The prevalence of hypoechoic carotid plaques isgreater in peripheral than in coronary arterydisease and is related to the neutrophil countGregorio Brevetti, MD, Giusy Sirico, MD, Simona Lanero, MD, Julieta Isabel De Maio, MD,Eugenio Laurenzano, MD, and Giuseppe Giugliano, MD, Naples, Italy

Objective: Previous reports indicate that the prevalence and severity of carotid stenoses is greater in peripheral arterydisease (PAD) than in coronary artery disease (CAD). To date, no study has compared these two populations with respectto 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 withhigh-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). Thecorresponding values for gray-scale median analysis were 34.9% and 14.0% (P � .024). At multivariate analysis, PADpatients 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 thismodel, only an increased neutrophil count was associated with hypoechoic plaques (P < .01 for both visual and gray-scalemedian 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 (� � 0.714,P < .01).Conclusions: Compared with CAD patients, those with PAD, in addition to a greater atherosclerotic burden, may havecharacteristics of instability of carotid plaques that, in turn, may result in cerebrovascular events. Prospective studies areneeded to assess specifically whether the greater prevalence of hypoechoic plaques in PAD vs CAD patients is associated

with a greater risk of cerebrovascular events. ( J Vasc Surg 2008;47:523-9.)

Atherosclerosis is a systemic disease and thus its local-ization is often associated with vascular alterations in othervascular districts. With respect to the coexistence of carotidstenoses with other arterial diseases, it seems to be morecommon and severe in peripheral arterial disease (PAD)than in coronary artery disease (CAD).1-5 In particular, theSecond Manifestations of ARTerial (SMART) diseasestudy4 showed that the prevalence of carotid stenosis �70%was 12.5% in PAD and only 3.1% in CAD. Similarly inanother series, carotid stenosis �70% was present in 24.5%of PAD patients and in 11.1% of CAD patients.5 This maypartly explain the higher incidence of stroke in the formergroup.

The Clopidogrel versus Aspirin in Patients at Risk ofIschaemic Events (CAPRI) study showed that the occur-rence of fatal and nonfatal stroke at follow-up in the PADsubgroup was double that in the myocardial infarctionsubgroup, in both the clopidogrel and aspirin arm.6 Fur-thermore, and probably more indicative of the greater riskof stroke in PAD are the results of the Reduction ofAtherothrombosis for Continued Health (REACH) Reg-

From the Department of Clinical Medicine and Cardiovascular and Immu-nological Sciences, University of Napoli “Federico II.”

Competition of interest: none.Reprint requests: Gregorio Brevetti, MD, Via G. Iannelli 45/A, 80131

Napoli, Italy (e-mail: brevetti@unina.it).0741-5214/$34.00Copyright © 2008 by The Society for Vascular Surgery.

doi:10.1016/j.jvs.2007.10.054

istry, which reported a greater 1-year stroke incidence inPAD patients with concomitant cerebrovascular diseasethan in patients with CAD and cerebrovascular disease.7

However, many cerebrovascular events are associatedwith carotid stenoses �75%, thus indicating that othermechanisms are involved such as cardiac or aortic embo-lism, lacunar infarction, valvular disease with atrial fibrilla-tion, and embolism from carotid bifurcation. The latterappears to be the most common pathogenetic mechanismfor cerebral ischemia.8,9 Indeed, plaque composition, asreflected by its echogenicity, is an independent risk factorfor incident stroke.10-12 Plaques that appear with low echo-genicity on B-mode ultrasound scanning have an increasedlipid content that renders them more prone to rupture,whereas plaques with high echogenicity consist mainly offibrin and collagen, which makes them more stable.13,14

Although previous reports indicate that the prevalence ofsignificant carotid stenoses is greater in PAD than in CADsubjects,1-5 to our knowledge, no study has compared thesetwo populations with respect to plaque echogenicity. Ac-cordingly, we investigated this neglected area.

