Journal of Vascular Surgery
Volume 47, Issue 3 , Pages 523-529, March 2008

The prevalence of hypoechoic carotid plaques is greater in peripheral than in coronary artery disease and is related to the neutrophil count

Department of Clinical Medicine and Cardiovascular and Immunological Sciences, University of Napoli “Federico II”, Naples, Italy.

Received 3 August 2007; accepted 25 October 2007. published online 31 January 2008.

Article Outline

Objective

Previous reports indicate that the prevalence and severity of carotid stenoses is greater in peripheral artery disease (PAD) than in coronary artery disease (CAD). To date, no study has compared these two populations with respect to plaque echogenicity, which is an independent risk factor for cerebrovascular events.

Methods

In 43 PAD patients without CAD and in 43 CAD patients without PAD, carotid plaques were studied with high-resolution B-mode ultrasound and by computerized measurement of the gray-scale median.

Results

At visual analysis, the prevalence of hypoechoic plaques was 39.5% in PAD and 18.6% in CAD (P = .033). The corresponding values for gray-scale median analysis were 34.9% and 14.0% (P = .024). At multivariate analysis, PAD patients showed a greater risk of having hypoechoic plaques than CAD patients at visual (odds ratio [OR], 4.39, 95% confidence interval [CI] 1.21-15.92, P = .025) and gray-scale median analysis (OR, 5.13; 95% CI, 1.27-20.67; P = .021). This association was no longer significant when neutrophil number was included among the covariates. In this model, only an increased neutrophil count was associated with hypoechoic plaques (P < .01 for both visual and gray-scale median analysis). Indeed, neutrophil count was greater in PAD than in CAD (4.4 ± 1.0 vs 3.9 ± 1.2 109/L, P = .030). The concordance between visual typing of carotid plaques and gray-scale median measurement was good (ρ = 0.714, P < .01).

Conclusions

Compared with CAD patients, those with PAD, in addition to a greater atherosclerotic burden, may have characteristics of instability of carotid plaques that, in turn, may result in cerebrovascular events. Prospective studies are needed to assess specifically whether the greater prevalence of hypoechoic plaques in PAD vs CAD patients is associated with a greater risk of cerebrovascular events.

 

Atherosclerosis is a systemic disease and thus its localization is often associated with vascular alterations in other vascular districts. With respect to the coexistence of carotid stenoses with other arterial diseases, it seems to be more common and severe in peripheral arterial disease (PAD) than in coronary artery disease (CAD).1, 2, 3, 4, 5 In particular, the Second Manifestations of ARTerial (SMART) disease study4 showed that the prevalence of carotid stenosis ≥70% was 12.5% in PAD and only 3.1% in CAD. Similarly in another series, carotid stenosis ≥70% was present in 24.5% of PAD patients and in 11.1% of CAD patients.5 This may partly explain the higher incidence of stroke in the former group.

The Clopidogrel versus Aspirin in Patients at Risk of Ischaemic Events (CAPRI) study showed that the occurrence of fatal and nonfatal stroke at follow-up in the PAD subgroup was double that in the myocardial infarction subgroup, in both the clopidogrel and aspirin arm.6 Furthermore, and probably more indicative of the greater risk of stroke in PAD are the results of the Reduction of Atherothrombosis for Continued Health (REACH) Registry, which reported a greater 1-year stroke incidence in PAD patients with concomitant cerebrovascular disease than in patients with CAD and cerebrovascular disease.7

However, many cerebrovascular events are associated with carotid stenoses <75%, thus indicating that other mechanisms are involved such as cardiac or aortic embolism, lacunar infarction, valvular disease with atrial fibrillation, and embolism from carotid bifurcation. The latter appears to be the most common pathogenetic mechanism for cerebral ischemia.8, 9 Indeed, plaque composition, as reflected by its echogenicity, is an independent risk factor for incident stroke.10, 11, 12 Plaques that appear with low echogenicity on B-mode ultrasound scanning have an increased lipid content that renders them more prone to rupture, whereas plaques with high echogenicity consist mainly of fibrin and collagen, which makes them more stable.13, 14 Although previous reports indicate that the prevalence of significant carotid stenoses is greater in PAD than in CAD subjects,1, 2, 3, 4, 5 to our knowledge, no study has compared these two populations with respect to plaque echogenicity. Accordingly, we investigated this neglected area.

