Alterations of baroreflex sensitivity after carotid endarterectomy according to the preoperative carotid plaque echogenicity

Alterations of baroreflex sensitivity after carotid endarterectomy according to the preoperative carotid plaque echogenicity Nikolaos S. Tsekouras, MD,a Athanasios Katsargyris, MD,b Ioanna Skrapari, MD,c Effie E. Bastounis, EEng, MSc,d Sotirios Georgopoulos, MD,e Chris Klonaris, MD,e Chris Bakoyiannis, MD,e and Efstathios Tsekouras, MD,f Toledo, Ohio; Athens, Greece; and San Diego, Calif Objective: Baroreflex sensitivity is lower in patients with echogenic carotid plaques compared with patients with echolucent ones. The purpose of our study was to compare the baroreflex function after carotid endarterectomy (CEA) between patients with different plaque echogenicity. Method: Spontaneous baroreflex sensitivity (sBRS), heart rate, and systolic and diastolic arterial pressure were calculated in 51 patients with a severe carotid stenosis (70%-99%) 24 hours before CEA, as well as 24 and 48 hours after CEA. Carotid plaque echogenicity was graded from 1 to 4 according to Gray-Weale classification, after duplex examination, and the patients were divided into two groups: the echolucent (grade 1 or 2) and the echogenic (grade 3 or 4). Results: The postoperative mean systolic arterial pressure values in all 51 patients at 24 and 48 hours (143.2 and 135.5 mm Hg, respectively) were found to be significantly increased compared with the preoperative value (132.5 mm Hg; x2 ⴝ 32, P < .001). Mean sBRS value, in all patients, was significantly reduced postoperatively to 2.1 ms mm Hgⴚ1, from the mean preoperative value, 3.7 ms mm Hgⴚ1, independently of plaque echogenicity. Twenty patients (39%) were included in the echolucent group and 31 (61%) in the echogenic. The two groups had significant differences in two parameters: the rate of diabetes mellitus and the rate of symptomatic plaques. After adjusting the two groups for these differences, we found that the preoperative difference in sBRS between the two groups (F[1,51] ⴝ 11, P < .003) was eliminated 24 and 48 hours after CEA (F[1,51] ⴝ .007, P < .9 and F[1,51] ⴝ .4, P < .5 for 24 and 48 hours, respectively). Conclusions: Before the removal of carotid atheroma, baroreflex sensitivity, which is a well established cardiovascular risk factor, seems to be affected by carotid plaque echogenicity. However, CEA has as a result a similar baroreflex response in all patients, regardless of plaque echogenicity, implying no association of plaque morphology and postoperative baroreflex sensitivity. ( J Vasc Surg 2012;56:1591-7.)

Carotid endarterectomy (CEA) reduces the future risk for a cerebrovascular event in patients with significant carotid artery stenosis, by removing the atheromatous plaque from the carotid bifurcation and the internal carotid artery.1,2 The carotid sinus, a significant baroreceptor regulating blood pressure, is located in this region. Blood pressure is in part controlled by the sensitivity of these baroreceptors, and this sensitivity (baroreflex sensitivity or BRS) can be quantified by the heart rate response to changes in blood pressure (ms/mm Hg). Several methods can be used for quantification of BRS, such as pharmacoFrom the Jobst Vascular Institute, Promedica Toledo Hospital,a Laiko General Hospital, Second Department of Propedeutic Surgery, Vascular Divisionb and Evangelismos General Hospital, First Department of Internal Medicine,c the University of Athens Medical School, the Department of Bioengineering, University of California, San Diego,d Laiko General Hospital, First Surgical Department, Vascular Division, University of Athens Medical School,e and Evangelismos General Hospital, Radiology Department.f Author conflict of interest: none. Reprint requests: Nikolaos S. Tsekouras, MD, 4373 Moser Ln, Perrysburg, OH 43551 (e-mail: [email protected]). The editors and reviewers of this article have no relevant financial relationships to disclose per the JVS policy that requires reviewers to decline review of any manuscript for which they may have a conflict of interest. 0741-5214/$36.00 Published by Elsevier Inc. on behalf of the Society for Vascular Surgery. http://dx.doi.org/10.1016/j.jvs.2012.05.103

