer remodeling, may be a feature of high-risk plaques Normotensive in Normotensive plaque (N ¼ 26) CCA (N ¼ 26) 27.4 (12.7) 26.1 (10.4) Hypertensive in Hypertensive plaque (N ¼ 66) CCA (N ¼ 66) 21.0 (9.8) 23.5 (9.0) Atheromatous Contralateral vessels vessels p ¼ 0.004 p ¼ 0.014 Severe stenosis (N ¼ 41) 1.60 (0.69) With plaque* (N ¼ 25)

Mild stenosis (N ¼ 44) 2.50 (1.04) Without plaque (N ¼ 37) 19.6 (15.4) Adjacent CCA 16.6 (12.4)

17.1 (10.3) Plaque Inward bending 22.3 (11.2) pattern (N ¼ 16) 13.1 (6.5) 18.2 (3.9) Outward bending pattern (N ¼ 8) Symptomatic Asymptomatic carotid (N ¼ 10) carotid (N ¼ 10) CCA 35.4 (6.12) 54.4 (7.88) 20.9 (4.39) 39.7 (14.4) At point of maximum stenosis Asymptomatic Asymptomatic left CCA right CCA (N ¼ 9) (N ¼ 9) CCA 1923* (1564) 1799* (1112) 880* (270) 930* (401) At point of maximum stenosis

Control (N ¼ 60) 2.94 (0.74)

p < 0.05 p < 0.001

p < 0.001 Linear regression coefficient vs No Plaque (95% CI)

(Q1, Q3 p ¼ 0.007)

(Q1, Q3 p ¼ 0.9)

(SD, NS)

(SD, p ¼ 0.02)

(1.96(SE), p not reported) *Performed in CCA proximal to plaque (SD, NS) (SD, p < 0.001) (SD, p ¼ 0.02)

(SD, p ¼ 0.03) (SD, p ¼ 0.37)

(SD, p ¼ 0.67) *as reported (SD, p ¼ 0.12) *as reported

(continued on next page)

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Table 2 (continued ) Index

Author, year (Ref.)

Modality Variation on formula [units]

Subgroups

CCA At point of maximum stenosis YEM

Garrard, 2013 US [54]

Hosomi, 2004 US [51]

Not defined, [kPa]

YEM ¼ (router/ho) (DPDd/DD), [kPa] Left CCA Right CCA

Lin, 1999 [69]

US

Not defined, [105 N m2]

H. Liu, 2012 [73]

MR

Effective YEM from MooneyeRivlin Model, [kPa] [kPa]

US Mokhtari eDizaji, 2006 [31] Nduwayo, 2012 [57] Paini, 2007 [32]



 Eq ¼ 12

ro ho

þ1

DhDP hmax

Elasticity

b-Stiffness index

Ramnarine, 2012 [74] Yamagishi, 2009 [75]

Okimoto, 2006 [76]

US

not defined, [kPa]

US

YEM ¼ [3(1 þ (A/ wall area))]/DC, [kPa]

US

US

US

Not defined, [kPa]

[kPa]

Calcification (N ¼ 36) Fibrosis (N ¼ 1) Plaque (N ¼ 270) Thrombus (N ¼ 1) Smooth Muscle (N ¼ 71) Lipid Core (N ¼ 18)

Not defined [values not reported]

[Unit-less] Left CCA Right CCA

Ichino, 2012 [77]

US

Contralateral asymptomatic (N ¼ 10) 54.4 (7.88) 39.7 (14.4)

Bilateral asymptomatic (N ¼ 9) Not reported Not reported

Symptomatic plaque* (N ¼ ?/ 59) 65 [52e77] Unstable plaque* (N ¼ ?/ 15) 67 Incident stroke (N ¼ 61) 543.3 (368.6) 473.5 (379.1) CHD þ carotid AS (N ¼ 12) 4.18 (0.30) Carotid AS (N ¼ 12) 478.8 (354.1) Severe stenosis (N ¼ 44) 577.228 (24.156) Echogenic plaque (N ¼ 17) 166.0 (6.97) With plaque* (N ¼ 37)

Asymptomatic plaque*(N ¼ ?/ 59) 88 (69e107) Stable plaque* (N ¼ ?/15) 83 No CVD (N ¼ 50) 490.4 (295.0) 426.7 (176.8) CHD only (N ¼ 13) 3.12 (0.43)

[Unit-less] With PLAQUE (N ¼ 14,64)