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Methods 

The PAD group consisted of subjects referred to our Angiology Section for intermittent claudication. Peripheral arterial disease was diagnosed by an ankle-brachial index (ABI) <0.90 associated with one or more stenoses of >50% in the arteries supplying the legs. Peripheral arterial disease patients with a documented history of CAD were excluded. Those without a CAD history underwent dipyridamole myocardial perfusion imaging to verify the presence or absence of ischemic heart disease.

The CAD group consisted of patients with stable CAD recruited at the Cardiology Section of our department. In these subjects, the diagnosis of CAD was considered positive when confirmed with hospital records documenting previous myocardial infarction, positive on a treadmill stress test result, positive myocardial scintigram result, or positive angiogram result. Coronary artery disease patients who had sustained a myocardial infarction or who underwent a coronary revascularization procedure in the previous 6 months were excluded. All CAD patients underwent vascular examination, and the presence of PAD was excluded by normal ABI and in the absence of peripheral artery stenoses on duplex ultrasound scanning.

Because we focused on the echogenicity of plaques, the inclusion criterion for this study was the presence of carotid plaques at the bifurcation ≥1.3 mm in thickness, the echolucency of which assessed by visual and computer-assisted techniques, is highly reproducible.15 Patients with smaller plaques were not included because such plaques could not be clearly separated from diffused, thickened, intima-media complex. B-mode ultrasound has been validated for the measurement of intima-media thickness in several independent laboratories and its reliability is well established.16, 17 Other exclusion criteria were absence of carotid plaques, calcified plaques with acoustic shadow because it was technically impossible to determine their echogenicity reliably, and carotid endarterectomy.

Each patient’s clinical history and risk factors were assessed. “Smokers” were current smokers. Hypertension was diagnosed if systolic arterial pressure was >140 mm Hg or diastolic arterial pressure was >90 mm Hg, or both, or if the patient used antihypertensive drugs. Hypercholesterolemia was diagnosed if plasma total cholesterol was >240 mg/dL, if plasma low-density lipoprotein cholesterol was >130 mg/dL, or if the patient used lipid-lowering drugs because of a history of hypercholesterolemia. Diabetes mellitus was diagnosed if plasma fasting glucose was >126 mg/dL or if the patient used hypoglycemic agents. All patients gave informed consent to the protocol, which was approved by the Ethics Committee at our institution.

Both carotid bifurcations were examined by high-resolution B-mode ultrasound. The B-mode and corresponding color Doppler images were recorded onto super-VHS videotape and digitized with PixelView, Hi Speed USB 2.0 TV/Capture box (PROLINK Microsystems Corp, Taipei, Taiwan). If plaque was found in both carotid bifurcations, the one with greater echolucency was used for the analysis.

Symptomatic patients who had experienced ischemic stroke, transient ischemic attack, or amaurosis fugax on the side related to the plaque with the greater echolucency were included. Conversely, we excluded three patients with a previous cerebrovascular event in the territory contralateral to that of the plaque showing the greatest echolucency because their inclusion could have had a confounding effect on the evaluation of the relationship between the gray-scale median (GSM) analysis and symptomatic plaques.

The diagnosis of ischemic stroke was confirmed by a computed tomography scan that showed ischemic infarction and ruled out cerebral hemorrhage. Patients with bilateral hemispheric symptoms and those with known cardiac mural thrombus (as verified on echocardiography) were excluded from the analysis because of suspected cardioembolic origin. Also excluded were patients with severe valvular disease and atrial fibrillation. Carotid stenosis ≥50% was defined by systolic velocity >130 cm/s.18 All examinations were done by the same well-trained sonographer (S. L.), who was blinded to patient clinical details.

After carotid examination, blood was drawn from an antecubital vein using a 19-gauge needle in a Vacutainer system (Becton-Dickson, Franklin Lakes, NJ). Neutrophil count was then measured by the Bayer H*2 hematology analyzer (Bayer Diagnostic Division, Tarrytown, NY).

