Gender-associated differences in plaque phenotype of patients undergoing carotid endarterectomy
Article Outline
- Abstract
- Patients and methods
- Results
- Discussion
- Conclusion
- Author contributions
- Acknowledgment
- References
- Copyright
Background
Carotid endarterectomy to prevent a stroke is less beneficial for women compared with men. This benefit is lower in asymptomatic women compared with asymptomatic men or symptomatic patients. A possible explanation for this gender-associated difference in outcome could be found in the atherosclerotic carotid plaque phenotype. We hypothesize that women, especially asymptomatic women, have more stable plaques than men, resulting in a decreased benefit of surgical plaque removal.
Methods
Carotid endarterectomy specimens of 450 consecutive patients (135 women, 315 men) were studied. The culprit lesions were semi-quantitatively analyzed for the presence of macrophages, smooth muscle cells, collagen, calcifications, and luminal thrombus. Plaques were categorized in three phenotypes according to overall presentation and the amount of fat. Protein was isolated from the plaques for determination of interleukin-6 (IL-6) and IL-8 concentrations and matrix metalloproteinase-8 (MMP-8) and MMP-9 activities.
Results
Atheromatous plaques (>40% fat) were less frequently observed in women than in men (22% vs 40%; P < .001). In addition, plaques obtained from women more frequently revealed low macrophage staining (11% vs 18%; P = .05) and strong smooth muscle cell staining (38% vs 24%; P = .001). Compared with men, women had a lower plaque concentration of IL-8 (P = .001) and lower MMP-8 activity (P = .01). The observed differences were most pronounced in asymptomatic women, who showed the most stable plaques, with an atheromatous plaque in only 9% of cases compared with 39% in asymptomatic men (P = .02). In addition, a large proportion of plaques obtained from asymptomatic women showed high smooth muscle cell content (53% vs 30%; P = .03) and high collagen content (55% vs 24%; P = .003). All relations between gender and plaque characteristics, except for MMP-8, remained intact in a multivariate analysis, including clinical presentation and other cardiovascular risk factors.
Conclusion
Carotid artery plaques obtained from women have a more stable, less inflammatory phenotype compared with men, independent of clinical presentation and cardiovascular risk profile. Asymptomatic women demonstrate the highest prevalence of stable plaques. These findings could explain why women benefit less from carotid endarterectomy compared with men.
Carotid endarterectomy (CEA) reduces the risk of stroke in both symptomatic and asymptomatic patients with high-grade carotid artery stenosis. The benefit of the operation in terms of stroke reduction differs among patient subgroups. Gender is a major determinant of the long-term outcome after carotid surgery.
It has been well established that CEA is more beneficial for men than for women. Carotid plaque associated stroke risk in patients on best medical treatment is higher in men than in women. After carotid surgery, stroke risk is reduced to comparable levels for both sexes, resulting in a larger reduction of stroke risk in men.1, 2, 3 This gender difference in outcome after CEA is evident in symptomatic and asymptomatic patients. Randomized trials suggest that although asymptomatic women still benefit from CEA, their benefit is smaller compared with asymptomatic men or symptomatic patients.1, 2, 4
Our understanding of these gender differences is incomplete. Different hypotheses have been raised that might account for the observed differences in outcome after carotid endarterectomy between men and women. Duplex analyses of the carotid artery before surgery have demonstrated that plaque volume is larger in men than in women at a comparable stenosis grade and that the plaque size is a predictor of clinical outcome.5 Effects of hormones on atherosclerosis are becoming better known with increasing research,6 but no direct pathophysiologic link has been recognized between hormones and outcome of carotid surgery.