(SD, p ¼ 0.007) (SD, p ¼ 0.02)

*All plaque >30% stenosis

(CI, p ¼ 0.038) *All plaque >30% stenosis

(no SD, p not provided)

(SD, NS) (SD, NS) Control (N ¼ 13) 2.34 (0.23)

(NS, p < 0.05, p < 0.01)

(SD, no comparison) Mild stenosis (N ¼ 41) 502.962 (7.784) Echolucent plaque (N ¼ 7) 91.4 (8.77) Without plaque (N ¼ 25) 677 (427) Adjacent CCA 802 (669)

751 (560) Plaque Inward bending 374 (173) pattern (N ¼ 16) 739 (497) 543(146) Outward bending pattern (N ¼ 8) Plaque (N ¼ 24) 116 (17e255)

Correlation with Max IMT Correlation with plaque Score

Hosomi, 2004 US [51]

Statistics & notes

Results

674 (384)

Control (N ¼ 60) 384.264 (38.986)

(1.96(SE), p not provided)

(SD, p < 0.0001) *Performed in CCA proximal to plaque (SD, NS) (SD, p < 0.01) (SD, p < 0.01)

(Range, no comparison) (SD, no comparison)

273 (173) 173 [69] 85 [68] 124 [41] 22 [15] All subjects (N ¼ 242) r ¼ 0.291

All plaques (N ¼ 160) e

p < 0.001

e

r ¼ 0.220

p < 0.01

Stroke (N ¼ 61) No CVD (N ¼ 50) 10.4 (7.6) 6.8 (4.2) 8.6 (5.8) 5.9 (2.1) Thickened IMT Unthickened (>1.0 mm) IMT (<1.0 mm) 11.49 (0.97) 10.60 (0.45)

(SD, p < 0.005) (SD, p < 0.005)

(SD, p < 0.005 in unthickened IMT group, NS in thickened IMT group)

M.E. Boesen et al. / Atherosclerosis 243 (2015) 211e222

219

Table 2 (continued ) Index

Author, year (Ref.)

Leskinen, 2003 [61]

Mitsumura, 2014 [52]

Modality Variation on formula [units]

US

US

US Mokhtari eDizaji, 2006 [31] Ogawa, 2009 US [78]

Shoji, 2010 [79]

US

Tripoten, 2011 [63]

US

Wada, 1994 [40]

US

[Unit-less]

Subgroups

Without plaque 11.35 (0.77) 8.88 (0.23) (N ¼ 22,247) Q1 of b in normal IMT subjects was significantly associated with plaque formation (OR ¼ 3.306) compared to Q4 Transplant Control Dialysis Pre-Dialysis (N ¼ 58, (N ¼ 58, 63.8% (N ¼ 36, 61.1% (N ¼ 41, 27.6% 51.2% w/ w/plaque) w/plaque) with plaque) plaque) 1.14 (0.52) 1.30 (0.77) 1.20 (0.67) 0.74 (0.31)

[Unit-less]

[Unit-less]

Statistics & notes

Results

Cerebrovascular infarction patients (N ¼ 31) 10.6 (8.8e16.1) 9.2 (6.9e14.5) 10.7 (8.9e14.8)

8.24 (0.88) With cerebral infarction (N ¼ 28)

6.94 (0.92) Without cerebral Infarction (N ¼ 34) 8.0 (2.4)

12.2 (3.9) Correlation to r ¼ 0.672 plaque score (N ¼ 62) [Unit-less] Correlation to r ¼ 0.419 IMT (N ¼ 423) 1.99 (1.65e2.42) HR of cardiovascular death (N ¼ 124) Not defined, [unit70e90% stenosis 25e40% less] (N ¼ 16) stenosis (N ¼ 33) 7.7 (5.04) 11.69 (6.84) [Unit-less] All subjects (N ¼ 60) 12.0 (5.21)

AS Grade 0e3 (N ¼ 15)

(SD, p ¼ 0.805 patient groups, p < 0.001 to controls)

Control subjects (N ¼ 38)

Right 7.0 (5.1e9.8) Left 6.8 (4.8e9.7) Large ARTERY AS Cardioembolic 8.7 (6.6e10.3) Small vessel 9.5 (8.6e14.9) Undertermined 15.2 (12.4e18.3) etiology Severe (N ¼ 44) Mild (N ¼ 41)

[Unit-less]

(SD, p < 0.05 between the two plaque-free groups)