METHODS

The PAD group consisted of subjects referred to ourAngiology Section for intermittent claudication. Peripheralarterial 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

523

JOURNAL OF VASCULAR SURGERYMarch 2008524 Brevetti et al

disease patients with a documented history of CAD wereexcluded. Those without a CAD history underwent dipy-ridamole myocardial perfusion imaging to verify the pres-ence or absence of ischemic heart disease.

The CAD group consisted of patients with stable CADrecruited at the Cardiology Section of our department. Inthese subjects, the diagnosis of CAD was considered posi-tive when confirmed with hospital records documentingprevious myocardial infarction, positive on a treadmill stresstest result, positive myocardial scintigram result, or positiveangiogram result. Coronary artery disease patients who hadsustained a myocardial infarction or who underwent acoronary revascularization procedure in the previous 6months were excluded. All CAD patients underwent vas-cular examination, and the presence of PAD was excludedby normal ABI and in the absence of peripheral arterystenoses on duplex ultrasound scanning.

Because we focused on the echogenicity of plaques, theinclusion criterion for this study was the presence of carotidplaques at the bifurcation �1.3 mm in thickness, theecholucency of which assessed by visual and computer-assisted techniques, is highly reproducible.15 Patients withsmaller plaques were not included because such plaquescould not be clearly separated from diffused, thickened,intima-media complex. B-mode ultrasound has been vali-dated for the measurement of intima-media thickness inseveral independent laboratories and its reliability is wellestablished.16,17 Other exclusion criteria were absence ofcarotid plaques, calcified plaques with acoustic shadowbecause it was technically impossible to determine theirechogenicity reliably, and carotid endarterectomy.

Each patient’s clinical history and risk factors wereassessed. “Smokers” were current smokers. Hypertensionwas diagnosed if systolic arterial pressure was �140 mm Hgor diastolic arterial pressure was �90 mm Hg, or both, or ifthe patient used antihypertensive drugs. Hypercholesterol-emia was diagnosed if plasma total cholesterol was �240mg/dL, if plasma low-density lipoprotein cholesterol was�130 mg/dL, or if the patient used lipid-lowering drugsbecause of a history of hypercholesterolemia. Diabetes mel-litus was diagnosed if plasma fasting glucose was �126mg/dL or if the patient used hypoglycemic agents. Allpatients gave informed consent to the protocol, which wasapproved by the Ethics Committee at our institution.

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

Symptomatic patients who had experienced ischemicstroke, transient ischemic attack, or amaurosis fugax on theside related to the plaque with the greater echolucency wereincluded. Conversely, we excluded three patients with aprevious cerebrovascular event in the territory contralateral

to that of the plaque showing the greatest echolucency

because their inclusion could have had a confounding effecton the evaluation of the relationship between the gray-scalemedian (GSM) analysis and symptomatic plaques.

The diagnosis of ischemic stroke was confirmed by acomputed tomography scan that showed ischemic infarc-tion and ruled out cerebral hemorrhage. Patients withbilateral hemispheric symptoms and those with knowncardiac mural thrombus (as verified on echocardiogra-phy) were excluded from the analysis because of sus-pected cardioembolic origin. Also excluded were pa-tients 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 samewell-trained sonographer (S. L.), who was blinded topatient clinical details.

After carotid examination, blood was drawn from anantecubital vein using a 19-gauge needle in a Vacutainersystem (Becton-Dickson, Franklin Lakes, NJ). Neutrophilcount was then measured by the Bayer H*2 hematologyanalyzer (Bayer Diagnostic Division, Tarrytown, NY).

Visual analysis. The recording was first evaluated byvisual analysis. All the images were transferred to a personalcomputer, enlarged twofold, and then studied. The plaquemargins were delineated using the color images as a guide.The plaques were classified according to a modified versionof the classification proposed by Gray-Weale et al19,20 andgraded as echolucent (type 1), predominantly echolucent(type 2), predominantly echogenic (type 3), or echogenic(type 4). To ensure uniformity and an unbiased approach inthe analysis, B-mode images were evaluated by the sameexaminer (S. G.), who was unaware of the clinical profile ofthe patients. Plaques were divided into two different typesfor analysis: hypoechoic when their echolucency involved�50% of the plaque area (type 1 and type 2 plaques) andechorich when the hyperechoic structure involved �50% ofthe plaque area (type 3 and type 4 plaques).