The observed clinical differences may also be a direct reflection of carotid plaque characteristics. If women have plaques that are less prone to cause a stroke owing to distal embolization, then removal of such a plaque would be less beneficial. In coronary circulation, certain plaque characteristics are strongly associated with unstable clinical presentation. The vulnerable plaque that gives rise to myocardial infarction or unstable angina is defined as a plaque with high fat content, low structural components (thin fibrous cap, low smooth muscle cell and collagen content), high inflammatory cell content, and increased protease activity.7, 8, 9
Recent large studies of endarterectomy specimens have shown that the pathophysiology of carotid artery disease is very similar to coronary artery disease. The vulnerable plaque characteristics known from coronary circulation have been linked to symptomatic presentation of carotid artery disease.10, 11, 12 In addition, the association between plaque destabilization and matrix metalloproteinase-8 (MMP-8) and MMP-9 activity in carotid artery plaques has been reported.13, 14
In this study we hypothesized that women who have been diagnosed with hemodynamically significant atherosclerotic carotid artery disease have more stable carotid plaques than men and that this is especially evident in women who are asymptomatic. This could explain the observation that CEA is less beneficial in women.
Patients and methods
Athero-Express biobank
The Athero-Express is an ongoing longitudinal biobank study with the objective of studying the relation between plaque characteristics and the occurrence of future cardiovascular events.15 All patients undergoing CEA in two participating Dutch hospitals are asked to participate in the study, with an inclusion rate of 94.6%. At baseline, patients complete an extensive questionnaire and blood is drawn and stored at –80°C.
During CEA, the plaque is transferred to the laboratory and processed and stored according to a standardized protocol. After surgery, patients undergo duplex and clinical follow-up. The Medical Ethical Committees of the participating hospitals have approved the study, and all patients provided written informed consent. For the purpose of the current research question, we studied all consecutive patients undergoing CEA who were included in the Athero-Express study between April 2002 and November 2005.
Patient inclusion and preoperative work-up
The indication for CEA was based on the recommendations published by the Asymptomatic Carotid Surgery Trial (ACST) for asymptomatic patients and European Carotid Surgery Trial (ECST)/North American Symptomatic Carotid Endarterectomy Trial for symptomatic patients (NASCET).2, 16, 17, 18 All patients were examined by a neurologist for assessment of their preoperative neurologic status. The percentage of stenosis was determined with duplex ultrasonography, using duplex criteria as described by Strandness et al.19, 20 If the duplex investigation was not conclusive, an additional imaging technique (magnetic resonance angiography, computed tomography angiography, conventional angiography) was used to determine the level of carotid stenosis. Excluded were patients with a terminal malignancy and those who were referred back to a hospital outside The Netherlands immediately after surgery.
Baseline characteristics
Baseline data were obtained by chart review and from extensive questionnaires completed by the participating patients that included questions on history of cardiovascular disease, cardiovascular risk factors (smoking, hypertension, diabetes), and use of medication. Presenting symptoms and duplex stenosis were retrieved from patient charts. Symptom categories were asymptomatic, defined as no carotid territory ischemic symptoms; amaurosis fugax, defined as ipsilateral mono-ocular blindness of acute onset lasting <24 hours; cerebral transient ischemic attack (TIA), defined as ipsilateral focal neurologic deficit of acute onset lasting <24 hours; and ipsilateral stroke. Lipid spectra were determined in blood specimens drawn at baseline.
Carotid endarterectomy
CEA was performed under general anesthesia. Patients received 5000 IU heparin intravenously before cross-clamping. All endarterectomies were performed by an open, noneversion technique, with careful dissection of the bifurcation into the internal and external carotid arteries. The atherosclerotic plaque was immediately transferred to the laboratory after removal.
Plaque processing
The atherosclerotic plaque was dissected into 5-mm segments by a dedicated technician. The segment having the greatest plaque area was defined as the culprit lesion. This segment was fixated in formaldehyde 4%, decalcified for 1 week in ethylenediaminetetraacetic acid, and embedded in paraffin. The other segments were snap frozen in liquid nitrogen and stored at –80°C. Sections of 5-μm thickness were cut on a microtome for immunohistochemical staining.