logic, valsalva maneuver, mechanical manipulations with a neck chamber, or analysis of spontaneous oscillations in blood pressure and inter-beat (RR) interval. The latter is called spontaneous BRS (sBRS)3 and seems to be advantageous compared with other methods, not only because it can cause much less discomfort or risk to the patients, but also because it has very good reproducibility, due to its automatic and standardized computations.4,5 Previous studies have shown that, in most patients, the removal of atherosclerotic plaques from the carotid lumen is associated with deterioration of baroreflex sensitivity. This impairment has been detected both intraoperatively and postoperatively.6,7 The presence of an atheroma in the carotid sinus region can impair the sensitivity of baroreceptors,8 and this impairment seems to be greater in patients with stiffer, more echogenic carotid plaques.9 However, it is currently unclear whether such sBRS deterioration after CEA correlates with the echogenicity of the removed carotid plaque. sBRS index is a significant and reliable clinical marker for cardiovascular morbidity and mortality. Specifically, a decreased sBRS index has been associated with enhanced sympathetic activity, increased coronary vasoconstriction, platelet aggregation, impaired ventricular remodeling, and life-threatening arrythmias. In such a perspective, determining possible factors affecting sBRS may be of potential 1591

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Table. Comparison of demographic and clinical characteristics between the two study groups Demographics/clinical characteristics Age (years) Men Obesity Diabetes mellitus History of heart infarct Hypertension Smoking Symptomatic stenosis Contralateral carotid stenosis ⬎70% Statins

Echolucent plaques (n ⫽ 20)

Echogenic plaques (n ⫽ 31)

P value

69.2 12 (60%) 3 (15%) 12 (60%) 8 (40%) 14 (70%) 13 (65%) 13 (65%) 6 (30%) 16 (80%)

67.4 19 (61.2%) 5 (16.1%) 6 (19.3%) 12 (38.7%) 21 (67.7%) 20 (64.5%) 7 (22.5%) 7 (22.5%) 24 (77.4%)

P ⫽ .4 (NS), (ISTT) P ⫽ .9 (NS), (x2) P ⫽ .9 (NS), (FET) P ⬍ .004, (x2) P ⫽ .9 (NS), (x2) P ⫽ .8 (NS), (FET) P ⫽ 1 (NS), (x2) (x2), P ⬍ .003 P ⫽ .5 (NS), (x2) P ⫽ .82 (NS), (x2)

FET, Fisher exact test; ISTT, independent samples t-test; NS, nonsignificant.

clinical significance. In this study, we investigated whether carotid plaque echogenicity correlates with the postoperative values of sBRS following carotid endarterectomy. This could be valuable clinical information allowing us to predict the postoperative cardiovascular risk according to the echogenicity of the plaque. METHODS Fifty-six patients undergoing elective CEA were included in this study, following approval of the study protocol by our institution’s ethics committee. Written informed consent was obtained from all subjects. All patients had carotid stenosis of 70% to 99%, as measured by digital subtraction angiography and calculated according to the North American Symptomatic Carotid Endarterectomy Trial1 criteria. Exclusion criteria have been previously described.9 Briefly, patients with cardiac rhythm disorders, heart failure, previous carotid endarterectomy or angioplasty, carotid dissection, carotid occlusion, and hemorrhagic stroke were not included in our cohort. More specifically, five patients were excluded from the study (one with cardiac rhythm disorder, one with a previous carotid angioplasty, and three with an inaccurate analysis of the electrocardiographic signal during the measurement of sBRS). Thus, a total of 51 patients (31 male; mean age, 68.8 years; range, 44-81 years) were finally evaluated. The demographic and clinical characteristics of the patients of the two groups are shown in the Table. Factors that could affect sBRS, such as age, myocardial ischemia, diabetes, obesity, history of stroke, end-stage renal disease, and depression,10 were recorded, and if a significant difference was identified between the two study groups, they were controlled as covariates in the comparative statistical analysis. Medications known to increase sBRS, such as neuroleptics, angiotensin receptor-1 blockers, angiotensinconverting-enzyme inhibitors, diuretics, and nitroglycerine, were stopped for 24 hours before the preoperative testing.11,12 The same was done for agents like ␤-blockers and calcium channel blockers, in order to avoid a possible autonomic interference, despite the fact that these specific agents are not always considered responsible for altering