Visual analysis 

The recording was first evaluated by visual analysis. All the images were transferred to a personal computer, enlarged twofold, and then studied. The plaque margins were delineated using the color images as a guide. The plaques were classified according to a modified version of the classification proposed by Gray-Weale et al19, 20 and graded as echolucent (type 1), predominantly echolucent (type 2), predominantly echogenic (type 3), or echogenic (type 4). To ensure uniformity and an unbiased approach in the analysis, B-mode images were evaluated by the same examiner (S. G.), who was unaware of the clinical profile of the patients. Plaques were divided into two different types for analysis: hypoechoic when their echolucency involved >50% of the plaque area (type 1 and type 2 plaques) and echorich when the hyperechoic structure involved >50% of the plaque area (type 3 and type 4 plaques).

Gray-scale median analysis 

The overall brightness of the carotid plaque was analyzed by a single investigator (D. M. J.), who was unaware of the visual analysis. The computer-assisted analysis used the software Image Processing and Analysis in Java (Image J, National Institutes of Health, Bethesda, Md) for standardization and echogenicity analysis. Standardization was achieved as previously reported.21 The GSM of the frequency distribution of gray values of the pixels within the plaque was used as the measurement of the echogenicity. After standardization, the plaque was outlined and its overall brightness evaluated by means of the median GSM range: 0 (black) to 255 (white). The median GSM value of the plaque was adjusted linearly so that the median value of blood was 0 and that of the adventitia was 190. To distinguish hypoechoic from echorich plaque on the computer-assisted analysis, we used the 25th percentile of GSM value of 34.9.

Statistical analysis 

The relationship between the plaque type (visual analysis) and the mean GSM was evaluated by the Spearman analysis (ρ). To assess the reproducibility, 30 plaques were re-evaluated by the same operator who was blinded to the results of previous examinations. Intraoperator agreement was assessed by κ statistics. Group comparisons were made by χ2 test, and the t test for unpaired samples, as appropriate. For both the visual and GSM method, multivariate regression analysis was used to identify the independent association of clinical variables with the presence of hypoechoic carotid plaques. Both analyses were initially adjusted for age, sex, and presence of PAD (model 1). We then included, as covariates, risk factors showing group difference (inclusion criteria P < .1)22 at the univariate analysis (model 2). In a third model, the neutrophil count exceeding the median was added to the other covariates. Data are presented as mean ± SD, unless indicated otherwise.

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Results 

We screened 128 consecutive PAD and 86 consecutive CAD patients. Absence of carotid plaque was observed in three PAD and in seven CAD patients. As required by the study protocol, 75 PAD patients with coexistent CAD and 19 CAD patients with coexistent PAD were excluded. Also excluded were 4 PAD and 7 CAD subjects with calcified plaques, and 1 PAD and 1 CAD subject who underwent a previous endarterectomy, 1 CAD patient with mitral stenosis and atrial fibrillation, and 7 CAD subjects with previous myocardial infarction or who had undergone coronary revascularization in the previous 6 months. Finally, two PAD patients and one CAD patient were excluded because of a previous cerebral event in the territory of the plaque contralateral to that showing the greater echolucency. After exclusion of these patients, the study sample comprised 43 PAD and 43 CAD patients. The principal characteristics of the study population are listed in Table I). Notably, the number of symptomatic plaques was 16 in the PAD group (37.2%) and seven in the CAD group (16.3%; P = .028), and the two groups had a similar prevalence of carotid artery stenoses ≥50%.

Table I. Characteristics of the study population
VariableCAD(n=43)PAD(n=43)P
Age, mean±SD y64.9±10.964.9±9.5>.99
Males, No.(%)35(81.4)31(72.1).307
Hypercholesterolemia, No.(%)34(79.1)35(81.4).776
Diabetes, No.(%)15(34.9)10(23.3).263
Hypertension, No.(%)39(90.7)27(62.8).003
Active smoking, No.(%)10(23.3)26(60.5).001
BMI mean±SD kg/m227.8±3.626.6±2.3.077
Symptomatic plaques, No.(%)7(16.3)16(37.2).028
Carotid stenosis ≥50%, No.(%)8(18.6)8(18.6)>.99
Hypoechoic plaques, No.(%)
At visual analysis8(18.6)17(39.5).033
At GSM analysis(%)6(14.0)15(34.9).024

BMI, body mass index; CAD, coronary artery disease; GSM, gray-scale median; PAD, peripheral arterial disease.