Plaques were characterized for macrophage content (CD68 staining), smooth muscle cell content (α-actin staining), collagen content (picrosirius red), and extent of calcification (hematoxylin and eosin [H&E] staining) and were analyzed semi-quantitatively and scored as no, minor, moderate, and heavy staining, as reported previously.15 Briefly, no and minor represent absent or minimal staining with few clustered cells, whereas moderate and heavy represent larger areas of positive staining. Presence of luminal thrombus (H&E and elastin van Gieson staining) was scored as absent or present. The percentage of atheroma of the total area of the plaque was visually estimated using the picrosirius red and H&E stains. Three overall phenotypes were considered according to overall presentation and visual estimation of the percentage of atheroma in the plaques: fibrous plaques containing <10% fat, fibroatheromatous, 10% to 40%; or atheromatous, >40% fat.
The scorings were done by observers blinded for patient characteristics. In addition, quantitative measurements were performed for macrophage and smooth muscle cell staining. For this purpose, images of plaque cross-sections were recorded onto a computer workstation using a microscope equipped with a digital camera. The images were captured and analyzed with AnalySIS 3.2 software (Soft Imaging System GmbH, Münster, Germany). The quantification was done as follows: in each plaque, three representative areas were defined and selected in such a way that no media (which was present in the specimen, in most cases) was included. The positive staining in these areas was measured as a percentage of total plaque area using AnalySIS software. The mean of these three measurements was used for further analysis.
Interleukin and matrix metalloproteinase measurements
The segment adjacent to the culprit lesion was used for protein isolation. This frozen segment was mechanically crushed in liquid nitrogen with a pestle and mortar. The protein isolation was done in two ways: (1) by using Tripure reagent (Boehringer Mannheim, Germany), according to the manufacturer’s protocol and (2) by dissolving in 40 mM Tris-HCl (pH, 7.5) at 4°C.
Protein from 301 plaques was available for analysis. Interleukin-6 (IL-6) and IL-8 concentrations were determined in all samples. The measurements were done on the Tris-solated samples using a multiplex suspension array system according to the manufacturer’s protocol (Bio-Rad Laboratories, Hercules, Calif). MMP-8 and MMP-9 activities were measured for a randomly selected group of 133 patients in Tripure isolated protein using Biotrak activity assays RPN 2635 and RPN 2634, respectively (Amersham Biosciences, Buckinghamshire, UK). MMP activities were expressed as an arbitrary unit. All measurements were done by investigators blinded for patient characteristics.
Data analysis
The statistical software SPSS 11.5 (SPSS Inc, Chicago, Ill) was used for data analysis. Continuous baseline variables are given as mean and standard deviation. All plaque measurements are expressed as median and interquartile range. Equal distribution of baseline variables was determined using the χ2 test for discrete variables, the Student’s t test for normally distributed continuous variables and the Mann Whitney U test for nonnormally distributed continuous variables. The Mann Whitney U test was used for comparison of plaque stainings, IL, and MMP levels between men and women and between combined groups according to gender and symptom status. The association between gender and plaque characteristics was adjusted for traditional cardiovascular risk factors, clinical presentation, and all baseline variables showing an association (P < .20) with gender, using multivariate logistic regression. For this purpose ordinal variables were dichotomized into two categories (no/minor staining vs moderate/heavy staining) and continuous variables were dichotomized at the median. Values of P < .05 were considered statistically significant.
Results
A total of 450 carotid plaques were obtained. The baseline characteristics are given in Table I. Clinical presentation was equal for men and women: 25% of women and 22% of men were asymptomatic. Women (n = 135) had higher total cholesterol, accompanied by a higher low-density-lipoprotein cholesterol as well as higher high-density-lipoprotein cholesterol. Use of 3-hydroxy-3-methylglutaryl-coenzyme A (HMG-CoA) reductase inhibitors (statins), aspirin, and oral anticoagulants did not differ between men and women. The other baseline characteristics, including duplex stenosis, were also comparable.