sBRS.13,14 To avoid the possible effect of intraoperative or postoperative use of vasoactive or cardioactive drugs, the first sBRS calculation was performed 24 hours after the procedure and each measurement was performed 3 hours after the last routine administration of the postoperative medication. No routine antihypertensive drug was given if the systolic blood pressure (SBP) was lower than 100 mm Hg. sBRS value calculation was achieved by simultaneous, continuous recordings of heart rate (via electrocardiography) and arterial pressure (via a radial tonometer, CBM 7000; Colins Medical Instruments Corp, San Antonio, Tex), for a period of 20 minutes. All patients were examined in the supine position under standardized conditions, at 8:00 am, after an 8-hour overnight fast, in a quiet room with stable temperature (22-24°C). The radial tonometer, via a validated generalized transfer function, enabled the calculation of the aortic blood pressure waveform from the radial artery waveform15 and, therefore, systolic arterial pressure (SAP), diastolic arterial pressure, and electrocardiography signals were digitized for storage and analysis by the BaroCor System (AtCor Medical, Sydney, Australia). This computer system, using appropriate software (BaroCor System Software, AtCor Medical), calculated sBRS by detecting and analyzing spontaneous oscillations in blood pressure and RR intervals, applying the principles of sequence method. Sequence method is based on the identification of progressive increases or decreases in SBP, followed by corresponding, progressive lengthening or shortening of RR intervals, in at least three consecutive heart beats. A linear regression was applied to each selected sequence and the mean slope (sBRS index) was calculated as the average of all slopes recorded during the 20-minute period.9 We estimated the sBRS values in three different times: 24 hours before endarterectomy (T0), as well as 24 and 48 hours postoperatively (T24 and T48, respectively). Duplex ultrasonography for assessment of carotid plaque echogenicity was performed, as previously described,9 according to a standardized ultrasound protocol that lowers interobserver variability.16 To increase precision in plaque visualization, the Speckle Reduction Imaging technique was utilized.17 Ultrasound scans were per-

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formed by two independent physicians with more than 10 years’ experience in carotid artery ultrasound. Both physicians were blinded to the clinical data, and their results were compared also blindly. Intra- and interobserver agreement were assessed to test the reproducibility of carotid plaque grading scale. Patients were divided into two groups according to plaque echogenicity: group A (plaques of grades 1 and 2) and group B (plaques of grade 3 and 4). Standardized general anesthesia, using sevoflurane, was performed in all patients. After routine exposure and heparinization, clamps were applied to the common, external, and internal carotid arteries. A longitudinal arteriotomy was performed along the diseased length of the common and internal carotid arteries. The exposure of the carotid bifurcation and the surrounding area of carotid sinus was performed very carefully, to minimize a potential hemodynamic instability caused by surgical dissection. An intraluminal shunt (Argyle; Sherwood Medical, St. Louis, Mo) was routinely placed in all cases to maintain adequate perfusion to the brain, and all arteriotomies were closed using a venous (great saphenous) patch. Hemodynamic instability, during or after CEA, was defined as hypotension, if SBP was ⬍90 mm Hg and/or bradycardia, if the heart rate was ⬍60 beats per min. Postoperative hypertension was defined as an elevation in SBP of ⬎160 mm Hg or a ⬎40% rise above normal, requiring pharmacologic management. In all patients, first treatment choice for either acute or sustained postoperative hypertension was atenolol, (either intravenously or orally), in an effort to treat the two groups in a similar way and, additionally, to minimize sBRS alteration.14 For statistical analysis, the package SPSS for Windows, release 12 (SPSS, Chicago, Ill) was used. Comparisons between the two groups were performed with either the independent samples t test and the ␹2 or Fisher exact test, accordingly. The comparison of all measured parameters, before and after the procedure, were performed either with the nonparametric Friedman test or the repeated measures analysis of variance test, appropriately. A comparison of pairs was also performed, with the Wilcoxon test, where two pairs of mean values were compared (T0-T24 and T0-T48, respectively). Groups A and B at the specific moments T0, T24, and T48, were compared with the analysis of covariance test, and finally, the change of hemodynamic parameters in the two groups, during the whole period of the study, from the first (T0) to the last (T48) measurement, were evaluated with the mixed multivariate analysis of covariance test. For the assessment of inter- and intraobserver agreement, ␬ statistics was used expressed as ␬ ⫾ SE. RESULTS Twenty patients (39.2%) were found to have echolucent plaques and the remaining 31 (60.8%) echogenic plaques. Intraobserver reproducibility for plaque echogenicity characterization was very good for both observers, as indicated by ␬ values (␬ ⫽ .96 ⫾ .04 for observer 1 and ␬ ⫽ .919 ⫾ .56 for observer 2). Interobserver agreement was