AS Grade 4e6 (N ¼ 45)

(Q1,Q3, p < 0.001) (Q1,Q3, p ¼ 0.005)

Normal (N ¼ 60) 6.12 (0.92)

(1.96(SE), p not provided)

(SD, p < 0.0001) (p < 0.0001)

(p < 0.001) (CI, p < 0.001)

(SD, p not provided)

(SD, Correlation to postmortem AS, (r ¼ 0.68, p < 0.0001)) Discrimination threshold ¼ 13 (80% sensitivity, 80% specificity)

*

Indicates that the notes column contains clarification on the group or measurement reported. US ¼ ultrasound, MR ¼ magnetic resonance, AS ¼ atherosclerosis, CCA ¼ common carotid artery, TIA ¼ transient ischemic attack, IMT ¼ intima-media thickness, HR ¼ hazard ratio, OR ¼ odds ratio, SD ¼ standard deviation, SE ¼ standard error, NS ¼ not significant, Q ¼ quartile, CHD ¼ coronary heart disease.

US is the predominant modality for determining carotid stiffness and provides a low-cost, readily accessible evaluation. However, cardiac-phase resolved (cine) MR techniques are starting to be used and provide high-resolution axial images of carotid artery and plaque. Beyond detection of systolic-diastolic area change, many of the stiffness indices reported rely on accurate determination of pulse pressure. Despite the recommendations of the First Consensus Conference [65] and Expert Consensus Document [66] on Arterial Stiffness to measure pulse pressure at the site of distension, many continue to determine pulse pressure from brachial artery measurements, which may not reflect the local pressure conditions at the carotid arteries. Surface tonometry

provides an equally non-invasive determination of pulse pressure, which may provide more accurate indications of carotid stiffness. The small number of studies showing non-significant effects of carotid atherosclerosis on local vessel elasticity and stiffness found in this systematic literature review should be interpreted with some caution. The fact that the literature reflects a higher number of studies reporting significant effects may be due to the fact that many negative results go unpublished. However, the many and, more importantly, repeated results from a number of different patient and research groups imply that some effect of plaque on carotid stiffness and stroke risk can be reasonably expected. Of note, because of the wide variability in reporting methods in

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literature, we did not attempt a meta-analysis pooling data or a quantitative assessment of reporting biases and study heterogeneity. Though some studies compared overall plaque composition to elasticity in general, only 5 studies (10%) [15,41e43,46] provided cross sectional maps of strain surrounding the lipid core or rupture points. Given the heterogeneous nature of atherosclerotic plaque, it would be interesting to study local stress concentrations and changes in stiffness according to plaque composition. Finite element models of variable plaque compositions demonstrate that distensibility may vary circumferentially about an atherosclerotic artery and that this may play a role in plaque vulnerability and rupture.

[7]

[8]

[9]

[10] [11] [12]

5. Conclusions The detrimental effects of carotid stiffness (decreased elasticity) on the cardiovascular system as a whole are generally well understood. Determination of carotid stiffness has become of widespread interest in research and clinical settings, albeit without standardized methodology. This systematic literature review focused on the effects of carotid plaque on local vessel elasticity. While some discrepancies between results were noted, the overwhelming conclusion of this body of literature is that decreased carotid elasticity (or increased carotid stiffness) is associated with atherosclerotic plaque presence and stroke risk. The precise amount by which carotid stiffness can be expected to increase with plaque presence is difficult to elucidate from the range of methods and indices presented here. In addition to following the recommendations of the first and expert consensus conferences on arterial stiffness, standardization of a single stiffness index could enable the direct comparison of reported carotid elasticity between studies.

[13]

[14]

[15]

[16] [17]

[18]

[19]

[20]

Acknowledgments

[21]

This study was supported by funding from the Natural Sciences and Engineering Research Council (NSERC) (RGPIN/261754-2013) of Canada and the Canadian Institutes for Health Research (CIHR) (MOP-106571). MEB was supported by an NSERC CREATE I3T studentship, a Queen Elizabeth II award and and the University of Calgary Biomedical Engineering Graduate Program. BKM holds the Heart and Stroke Foundation of Canada/University of Calgary Professorship in Stroke Imaging. RF is the Hopewell Professor of Brain Imaging.

[22]

[24] [25]

Appendix A. Supplementary data

[26]

Supplementary data related to this article can be found at http:// dx.doi.org/10.1016/j.atherosclerosis.2015.09.008.

[27]

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