Table I. Baseline characteristics of patients undergoing carotid endarterectomy
| Variable⁎ | Women, n (%) | Men, n (%) | P |
|---|---|---|---|
| Patients (n) | 135 | 315 | |
| Age (year) | 66.2 ± 9.3 | 67.7 ± 8.5 | .09 |
| Hypertension | 100 (74) | 211(67) | .15 |
| Diabetes | 30(22) | 62(20) | .53 |
| Prior intervention | |||
| Vascular | 41(30) | 128(41) | .04† |
| Ipsilateral carotid | 9(7) | 11(4) | .14 |
| Smoking | 41(31) | 76(25) | .20 |
| Hypercholesterolemia | 68(62) | 156(62) | .96 |
| HRT | 6(7) | ||
| Statins | 79(66) | 182(63) | .58 |
| Aspirin | 106(85) | 249(85) | .90 |
| Oral anticoagulation | 17(14) | 48(16) | .46 |
| NSAID | 8(6) | 12(4) | .32 |
| Cholesterol, mmol/L | 5.4 ± 1.1 | 4.9 ± 1.2 | .006† |
| HDL, mmol/L | 1.3 ± 0.36 | 1.1 ± 0.35 | .004† |
| LDL, mmol/L | 3.2 ± 1.0 | 2.9 ± 1.0 | .04† |
| Triglycerides, mmol/L | 2.1 ± 1.2 | 2.1 ± 1.0 | .96 |
| Symptoms | |||
| Asymptomatic | 33(25) | 69(22) | |
| Amaurosis fugax | 18(13) | 45(14) | .91 |
| TIA | 47(35) | 118(38) | |
| Stroke | 37(27) | 83(26) | |
| Duplex stenosis | |||
| 50% to 64% | 3(2) | 9(3) | |
| 65% to 89% | 46(36) | 112(37) | .84 |
| 90% to 100% | 79(62) | 181(60) |
⁎Categoric variables are presented as n (%); continuous variables as mean ± standard deviation. |
†Statistically significant (P < .05). |
The plaques obtained from women demonstrated a more fibrous phenotype compared with those obtained from men. Atheromatous plaques were present in 22% of women compared with 40% of men (P < .001; Table II). In 38% of women, a heavy smooth muscle cell staining was present, compared with 24% in men (P = .001). Heavy macrophage staining was found in 14% of women compared with 21% in men (P = .05). Luminal thrombus, calcifications, and collagen staining did not differ consistently between men and women. Assessment of lipid spectra in relation to overall plaque phenotype did not reveal any associations (data not shown).
Table II. Comparison of carotid plaque histology between men and women
| Women⁎ (%) | Men⁎ (%) | P (univariate) | P (multivariate)† | |
|---|---|---|---|---|
| Overall phenotype (semi-quantitative) | <.001‡ | .006‡ | ||
| Fibrous | 40.7 | 24.4 | ||
| Fibroatheromatous | 37.8 | 35.2 | ||
| Atheromatous | 21.5 | 40.3 | ||
| Luminal thrombus | .26 | .45 | ||
| No | 77.0 | 70.6 | ||
| Yes | 23.0 | 29.4 | ||
| Macrophages (semi-quantitative) | .05† | .20 | ||
| No | 18 | 10.6 | ||
| Minor | 31.6 | 33.2 | ||
| Moderate | 36.8 | 35.2 | ||
| Heavy | 13.5 | 21 | ||
| Macrophages (quantitative) | .12 | .36 | ||
| Median area % | 0.26 | 0.39 | ||
| IQR | (0.08-0.95) | (0.07-1.30) | ||
| SMC (semi-quantitative) | .001‡ | .01‡ | ||
| No | 0.8 | 1.9 | ||
| Minor | 20.3 | 32.9 | ||
| Moderate | 41.4 | 41.9 | ||
| Heavy | 37.6 | 24.2 | ||
| SMC (quantitative) | .03‡ | .03‡ | ||
| Median area % | 2.27 | 1.62 | ||
| IQR | (0.86-4.35) | (0.47-3.58) | ||
| Collagen (semi-quantitative) | .08 | .39 | ||
| No | 0.0 | 0.3 | ||
| Minor | 19.4 | 22.6 | ||
| Moderate | 53.0 | 57.6 | ||
| Heavy | 27.6 | 19.4 | ||
| Calcifications (semi-quantitative) | .41 | .88 | ||
| No | 29.6 | 25.7 | ||
| Minor | 15.6 | 24.8 | ||
| Moderate | 28.9 | 31.1 | ||
| Heavy | 25.9 | 18.4 |
⁎Data presented as percentage or median (IQR), as noted. |
†Adjusted for symptom status, age, hypertension, diabetes, smoking, prior vascular intervention, prior ipsilateral carotid intervention, and cholesterol levels. |
‡Statistically significant (P < .05). |
Plaque characteristics were compared between men and women within the symptom groups (asymptomatic vs TIA/stroke). This analysis shows that differences in plaque characteristics were comparable or even more evident in asymptomatic male and female patients (Fig). Plaque overall phenotype was more atheromatous in asymptomatic men than in asymptomatic women. Atheromatous plaques were found in 9% of asymptomatic women compared with 39% of asymptomatic men (P = .02) and 44% of symptomatic men (P < .001). This difference was also evident but less prominent when symptomatic women were compared with symptomatic men (27% vs 44%; P = .003).