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also high (␬ ⫽ of .92 ⫾ .06). Forty-five patients (88% of the cohort) had a contralateral atherosclerotic plaque (13 patients had contralateral stenosis ⬎70%), 32 patients had a mild contralateral stenosis within a range between 30% and 50%, and only six patients (12% of the cohort) did not have any atherosclerotic plaque on the contralateral side. Postoperative mean SAP values at 24 and 48 hours (143.2 and 135.5 mm Hg, respectively) were found to be significantly increased compared to the preoperative value (132.5 mm Hg; x2 ⫽ 32, P ⬍ .001). Similar results were obtained by comparing separate pairs of SAP values, between T0 and T24, as well as between T0 and T48, using the Wilcoxon test (z ⫽ ⫺3.7, P ⬍ .001 and z ⫽ ⫺2.7, P ⬍ .001, for the pair T0-T24 and T0-T48, respectively; Fig 1, A). Similarly, the mean sBRS value was significantly reduced from a mean value of 3.7 ms mm Hg⫺1 preoperatively to 2.1 ms mm Hg⫺1 postoperatively; this alteration was independent of plaque echogenicity, as shown both with Friedman (x2 ⫽ 32.6, P ⬍ .001) and Wilcoxon test (z ⫽ ⫺4, P ⬍ .001; Fig 1, B). It should be noted that, in seven out of 51 patients of our cohort, the postoperative sBRS did not change significantly postoperatively. The percentage of patients with a history of diabetes mellitus was higher in the echolucent (60%) compared with the echogenic group (19.3%, x2 ⫽ 8.7, P ⬍ .004), while the rate of symptomatic plaques was significantly higher in the echolucent group (65% vs 22.5%, x2 ⫽ 9.1, P ⬍ .003; Table). To control for these differences, we used statistical tests of covariance (analysis of covariance), and we found that preoperatively, the mean sBRS value in the echogenic group (2.8 ms mm Hg⫺1) was significantly lower than the mean value in the echolucent group (5.0 ms mm Hg⫺1), (F [1,51] ⫽ 11, P ⬍ .003). However, at T24 and T48, no statistically significant difference was found between the mean sBRS values of the two groups (F [1,51] ⫽ .007, P ⬍ .9 and F [1,51] ⫽ .4, P ⬍ .5 for T24 and T48, respectively). Thus, the difference in baroreflex sensitivity between the two groups did not persist after CEA (Fig 2). Mixed multivariate analysis of covariate also confirmed that the preoperative difference of baroreflex sensitivity in patients with different plaque echogenicity disappears after CEA. This analysis estimated the difference in sBRS values between the two groups, in different time moments, adjusting for the covariates “history of diabetes” and “symptomatic nature of the plaque.” Indeed, sBRS values were found to differ significantly between the two groups, during the whole study period, from T0 (preoperatively), to T48 (postoperatively), and this difference was found to be due to the preoperative differences and not due to postoperative alterations in sBRS (F ⫽ 5.6, P ⬍ .007). All other hemodynamic factors (SAP, diastolic arterial pressure, heart rate) were similarly tested, and no significant differences were found between the two groups. During carotid dissection, five patients (two in the echolucent group and three in the echogenic group) suffered hemodynamic instability. Two of the five patients had both hypotension and bradycardia, two had only bradycardia, and one had only hypotension. Postoperatively, 2