Gray-scale median analysis. The overall brightness ofthe carotid plaque was analyzed by a single investigator(D. M. J.), who was unaware of the visual analysis. Thecomputer-assisted analysis used the software Image Pro-cessing and Analysis in Java (Image J, National Institutes ofHealth, Bethesda, Md) for standardization and echogenic-ity analysis. Standardization was achieved as previouslyreported.21 The GSM of the frequency distribution of grayvalues of the pixels within the plaque was used as themeasurement of the echogenicity. After standardization,the plaque was outlined and its overall brightness evaluatedby means of the median GSM range: 0 (black) to 255(white). The median GSM value of the plaque was adjustedlinearly so that the median value of blood was 0 and that ofthe adventitia was 190. To distinguish hypoechoic fromechorich plaque on the computer-assisted analysis, we usedthe 25th percentile of GSM value of 34.9.

Statistical analysis. The relationship between theplaque type (visual analysis) and the mean GSM was evalu-ated by the Spearman analysis (�). To assess the reproduc-

ibility, 30 plaques were re-evaluated by the same operator

ian; P

JOURNAL OF VASCULAR SURGERYVolume 47, Number 3 Brevetti et al 525

who was blinded to the results of previous examinations.Intraoperator agreement was assessed by � statistics. Groupcomparisons were made by �2 test, and the t test forunpaired samples, as appropriate. For both the visual andGSM method, multivariate regression analysis was used toidentify the independent association of clinical variableswith the presence of hypoechoic carotid plaques. Bothanalyses were initially adjusted for age, sex, and presence ofPAD (model 1). We then included, as covariates, riskfactors showing group difference (inclusion criteriaP � .1)22 at the univariate analysis (model 2). In a thirdmodel, the neutrophil count exceeding the median wasadded to the other covariates. Data are presented asmean � SD, unless indicated otherwise.

RESULTS

We screened 128 consecutive PAD and 86 consecutiveCAD patients. Absence of carotid plaque was observed inthree PAD and in seven CAD patients. As required by thestudy protocol, 75 PAD patients with coexistent CAD and19 CAD patients with coexistent PAD were excluded. Alsoexcluded were 4 PAD and 7 CAD subjects with calcifiedplaques, and 1 PAD and 1 CAD subject who underwent aprevious endarterectomy, 1 CAD patient with mitral steno-sis and atrial fibrillation, and 7 CAD subjects with previousmyocardial infarction or who had undergone coronaryrevascularization in the previous 6 months. Finally, twoPAD patients and one CAD patient were excluded becauseof a previous cerebral event in the territory of the plaquecontralateral to that showing the greater echolucency. Afterexclusion of these patients, the study sample comprised 43PAD and 43 CAD patients. The principal characteristics ofthe study population are listed in Table I). Notably, thenumber 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 carotidartery stenoses �50%.

With respect to the relationship between hypoechoge-nicity and symptomatic plaques, multivariate analysisshowed that hypoechoic carotid plaques (GSM �34.9)were significantly associated with previous cerebrovascular

Table I. Characteristics of the study population

Variable CAD (n �

Age, mean � SD y 64.9 � 1Males, No. (%) 35 (81.4Hypercholesterolemia, No. (%) 34 (79.1Diabetes, No. (%) 15 (34.9Hypertension, No. (%) 39 (90.7Active smoking, No. (%) 10 (23.3BMI mean � SD kg/m2 27.8 � 3Symptomatic plaques, No. (%) 7 (16.3Carotid stenosis �50%, No. (%) 8 (18.6Hypoechoic plaques, No. (%)