Fig.
Comparison of carotid plaque histology between men and women, subdivided by symptom status: asymptomatic vs transient ischemic attack/stroke (TIA). A, Plaque overall phenotype. B, Luminal thrombus. C, Macrophages. D, Smooth muscle cells. E, Collagen. F, Calcification. *P < .05.
Smooth muscle cell staining also revealed strong differences within the asymptomatic group. High staining for smooth muscle cells was observed in 53% of asymptomatic women compared with 30% of asymptomatic men (P = .03) and 20% of symptomatic men (P < .001). High collagen staining was present in 53% of asymptomatic women compared with 22% of asymptomatic men (P = .003) and 15% of symptomatic men (P < .001). No gender-related difference in collagen staining was observed in the symptomatic patient group. Macrophage staining was not significantly different between men and women within the asymptomatic or symptomatic patient group.
The differences in plaque histology between men and women were paralleled by the inflammatory and protease activity in atherosclerotic plaques (Table III). Women showed lower values of the proinflammatory cytokine IL-8 compared with men (25.9 vs 51.3 pg/mL; P = .001). Levels of proinflammatory cytokine IL-6 were not different between men and women. Protease activity was lower in women, with MMP-8 showing significantly lower values than in men (4.2 vs 7.1; P = .01), whereas MMP-9 activity was lower without reaching statistical significance (1.6 vs 2.6; P = .07). These differences were still present when men and women were subdivided into symptomatic and asymptomatic groups (Table IV). Asymptomatic women showed lower levels of interleukins and MMPs compared with the other groups: IL-8 levels (14.1 vs 83.3 pg/mL; P < .001), MMP-8 activity (2.6 vs 9.2; P = .003), and MMP-9 activity (1.1 vs 2.9; P = .002) were significantly decreased compared with symptomatic men.
Table III. Interleukin and matrix metalloproteinase measurements in the plaque compared between men and women
| Women | Men | P (univariate) | P (multivariate)⁎ | |
|---|---|---|---|---|
| IL-6 | .2 | .89 | ||
| Median | 6.7 | 8.8 | ||
| IQR | 0.5-21.1 | 3.6-19.3 | ||
| IL-8 | .001† | .01† | ||
| Median | 25.9 | 51.3 | ||
| IQR | 0-59.3 | 8.8-147.4 | ||
| MMP-8 | .01† | .34 | ||
| Median | 4.2 | 7.1 | ||
| IQR | 1.2-8.1 | 3.7-11.4 | ||
| MMP-9 | .07 | .42 | ||
| Median | 1.6 | 2.6 | ||
| IQR | 0.9-3.1 | 0.8-6.4 |
⁎Adjusted for symptom status, age, hypertension, diabetes, smoking, prior vascular intervention, prior ipsilateral carotid intervention, and cholesterol levels. |
†Statistically significant (P < .05). |
Table IV. Interleukin and matrix metalloproteinase measurements in the plaque compared between men and women, subdivided by symptom status
| 1 Asymptomatic women | 2 Asymptomatic Men | 3 Symptomatic women | 4 Symptomatic Men | 1 vs 2 | 3 vs 4 | 1 vs 4 | |
|---|---|---|---|---|---|---|---|
| IL-6 | .81 | .56 | .23 | ||||
| Median | 6.3 | 7.9 | 11.0 | 10.3 | |||
| IQR | 1.6-23.4 | 3.6-12.0 | 1.0-23.8 | 3.9-23.8 | |||
| IL-8 | .18 | .01⁎ | <.001⁎ | ||||
| Median | 14.1 | 17.2 | 41.9 | 83.3 | |||
| IQR | 0-31.6 | 0.5-53.6 | 7.5-90.8 | 25.6-178.7 | |||
| MMP-8 | .18 | .04⁎ | .003⁎ | ||||
| Median | 2.6 | 5.0 | 5.7 | 9.2 | |||
| IQR | 0-6.6 | 2.5-8.5 | 2.1-8.8 | 4.5-12.7 | |||
| MMP-9 | .19 | .12 | .002⁎ | ||||
| Median | 1.1 | 1.4 | 1.7 | 2.9 | |||
| IQR | 0.3-2.7 | 0.4-3.6 | 1.0-3.7 | 1.2-7.0 |
⁎Statistically significant (P < .05). |