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echogenic group did not have a history of hypertension and were not on antihypertensive treatment. DISCUSSION

Fig 1. Box plot diagram reflecting mean systolic arterial blood pressure (A), and mean spontaneous baroreflex sensitivity (sBRS) value (B) at the three study periods (before the procedure [T0], and 24 and 48 hours postoperatively [T24 and T48, respectively]), in all patients, regardless of their plaque echogenicity. It shows graphically the postoperative increase of mean arterial blood pressure and the respective decrease of sBRS, after the carotid endarterectomy. The distance between the upper and lower sides of each box represents the distance between the 25th and 75th percentile (interquartile range). Outside values, which are represented as circles in this figure, are defined as the values that are 1.5 to 3.0 times smaller than the lower quartile, or 1.5 to 3.0 times larger than the upper quartile. Far outside values, represented as stars in this figure, are defined as those values that are either more than 3.0 times larger than the upper quartile, or more than 3.0 times smaller than the lower quartile. The number accompanying the circles or the star reflect the specific patient (n ⫽ 1-51) from our database (51 patients in total) with an outlier value. In A, 24 hours after the procedure, two different patients (n ⫽ 34 and n ⫽ 40) had the same outlier value of systolic arterial blood pressure, so, there is just one circle representing that same value. SAP, Systolic arterial pressure.

patients out of 14 (14%) from the echolucent group and 3 out of 21 (14%) from the echogenic group, who were on antihypertensive treatment, did not receive a routine dose, due to an SBP ⬍100 mm Hg. Finally, nine patients from the echolucent group (45%) and 15 from the echogenic group (48%) required extra antihypertensive medication (atenolol) for treating refractory hypertension. Two out of nine from the echolucent group and 4 out of 15 from the

sBRS index is a significant and reliable clinical marker for cardiovascular morbidity and mortality.18,19 A decreased sBRS index has been shown to be associated with increased sympathetic activity, which can lead to increased coronary vasoconstriction, platelet aggregation, impaired ventricular remodeling, and, more importantly, to lifethreatening arrythmias.20-22 Previous studies have also demonstrated that sBRS is not only impaired in patients with either unilateral or bilateral carotid disease,23,24 but also in patients after CEA.6,7,25 In such a perspective, determining possible factors affecting sBRS may be of potential clinical significance. Previously, we have shown that plaque echogenicity can determine the sensitivity of baroreceptors, and that patients with echogenic plaques have a significantly lower sBRS value compared with patients with echolucent ones.9 In this study, we investigated whether plaque echogenicity correlates also with the postoperative values of sBRS following CEA. A noninvasive method of estimating sBRS was performed based on central blood pressure changes, which were recorded indirectly from radial artery readings. This method has been previously described9 and is considered to be more accurate compared with others, which are based on blood pressure changes measured in the peripheral arteries.24 Moreover, the sequence method we used to calculate sBRS has significant advantages regarding reproducibility, due to the fact that all computations are automatic and standardized. So, intra- and intersubject measurement variability is virtually eliminated.4 Additionally, all patients were examined under standardized conditions regarding timing, medications, diet, and environmental conditions. It is the first time estimating sBRS with this specific way in patients undergoing carotid surgery. The present study confirmed our previous finding of preoperative sBRS correlation with plaque echogenicity in a slightly larger cohort of patients. Additionally, it was shown that, following CEA, the mean sBRS value is the same in both groups irrespective of the echogenicity of the removed plaque. Thus, the preoperative difference in baroreceptors’ function, between patients with different plaque echogenicity, does not persist after removal of the atheroma. To our knowledge, there is no similar study in the literature correlating plaque echogenicity with postoperative baroreflex function after CEA. The above two findings are biologically reasonable and in accordance with each other. Indeed, the herein reported finding of postoperative elimination of sBRS value differences between patients with different plaque echogenicity strongly supports our previous conclusion that plaque echogenicity is an sBRS determinant in patients with significant carotid disease. In other words, the procedure of CEA seems to abolish the role of “plaque echogenicity” as a differentiation factor between the two study groups and,