With respect to the relationship between hypoechogenicity and symptomatic plaques, multivariate analysis showed that hypoechoic carotid plaques (GSM <34.9) were significantly associated with previous cerebrovascular events and also when adjusted for severity of stenosis (odds ratio [OR], 3.61; 95% confidence interval [CI], 1.05-12.65; P = .048).

The prevalence of hypoechoic plaques was markedly higher in the PAD group than in the CAD group both at visual analysis (39.5% vs 18.6%, P = .033) and at GSM analysis (34.9% vs 14.0%, P = .024) when the 25th percentile of the GSM was used as cutoff. Furthermore, the GSM score was significantly lower in PAD than in CAD patients (53.6 ± 32.6 vs 67.1 ± 25.4, P = .035). These observations are supported by the finding that the GSM results are in agreement with the echogenicity as established visually: the lowest GSM score (9.6 ± 7.8) corresponded to type 1 plaques, and the highest GSM score (81.3 ± 17.5) corresponded to type 4 plaques. Plaques of type 2 and 3 presented intermediate values (39.6 ± 28.03 and 69.2 ± 17.7, respectively). As reported in Fig 1, Spearman analysis showed that plaque type and mean GSM values were significantly correlated (ρ = 0.714, P < .01).

  • View full-size image.
  • Fig 1. 

    Correlation between visual classification of plaque echogenicity (four types) and mean gray-scale median values (GSM) presented with the standard deviation (whiskers). Spearman analysis ρ = 0.714; P < .01.

Multivariate analysis (Table II, model 2) showed that after adjustment for potential confounders, PAD patients had a 4.4-fold increased risk of having carotid plaques of type 1 or 2 (hypoechoic) compared with CAD subjects. Also, age was independently associated with the presence of hypoechoic plaques (Table II, model 2). Actually, subjects with hypoechoic plaques were younger than those with echorich plaques (61.1 ± 10.1 vs 66.5 ± 9.9 yr, P = 0.024).

Table II. Predictors of hypoechoic carotid plaques evaluated by visual analysis at univariate and multivariate analyses
Model 1aModel 2bModel 3c
OR95% CIPOR95% CIPOR95% CIPOR95% CIP
PAD2.861.07-7.63.0363.641.26-10.53.0174.391.21-15.92.0252.830.72-11.05.135
Age 0.940.90-0.99.0310.940.89-0.99.0470.950.89-1.01.098
Male sex 3.330.80-13.83.0983.830.80-18.35.0934.110.70-24.25.118
Hypertension 0.760.21-2.70.6710.820.21-3.16.769
Active smoking 1.480.41-5.29.5491.530.37-6.41.557
Body mass index 1.140.93-1.41.2091.130.90-1.41.298
Neutrophil count >median 9.342.30-37.96.002

CI, Confidence interval; OR, odds ratio; PAD, peripheral arterial disease.

aAnalyses adjusted for age, sex, and presence of PAD.

bAnalysis includes risk factors showing group difference (inclusion criteria P < .1) at the univariate analysis as covariates.

cNeutrophil count exceeding the median was added to the other covariates.

Results of the GSM analysis confirmed the results obtained by visual analysis. The presence of PAD and younger age were independently associated with a GSM <34.9, indicating lower plaque echogenicity (Table III, model 2).