All associations between gender and plaque phenotype, except MMP-8, which were significant in univariate analysis, were also significant when adjusting for symptom status, age, hypertension, diabetes, smoking, prior vascular intervention, prior ipsilateral carotid intervention, and cholesterol levels. This suggests that the observed gender-associated differences in plaque characteristics are not caused by differences in cardiovascular risk factors or clinical presentation.
Discussion
The main finding of this study is that women undergoing CEA have more stable plaques compared with men. Plaques obtained from women contain less fat and macrophages and more smooth muscle cells. This is accompanied by lower IL-8 content and lower MMP-8 activity.
It has been recognized that histologic plaque characteristics are related to the clinical presentation of atherosclerotic coronary and carotid artery disease. To our knowledge, no study has reported on gender differences in carotid plaque phenotype, probably because of the number of patients required. In coronary artery disease, gender-associated differences in plaque morphology have been described that point to a higher prevalence of fresh thrombus and plaque rupture in men.21, 22 These studies did not, however, specifically address gender-related differences in plaque phenotype but focused on changes in plaque morphology in relation to clinical syndromes like acute myocardial infarction or coronary death.
Our present study indicates that women operated on for carotid artery disease show more stable atherosclerotic plaques than men. These results suggest that not just plaque volume but also plaque phenotype may be associated with adverse outcomes. Iemolo et al5 found that outward remodeling of the carotid artery was more evident in men than in women. This outward remodeling was predictive of stroke and other cardiovascular events. Outward remodeling has previously been associated with unstable plaque characteristics, rendering the results from Iemolo et al very consistent with ours.23
IL-8 was significantly higher in men compared with women, but IL-6 showed no statistically significant difference. Most reduced levels of both cytokines were observed in the asymptomatic women. Both proinflammatory cytokines can be produced by a variety of cells within the atherosclerotic plaque and play an important role in atherosclerosis.24 It remains to be elucidated whether a differential effect exists between IL-6 and IL-8, which could explain the fact that IL-8 has a stronger relation to gender and plaque instability than IL-6.
In the current study, women showed significantly lower MMP-8 activity in their plaques than did men. MMP-9 was lower in asymptomatic women compared with symptomatic men. Experimental models and previous human endarterectomy series have shown that the presence of these MMPs contributes to plaque instability.13, 14 MMPs are important in cell migration, degradation of the fibrous cap, expansive remodeling, and intraplaque neovessel formation.25 Their production can be directly inhibited by statins.26
To our knowledge, no gender differences in MMP activity have been described in human atherosclerotic disease before. Two studies on rat aortas show higher MMP-9 production in male rat aortas compared with females, which could be partially reversed by estrogen treatment or transplantation of the artery into a female rat.27, 28 This suggests that there may be a direct effect of sex hormones on MMP production contributing to attenuation of atherosclerotic disease in females. It is difficult to extrapolate these findings to our population because most of the women in our study cohort are postmenopausal. The observed differences in plaque phenotype could be due to estrogen exposure earlier in life resulting in a more stable plaque phenotype with inherent lower MMP-8 and MMP-9 activity compared with unstable plaques.