At visual analysis 8 (18.6At GSM analysis (%) 6 (14.0

BMI, body mass index; CAD, coronary artery disease; GSM, gray-scale med

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 markedlyhigher in the PAD group than in the CAD group both atvisual analysis (39.5% vs 18.6%, P � .033) and at GSManalysis (34.9% vs 14.0%, P � .024) when the 25th percen-tile of the GSM was used as cutoff. Furthermore, the GSMscore was significantly lower in PAD than in CAD patients(53.6 � 32.6 vs 67.1 � 25.4, P � .035). These observa-tions are supported by the finding that the GSM results arein agreement with the echogenicity as established visually:the lowest GSM score (9.6 � 7.8) corresponded to type 1plaques, and the highest GSM score (81.3 � 17.5) corre-sponded to type 4 plaques. Plaques of type 2 and 3 pre-sented intermediate values (39.6 � 28.03 and 69.2 � 17.7,respectively). As reported in Fig 1, Spearman analysisshowed that plaque type and mean GSM values were sig-nificantly correlated (� � 0.714, P � .01).

Multivariate analysis (Table II, model 2) showed thatafter adjustment for potential confounders, PAD patientshad a 4.4-fold increased risk of having carotid plaques oftype 1 or 2 (hypoechoic) compared with CAD subjects.

PAD (n � 43) P

64.9 � 9.5 �.9931 (72.1) .30735 (81.4) .77610 (23.3) .26327 (62.8) .00326 (60.5) .001

26.6 � 2.3 .07716 (37.2) .0288 (18.6) �.99

17 (39.5) .03315 (34.9) .024

AD, peripheral arterial disease.

Fig 1. Correlation between visual classification of plaque echoge-nicity (four types) and mean gray-scale median values (GSM)presented with the standard deviation (whiskers). Spearman analy-sis � � 0.714; P � .01.

43)

0.9)))))

.6))

))

Also, age was independently associated with the presence of

.

.

JOURNAL OF VASCULAR SURGERYMarch 2008526 Brevetti et al

hypoechoic plaques (Table II, model 2). Actually, subjectswith hypoechoic plaques were younger than those withechorich plaques (61.1 � 10.1 vs 66.5 � 9.9 yr, P �0.024).

Results of the GSM analysis confirmed the results ob-tained by visual analysis. The presence of PAD and youngerage were independently associated with a GSM �34.9,indicating lower plaque echogenicity (Table III, model 2).

We found a significant inverse relationship between thefour plaque types and the neutrophil count (� � �0.411,P � .01). The echogenicity measured by GSM analysis alsocorrelated negatively with the number of neutrophils (� ��0.423, P � .01). The number of neutrophils was higherin type 1 and 2 plaques (considered collectively) than in thesubgroup comprising type 3 and 4 plaques (4.9 � 1.0 vs3.8 � 1.1 109/L, P � .01; Fig 2). Similarly, when the25th percentile of the GSM median value was used todivide plaques into two groups, the neutrophil count was4.9 � 1.0 109/L in hypoechoic and 3.9 � 1.0 109/L(P � .01) in echorich plaques (Fig 2). Fig 2 similarly showsthat hypoechoic plaques were much more common in thegroup of patients with neutrophil numbers exceeding the

Table II. Predictors of hypoechoic carotid plaques evalua

Model 1

OR 95% CI P OR 95% C

PAD 2.86 1.07-7.63 .036 3.64 1.26-10.Age 0.94 0.90-0.9Male sex 3.33 0.80-13.HypertensionActive smokingBody mass indexNeutrophil count

�median

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 PcNeutrophil count exceeding the median was added to the other covariates

Table III. Predictors of hypoechoic carotid plaques (grayanalyses

Model 1

OR 95% CI P OR 95% CI

PAD 3.30 1.14-9.60 .028 4.37 1.38-13.8Age 0.94 0.89-1.00Male sex 4.52 0.87-23.5HypertensionActive smokingBody mass indexNeutrophil count

�median

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 PcNeutrophil count exceeding the median was added to the other covariates

median (3.8 109/L) than in those with lower neutrophil

levels (48.8% vs 9.3%, P � .01, for visual analysis; 41.9% vs7.0%, P � .01, for GSM analysis). Notably, the increasedrisk associated with PAD of having hypoechoic plaques wasno longer significant when the neutrophil number exceed-ing the median was added to the multivariate analyses(Tables II and III, model 3). In this model, only anincreased neutrophil count was independently associatedwith the presence of hypoechoic plaques (Table II and III,model 3). It is noteworthy that these findings did notchange when the neutrophil count was included in themodel as a continuous variable (results not shown). Indeed,PAD patients showed a greater number of neutrophils thanpatients with CAD (4.4 � 1.0 vs 3.9 � 1.2 109/L,P � .03).