Table III. Predictors of hypoechoic carotid plaques (gray-scale median score < 34.9) at univariate and multivariate analyses
Model 1aModel 2bModel 3c
OR95% CIPOR95% CIPOR95% CIPOR95% CIP
PAD3.301.14-9.60.0284.371.38-13.88.0125.131.27-20.67.0213.390.81-14.14.094
Age 0.940.89-1.00.0420.940.88-0.99.0470.940.88-1.01.090
Male sex 4.520.87-23.51.0734.430.75-26.15.1014.450.61-32.41.140
Hypertension 0.740.20-2.82.6590.760.19-3.09.701
Active smoking 1.260.33-4.86.7331.260.28-5.63.762
Body mass index 1.070.85-1.33.5771.030.81-1.30.831
Neutrophil count >median 10.832.09-56.03.005

CI, Confidence interval; OR, odds ratio; PAD, peripheral arterial disease.

aAnalyses adjusted for age, sex, and presence of PAD.

bAnalysis includes risk factors showing group difference (inclusion criteria P < .1) at the univariate analysis as covariates.

cNeutrophil count exceeding the median was added to the other covariates.

We found a significant inverse relationship between the four plaque types and the neutrophil count (ρ = −0.411, P < .01). The echogenicity measured by GSM analysis also correlated negatively with the number of neutrophils (ρ = −0.423, P < .01). The number of neutrophils was higher in type 1 and 2 plaques (considered collectively) than in the subgroup comprising type 3 and 4 plaques (4.9 ± 1.0 vs 3.8 ± 1.1× 109/L, P < .01; Fig 2). Similarly, when the 25th percentile of the GSM median value was used to divide plaques into two groups, the neutrophil count was 4.9 ± 1.0 × 109/L in hypoechoic and 3.9 ± 1.0 × 109/L (P < .01) in echorich plaques (Fig 2). Fig 2 similarly shows that hypoechoic plaques were much more common in the group of patients with neutrophil numbers exceeding the median (3.8 × 109/L) than in those with lower neutrophil levels (48.8% vs 9.3%, P < .01, for visual analysis; 41.9% vs 7.0%, P < .01, for GSM analysis). Notably, the increased risk associated with PAD of having hypoechoic plaques was no longer significant when the neutrophil number exceeding the median was added to the multivariate analyses (Table II, Table III, model 3). In this model, only an increased neutrophil count was independently associated with the presence of hypoechoic plaques (Table II, Table III, model 3). It is noteworthy that these findings did not change when the neutrophil count was included in the model as a continuous variable (results not shown). Indeed, PAD patients showed a greater number of neutrophils than patients with CAD (4.4 ± 1.0 vs 3.9 ± 1.2 × 109/L, P = .03).

  • View full-size image.
  • Fig 2. 

    Number of neutrophils in coronary artery disease and peripheral arterial disease patients evaluated by visual analysis (upper panel) and gray-scale median (GSM) analysis (lower panel). With both procedures, the neutrophil count was higher in patients with hypoechoic than in those with echorich plaques. Furthermore, the prevalence of hypoechoic plaques in patients with a neutrophil number that exceeded the median was markedly higher than in those with a neutrophil number that was less than the median. Type 1 and type 2 plaques were considered hypoechoic for the visual analysis; whereas plaques with a GSM value of <34.9 (ie, the 25th percentile of the GSM median value) were considered “hypoechoic” for the GSM analysis. Data are presented with the standard deviation (error bars).

Overall, 53 patients (61.6%) were taking statins (29 in the CAD and 24 in the PAD group). Statistical analysis did not show any difference in plaque echogenicity related to the use of statins, GSM being 60.2 ± 28.9 in patients with statin use and 59.6 ± 31.4 in those without.

The agreement between two repeated evaluations of the plaques was excellent for both visual analysis (κ = 0.83) and GSM analysis (κ = 0.87).

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Discussion 

The results of this study suggest that hypoechoic plaques are much more common in patients with PAD than in patients with chronic stable CAD. Actually, at visual analysis, the number of PAD patients with hypoechoic plaques was double that observed in the CAD group. The prevalence of carotid plaques with a very low GSM score (<34.9) was also markedly higher in PAD than in CAD. These findings may have clinical relevance because type 1 and 2 carotid plaques11 and plaques with a GSM value <32 or 40 have been reported to be closely associated with cardiovascular events.23, 24 Of interest in our series is that the number of symptomatic plaques was significantly greater in PAD patients than in CAD patients. We considered plaque as a tract of the carotid where the intima-media thickness was >1.3 mm, which is the limit suggested by the Prevention Conference V25 and used in most studies on plaque echogenicity.26, 27, 28 However, the extent to which carotid intima-media thickness is a manifestation of early or diffuse atherosclerosis, as opposed to smooth-muscle hypertrophy or hyperplasia, or both, is uncertain.29

The higher prevalence of hypoechoic carotid plaques in PAD may not be attributed to group differences in classic risk factors, which were not significantly associated with this plaque type at the multivariate analyses. Therefore, other mechanisms are likely to be involved in determining plaque hypoechogenicity.