The gender-related differences we observed in plaque histology, inflammation, and protease activity were evident within all symptom categories. Therefore, the gender differences cannot merely be explained by different clinical presentation of the carotid artery disease; neither can they be attributed to differences in cardiovascular risk profiles, because all associations between gender and plaque characteristics, except MMP-8, remained intact when correcting for cardiovascular risk factors. The differences are most pronounced in the asymptomatic group: Among asymptomatic women, the prevalence of stable plaques is very high. Although speculative, one of the reasons for the large differences within the asymptomatic group compared with the symptomatic group is that when a plaque becomes symptomatic, some features have already changed, both in men and women. The asymptomatic group probably better represents the true gender-associated differences in plaque phenotype. Nevertheless, we also found gender-associated differences in the symptomatic patient group.
The more prevalent stable plaque phenotype found in women may explain why CEA is less effective in preventing a stroke in women. In all randomized, controlled trials of CEA, women have a lower baseline risk of stroke compared with men that is reduced to an equal level for both sexes after surgery. Thus, women benefit less from CEA then men.1, 2, 16, 17, 18, 29 Asymptomatic women benefit the least from CEA, as shown in the ACST and Asymptomatic Carotid Atherosclerosis Study trials.1, 2, 4 Stable, fibrous plaques are less prone to cause ischemic events in the coronary and the carotid arteries.7, 8, 9, 10, 11, 12
Our observations led us to hypothesize that removal of a stable plaque is less beneficial than removal of a vulnerable plaque, which is more frequently found in asymptomatic men and symptomatic patients. In addition, the aforementioned studies showed that women have a slightly higher perioperative risk than men, also contributing to gender differences in benefit of CEA. Interestingly, the presence of a fibrous plaque is associated with an increased amount of microembolization during CEA.30
Our results suggest that selecting patients for CEA on the basis of plaque characteristics may hold a promise for the future. This is especially true for patient groups with a small margin of benefit from the operation. We show that variations in plaque phenotype that exist within different patient groups are consistent with previously reported outcomes after CEA. Selection of asymptomatic women for CEA who have vulnerable, unstable plaques might improve the long-term outcome. High-risk groups that benefit greatly from CEA, such as symptomatic men with high-grade stenosis, would probably benefit to a lesser extent from such a strategy. The new imaging techniques such as high-resolution magnetic resonance imaging, single photon emission computed tomography, and palpography may bring the potential of the observed differences in plaque level into clinical practice.31, 32, 33
Limitations
In the current study, we examined the segment with the largest plaque area and not the entire plaque. The rationale for this method is that the segment of the plaque with the largest plaque burden is the part with the most inflammation and the largest atheroma.23 It has also been shown that assessment of the culprit segment is reasonably representative for the plaque as a whole.34 In some cases, an important feature might be missed when only the culprit lesion is studied, potentially masking differences between groups. This drawback is overcome by the large number of patients in our study.
Conclusion
Women undergoing CEA have more stable carotid plaques than men, with lower fat, lower macrophage and higher smooth muscle cell content, and lower inflammatory and protease activity. This is not explained by clinical presentation and cardiovascular risk factors, suggesting an independent gender-related effect on carotid plaque phenotype of patients undergoing carotid endarterectomy. The gender-associated differences in plaque phenotype are most evident in asymptomatic women, which could explain why especially asymptomatic women have lower long-term stroke reduction after carotid endarterectomy.
Author contributions
We would like to thank Els Busser and Evelyn Velema for their excellent technical support.
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Competition of interest: none.CME article
PII: S0741-5214(06)01832-5
doi:10.1016/j.jvs.2006.09.051
© 2007 The Society for Vascular Surgery. Published by Elsevier Inc. All rights reserved.
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- Invited commentary