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sBRS-T0

10

sBRS-T24 sBRS-T48

8

6 40

6

4

2

0

Echolucent

Echogenic

Plaque Fig 2. Box plot diagram reflecting the mean spontaneous baroreflex sensitivity (sBRS) values in the two study groups at the three different measurements of the study (before the procedure [T0], and 24 and 48 hours postoperatively [T24 and T48, respectively]). It shows graphically a significant difference of the mean sBRS value, between the two study groups, only during the first measurement (T0), but not during the subsequent postoperative measurements (T24 and T48). Outside values are represented with circles and far outside values are represented with stars.

thus, similar baroreceptors’ function can be expected postoperatively in all patients irrespective of their preoperative plaque characteristics. Moreover, our study indicates that CEA is associated with a deterioration of baroreflex sensitivity, at least for 48 hours. This deterioration was found to be independent of plaque echogenicity. Additionally, sBRS values were found to be decreased in both echolucent and echogenic plaques. The difference between the two groups was that the deterioration of sBRS was less in echogenic plaques than in echolucent plaques. A significant increase of mean SAP after CEA, which, however, was not accompanied by a significant change of heart rate, implies baroreflex dysfunction and is consistent with our results regarding sBRS. The impairment of sBRS after CEA could be explained by the denervation of the baroreceptor nerve fibers within the artery wall during endarterectomy.6,26 Several studies in the literature, both in animals27 and humans,6,25,28 support postoperative dysfunction of baroreceptors in the carotid sinus area. The duration of this phenomenon varies among different series and can last from hours up to years.6,28 Despite the above studies, controversy exists in the literature regarding sBRS after CEA. Other studies have reported stable or even increased BRS after plaque removal.29-31 In these studies, hypotension is the principal postoperative change in blood pressure, and an improvement in carotid wall stiffness seems to be responsible for

this phenomenon.31 Based on this mechanism, one could expect that the removal of an echogenic carotid plaque could lead in a greater improvement of sBRS compared with a removal of an echolucent plaque, because of the likely greater improvement of carotid wall stiffness in patients of the echogenic group. The smaller impairment of sBRS in patients of the echogenic group could be explained by the simultaneous action of the two above contrasting mechanisms (neural damage and stiffness improvement). It has been shown that endarterectomy does not destroy all neural fibers, which are involved in the baroreflex response,32 and the remaining functional baroreceptors preserve their ability to respond to blood pressure changes, eliciting an appropriate baroreflex response. A partial and not a complete destruction of baroreceptors after CEA can justify the presence of both the above contrasting mechanisms. The first mechanism (neural damage) is probably the same in the two study groups, because the technique of endarterectomy is always the same and independent of the type of the removed plaque. The factor that seems to change between the two groups after CEA is the second mechanism, the improvement in carotid wall distensibility. A possible greater improvement in carotid distensibility, in the echogenic group after CEA, could explain the smaller impairment of sBRS compared with the echolucent group. In other words, it seems that before CEA, carotid stiffness may play a role in the baroreceptors’ function, but