Inflammation has a key role in every aspect of the atherosclerotic process, and recent investigations report that the presence of high-risk carotid plaques is associated with increased levels of inflammatory markers, such as C-reactive protein, leukocyte count, and fibrinogen.30, 31, 32 In our study, we found a significant inverse relationship between plaque echogenicity and the neutrophil count. Patients with hypoechoic plaques therefore had a significantly higher number of neutrophils than those with echorich plaques, independently of age, sex, and classic risk factors. Notably, at the multivariate analyses, when neutrophil count exceeding the median was added to the other covariates, the association between PAD and hypoechoic plaques was no longer significant. Indeed, PAD patients showed a higher number of neutrophils than those with CAD. Therefore, the finding that the prevalence of hypoechoic plaques was higher in PAD than in CAD patients was probably because, consistent with previous studies,33, 34 the PAD group had a more pronounced inflammatory profile. Because administration of statins is reported to have a stabilizing effect on carotid plaques,35 we compared plaque echogenicity in patients who were on statin treatment with that in patients not taking statins. No group differences were observed. We were unaware of the duration of statin treatment in each patient however; therefore, we cannot exclude that some patients had only recently started taking statins.

Another important result of our study is that, as already reported,36, 37 there was a good concordance between visual typing of carotid plaques and GSM measurement. Types of carotid plaques and GSM scores were linearly correlated, with a low GSM corresponding to echolucent (type 1) carotid plaques and a high GSM to echogenic (type 4) carotid plaques. It is therefore questionable whether the GSM method, although accurate and objective, should be preferred to the visual analysis, considering that it requires additional equipment and is time-consuming.

Study limitation 

A limitation of our study is that the results were obtained in a relatively small cohort. However, the differences between the CAD and PAD groups were so marked that they argue convincingly in favor of a higher prevalence of hypoechoic plaques in PAD patients. A second limitation is that we used the 25th percentile of the median GSM value as an arbitrary end point to distinguish hypoechoic from hyperechoic plaques. To the best of our knowledge, however, no GSM cutoff has been established to identify hypoechoic plaques and thus far, various cutoff values have been used.23, 24, 38, 39 We used the 25th percentile of the median GSM because this value was low enough to identify hypoechoic plaques in a number of patients sufficiently high for statistical analysis purposes. In this context, it is noteworthy that the prevalence of hypoechoic plaques measured with the two techniques was very similar in the two groups of patients. Furthermore, the value we found of 34.9 is very similar to those used by others to identify hypoechoic plaques.23, 24, 38, 39

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Conclusions 

Our findings suggest that compared with CAD patients, those with PAD, probably as a consequence of a greater inflammatory status, may have not only a greater carotid atherosclerotic burden1, 2, 3, 4, 5 but also morphologic characteristics associated with instability of carotid artery plaques, which in turn might result in cerebrovascular ischemic events.10, 11, 12 However, prospective studies are needed to assess specifically whether the greater prevalence of hypoechoic plaques in PAD vs CAD patients is associated with a greater risk of cerebrovascular events.

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Author contributions 


Conception and design: GB

Analysis and interpretation: GB, GG

Data collection: GS, SL, JDM, EL, GG

Writing the article: GB, GS

Critical revision of the article: GB, GS, SL, JDM, EL, GG

Final approval of the article: GB, GS, SL, JDM, EL, GG

Statistical analysis: GB, GG

Obtained funding: Not applicable

Overall responsibility: GB

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 Competition of interest: none.

PII: S0741-5214(07)01758-2

doi:10.1016/j.jvs.2007.10.054

Journal of Vascular Surgery
Volume 47, Issue 3 , Pages 523-529, March 2008

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