Overall, 53 patients (61.6%) were taking statins (29 inthe CAD and 24 in the PAD group). Statistical analysis didnot show any difference in plaque echogenicity related tothe use of statins, GSM being 60.2 � 28.9 in patients withstatin use and 59.6 � 31.4 in those without.

The agreement between two repeated evaluations ofthe plaques was excellent for both visual analysis (� � 0.83)

y visual analysis at univariate and multivariate analyses

Model 2b Model 3c

P OR 95% CI P OR 95% CI P

.017 4.39 1.21-15.92 .025 2.83 0.72-11.05 .135

.031 0.94 0.89-0.99 .047 0.95 0.89-1.01 .098

.098 3.83 0.80-18.35 .093 4.11 0.70-24.25 .1180.76 0.21-2.70 .671 0.82 0.21-3.16 .7691.48 0.41-5.29 .549 1.53 0.37-6.41 .5571.14 0.93-1.41 .209 1.13 0.90-1.41 .298

9.34 2.30-37.96 .002

) at the univariate analysis as covariates.

median score � 34.9) at univariate and multivariate

Model 2b Model 3c

P OR 95% CI P OR 95% CI P

.012 5.13 1.27-20.67 .021 3.39 0.81-14.14 .094

.042 0.94 0.88-0.99 .047 0.94 0.88-1.01 .090

.073 4.43 0.75-26.15 .101 4.45 0.61-32.41 .1400.74 0.20-2.82 .659 0.76 0.19-3.09 .7011.26 0.33-4.86 .733 1.26 0.28-5.63 .7621.07 0.85-1.33 .577 1.03 0.81-1.30 .831

10.83 2.09-56.03 .005

) at the univariate analysis as covariates.

ted b

a

I

53983

� .1

-scale

a

8

1

� .1

and GSM analysis (� � 0.87).

JOURNAL OF VASCULAR SURGERYVolume 47, Number 3 Brevetti et al 527

DISCUSSION

The results of this study suggest that hypoechoicplaques are much more common in patients with PAD thanin patients with chronic stable CAD. Actually, at visualanalysis, the number of PAD patients with hypoechoicplaques was double that observed in the CAD group. Theprevalence 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 1and 2 carotid plaques11 and plaques with a GSM value �32or 40 have been reported to be closely associated withcardiovascular events.23,24 Of interest in our series is that

Fig 2. Number of neutrophils in coronary artery disease andperipheral arterial disease patients evaluated by visual analysis (up-per panel) and gray-scale median (GSM) analysis (lower panel).With both procedures, the neutrophil count was higher in patientswith hypoechoic than in those with echorich plaques. Further-more, the prevalence of hypoechoic plaques in patients with aneutrophil number that exceeded the median was markedly higherthan in those with a neutrophil number that was less than themedian. Type 1 and type 2 plaques were considered hypoechoic forthe 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 thestandard deviation (error bars).

the number of symptomatic plaques was significantly

greater in PAD patients than in CAD patients. We consid-ered plaque as a tract of the carotid where the intima-mediathickness was �1.3 mm, which is the limit suggested by thePrevention Conference V25 and used in most studies onplaque echogenicity.26-28 However, the extent to whichcarotid intima-media thickness is a manifestation of early ordiffuse atherosclerosis, as opposed to smooth-muscle hy-pertrophy or hyperplasia, or both, is uncertain.29

The higher prevalence of hypoechoic carotid plaques inPAD may not be attributed to group differences in classicrisk factors, which were not significantly associated withthis plaque type at the multivariate analyses. Therefore,other mechanisms are likely to be involved in determiningplaque hypoechogenicity.