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after CEA, the neural damage in the carotid wall does not let a possible improvement of sBRS be expressed to the fullest extent. Our results imply that the destructive effect of endarterectomy might be smaller in the echogenic group, because of the higher improvement in distensibility, after the plaque removal, due to the action of the remaining functional baroreceptors. Possibly, neural damage plays a stronger role than distensibility after CEA, but certainly, larger studies investigating also carotid wall stiffness are needed to further clarify this issue. Interestingly, a subset of seven patients, without significant postoperative change in sBRS, was identified in this study. Five of these patients (71.4%) had only ipsilateral carotid atherosclerosis, while the respective ratio among patients with postoperative sBRS alteration was 2.3%. This finding could be explained by a possible compensation of the intact contralateral baroreceptors, which become overactive after the removal of ipsilateral atheroma and do not let the overall baroreflex sensitivity decrease.24 Hemodynamic instability occurs frequently during carotid CEA, most commonly before the arteriotomy, due to general anesthesia, surgical manipulation of the carotid sinus, alterations in renin-angiotensin system, vasopressin concentrations, central cathecholaminergic activity, or the presence of the atheroma itself.33 Such events can be treated with carotid sinus nerve injection of lidocaine or intavenous administration of atropine or other vasoactive drugs. In this patient cohort, we avoided the use of such agents, so as to eliminate the possibility of postoperative sBRS impairment. Instead, we managed the intraoperative hemodynamic instability events conservatively, with intravenous fluids administration and a short pause of manipulations on the carotid sinus, when bradycardia was noticed. A potential factor that could affect baroreflex sensitivity after CEA is any period of severe cerebral ischemia during the procedure. Indeed, it is well established, in both animal and patient studies with chronic cerebrovascular disease,34-37 that cerebral ischemia can lead to impairment of central autoregulation mechanisms and alteration of the baroreceptor response. To preclude such a possibility in our study, we performed routine endoluminal shunting in all patients, to ensure avoidance of any severe brain hypoperfusion.38 Administration of vasoactive or cardioactive agents can affect baroreflex sensitivity and thus could have influenced our results. Indeed, some antihypertensive agents can increase sBRS,11,12 while other drugs, such as ␤-blockers or calcium channel blockers, do not always alter it.13,14 More specifically, it seems that atenolol can cause an acute decrease in SBP and an analog increase in RR intervals, without any change in sBRS, indicating just a “resetting” of baroreflex function.14 To control for the administration of vasoactive agents preoperatively, we discontinued them for 24 hours prior to sBRS measurement. Moreover, the percentage of hypertensive patients and the type of the specific antihypertensive drugs were similar in both groups. Thus, antihypertensive medications were not considered responsible for preopera-

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tive sBRS differences in our comparative analysis. Unfortunately, we could not discontinue these drugs, intraoperatively, for obvious ethical reasons. To control for such an effect, the first postoperative calculation of sBRS was performed 24 hours after CEA. Regarding the postoperative use of vasoactive drugs, we found that the number of patients on antihypertensive therapy who did not take a routine dose of their medication due to hypotension and the number of patients who needed extra vasoactive drugs to control their blood pressure was similar between the two study groups. Thus, these parameters, as statistical variables, would be mutually exclusive in the comparative group analysis. Besides, the same standardized agent was used in all patients (atenolol) as first line treatment of postoperative hypertension, not only for treating the two groups in a similar way, but also because beta blockers usually do not alter sBRS.14 We believe that, taking into account the above parameters, we achieved a good control of all vasoactive agents as cofounders, but certainly, this issue remains the main limitation of our study. One could argue that the ultrasonographic results regarding carotid plaque echogenicity were not verified either by intraoperative intravascular ultrasound or postoperative histologic examination of the plaque in this study. Although such a verification could be useful, it should be noted that plaque echogenicity was assessed with a standardized ultrasound protocol that lowers interobserver variability16 by two independent observers with more than 10 years’ experience in carotid ultrasound imaging, with very good inter- and intraobserver agreement as shown in the results. Besides, plaque echogenicity was assessed using Speckle Reduction Imaging Ultrasound, a technique that improves significantly image quality, thus offering a more precise and objective visualization of carotid plaque echogenicity and enhancing reproducibility of the method.17 In conclusion, the present study shows that CEA results in an sBRS reduction, probably due to the prevailing effect of carotid sinus denervation compared with a possible gain in carotid wall distensibility during the procedure. Moreover, plaque echogenicity may not predict postoperative hemodynamic stress, since postoperative sBRS is unrelated to plaque characteristics. It seems that the role of plaque echogenicity on preoperative sBRS ceases with the removal of the carotid plaque. AUTHOR CONTRIBUTIONS Conception and design: NT, IS, SG, CK, CB Analysis and interpretation: NT, AK, IS, EB, CK, ET Data collection: NT, IS, CB Writing the article: NT, AK Critical revision of the article: NT, AK, IS, EB, SG, CK, CB, ET Final approval of the article: NT, AK, IS, EB, SG, CK, CB, ET Statistical analysis: NT, AK, EB, SG Obtained funding: Not applicable Overall responsibility: NT

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