Inflammation has a key role in every aspect of theatherosclerotic process, and recent investigations reportthat the presence of high-risk carotid plaques is associatedwith increased levels of inflammatory markers, such asC-reactive protein, leukocyte count, and fibrinogen.30-32

In our study, we found a significant inverse relationshipbetween plaque echogenicity and the neutrophil count.Patients with hypoechoic plaques therefore had a signifi-cantly higher number of neutrophils than those withechorich plaques, independently of age, sex, and classic riskfactors. Notably, at the multivariate analyses, when neutro-phil count exceeding the median was added to the othercovariates, the association between PAD and hypoechoicplaques was no longer significant. Indeed, PAD patientsshowed a higher number of neutrophils than those withCAD. Therefore, the finding that the prevalence of hypo-echoic plaques was higher in PAD than in CAD patientswas probably because, consistent with previous stud-ies,33,34 the PAD group had a more pronounced inflamma-tory profile. Because administration of statins is reported tohave a stabilizing effect on carotid plaques,35 we comparedplaque echogenicity in patients who were on statin treat-ment with that in patients not taking statins. No groupdifferences were observed. We were unaware of the dura-tion of statin treatment in each patient however; therefore,we cannot exclude that some patients had only recentlystarted taking statins.

Another important result of our study is that, as alreadyreported,36,37 there was a good concordance between vi-sual typing of carotid plaques and GSM measurement.Types of carotid plaques and GSM scores were linearlycorrelated, with a low GSM corresponding to echolucent(type 1) carotid plaques and a high GSM to echogenic (type4) carotid plaques. It is therefore questionable whether theGSM method, although accurate and objective, should bepreferred to the visual analysis, considering that it requiresadditional equipment and is time-consuming.

Study limitation. A limitation of our study is that theresults were obtained in a relatively small cohort. However,the differences between the CAD and PAD groups were somarked that they argue convincingly in favor of a higherprevalence of hypoechoic plaques in PAD patients. A sec-ond limitation is that we used the 25th percentile of the

median GSM value as an arbitrary end point to distinguish

JOURNAL OF VASCULAR SURGERYMarch 2008528 Brevetti et al

hypoechoic from hyperechoic plaques. To the best of ourknowledge, however, no GSM cutoff has been establishedto identify hypoechoic plaques and thus far, various cutoffvalues have been used.23,24,38,39 We used the 25th percen-tile of the median GSM because this value was low enoughto identify hypoechoic plaques in a number of patientssufficiently high for statistical analysis purposes. In thiscontext, it is noteworthy that the prevalence of hypoechoicplaques measured with the two techniques was very similarin the two groups of patients. Furthermore, the value wefound of 34.9 is very similar to those used by others toidentify hypoechoic plaques.23,24,38,39

CONCLUSIONS

Our findings suggest that compared with CAD pa-tients, those with PAD, probably as a consequence of agreater inflammatory status, may have not only a greatercarotid atherosclerotic burden1-5 but also morphologiccharacteristics associated with instability of carotid arteryplaques, which in turn might result in cerebrovascularischemic events.10-12 However, prospective studies areneeded to assess specifically whether the greater prevalenceof hypoechoic plaques in PAD vs CAD patients is associatedwith a greater risk of cerebrovascular events.

AUTHOR CONTRIBUTIONS

Conception and design: GBAnalysis and interpretation: GB, GGData collection: GS, SL, JDM, EL, GGWriting the article: GB, GSCritical revision of the article: GB, GS, SL, JDM, EL, GGFinal approval of the article: GB, GS, SL, JDM, EL, GGStatistical analysis: GB, GGObtained funding: Not applicableOverall responsibility: GB

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REQUEST FOR SUBMISSION OF SURGICAL ETHICS CHALLENGES ARTICLES

The Editors invite submission of original articles for the Surgical Ethics Challenges section, following the general format established by Dr. James Jones in 2001. Readers have benefitted greatly from Dr. Jones' monthly ethics contributions for more than 6 years. In order to encourage contributions, Dr. Jones will assist in editing them and will submit his own articles every other month, to provide opportunity for others. Please submit articles under the heading of “Ethics” using Editorial Manager, and follow the format established in previous issues.