European Journal of Vascular & Endovascular Surgery
Volume 39, Issue 3 , Pages 258-265, March 2010

Beneficial Changes of Serum Calcification Markers and Contralateral Carotid Plaques Echogenicity after Combined Carotid Artery Stenting Plus Intensive Lipid-lowering Therapy in Patients with Bilateral Carotid Stenosis☆

  • N.P.E. Kadoglou

      Affiliations

    • First Department of Internal Medicine, ‘Hippokratio’ General Hospital of Thessaloniki, Thessaloniki, Greece
    • Department of Vascular Surgery, Medical School, University of Athens, Athens, Greece
    • Corresponding Author InformationCorresponding author at: N.P.E. Kadoglou, 124 Vosporou str, GR-54454, Thessaloniki, Greece. Tel./fax: +30 2310905178.
    • ,
  • T. Gerasimidis

      Affiliations

    • Fifth Surgical Department, Aristotle University of Thessaloniki, Thessaloniki, Greece
    • ,
  • A. Kapelouzou

      Affiliations

    • Center of Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece
    • ,
  • A. Moumtzouoglou

      Affiliations

    • Laboratory of Radiology, ‘Hippokratio’ General Hospital of Thessaloniki, Thessaloniki, Greece
    • ,
  • E.D. Avgerinos

      Affiliations

    • Department of Vascular Surgery, Medical School, University of Athens, Athens, Greece
    • ,
  • J.D. Kakisis

      Affiliations

    • Department of Vascular Surgery, Medical School, University of Athens, Athens, Greece
    • ,
  • P.E. Karayannacos

      Affiliations

    • Center of Experimental Surgery, Biomedical Research Foundation, Academy of Athens, Athens, Greece
    • ,
  • C.D. Liapis

      Affiliations

    • Department of Vascular Surgery, Medical School, University of Athens, Athens, Greece

Received 1 September 2009; accepted 15 November 2009. published online 09 December 2009.

Article Outline

Abstract 

Objectives/design

In symptomatic patients treated with ipsilateral carotid artery stenting (CAS) plus intensive lipid lowering, we assessed the changes of osteopontin (OPN), osteoprotegerin (OPG) and the Gray-Scale Median (GSM) score contralateral to symptomatic carotid stenosis.

Materials/methods

Forty-six symptomatic patients (group A) with significant carotid stenosis (North American Symptomatic Carotid Endarterectomy Trial (NASCET): >70%) underwent ipsilateral CAS. Those patients had simultaneously contralateral low-grade carotid stenosis (NASCET: 30–69%). Group B included 67 symptomatic patients with low-grade bilateral carotid stenosis (NASCET: 30–69%), but without indications for revascularisation. All patients were treated with atorvastatin (10–80mg) to target low-density lipoprotein (LDL)<100mgdl−1. Blood samples and plaques' GSM score contralateral to brain infarct were assayed at baseline and after 6 months.

Results

At baseline, there were no significant differences between groups (p>0.05). Six-month atorvastatin treatment equivalently improved lipid profile in both groups (p<0.05). The parameters hsCRP, OPN and OPG were significantly down-regulated within both groups, but to a greater extent in group A (p<0.05). Besides this, contralateral GSM score was significantly improved from baseline in both groups (p<0.01), but that increment was more pronounced in group A (vs. group B; p=0.041). These changes were inversely correlated with changes in OPN (p=0.014), OPG (p=0.011) and LDL (p=0.041).

Conclusion

Ipsilateral CAS plus intensive lipid-lowering therapy was associated with enhanced contralateral carotid plaque stability and attenuated inflammatory burden and calcification inhibitors to a greater extent than atorvastatin therapy alone in patients with bilateral carotid stenosis.

Keywords: Carotid artery stenting, Statin, Osteoprotegerin, Osteopontin, Gray-Scale Median, Plaque echogenicity, Plaque stability

 

Carotid plaque echolucency is a well-established index of plaque vulnerability, and has been found to reliably predict plaque composition and the occurrence of cerebrovascular ischaemic events.1 Echolucent plaques are histologically rich in lipid and macrophage and consist of less fibrous tissue and less calcification, which make them vulnerable and prone to rupture.2 The ultrasound-derived Gray-Scale Median (GSM) score has emerged as a valid, quantified index of carotid plaque echogenicity inversely associated with plaque vulnerability.3

The combination of ultrasound indices with cardiovascular biomarkers seems to be a noteworthy model for effective cardiovascular risk stratification and monitoring of therapeutic interventions. Among numerous cardiovascular biomarkers, osteopontin (OPN) and osteoprotegerin (OPG) constitute physiologically potent inhibitors of osteoclastogenesis and vascular calcification.4 Both of these pro-inflammatory cytokines are highly expressed at macrophages- and foam cell-rich sites within the atherosclerotic plaques.5 Accumulating evidence supports the association of serum OPN and OPG with cardiovascular diseases6 and carotid plaque vulnerability.3 Although pharmaceutical modulation of vascular calcification inhibitors and carotid echogenicity seems quite promising,7 data regarding their long-term response to interventional procedure are missing.

The compounds 3-hydroxy-3-methylglutaryl coenzyme A (HMG-CoA) reductase inhibitors (statins) administration is the most commonly effective therapeutical intervention to mitigate atherosclerosis.8 Numerous studies have demonstrated resounding and sustained benefits from statins in primary and secondary cardiovascular disease prevention.9 Besides lipid lowering, statins exerts ‘pleiotropic’ properties, including anti-inflammatory, anti-thrombogenic, anti-oxidative and direct anti-atherogenic effects, leading to atherosclerotic plaque stabilisation.8, 9 Using GSM score, we have recently shown the favourable effects of statin therapy on carotid lesions echogenicity associated with considerable suppression of OPN and OPG levels.7

Carotid artery stenting (CAS) has emerged as an alternative treatment for carotid artery disease, at least in patients considered to be at increased risk for carotid endarterectomy (CEA).10 The peri-procedural as well as the long-term efficacy of CAS compared with CEA is the subject of controversy, and more data are required.10 Perhaps, a critical issue for improving CAS outcome could be the concomitant medications. Nowadays, statin treatment is advocated as an adjunct in CEA, minimising the peri- and postoperative mortality and morbidity.11 This raises the question of whether a similar benefit would translate into outcomes of CAS. No prospective studies exist and it is still questionable whether unilateral carotid revascularisation could beneficially influence either serum cardiovascular biomarkers or the natural history of the contralateral carotid plaques.

Thus, the aim of the present study was to evaluate the changes of serum vascular calcification inhibitors and GSM score of the contralateral atherosclerotic lesions after ipsilateral CAS plus atorvastatin treatment in patients with bilateral carotid stenosis.

Back to Article Outline

Materials and Methods 

Patients and study design 

This was a two-centre, prospective, open-label trial. Initially, 466 consecutive patients were admitted, between January 2005 and December 2007, to our hospitals with recent, within 15 days, ischaemic stroke or transient ischaemic attack (TIA) attributed to carotid atherosclerosis. Among them, we selected 132 patients with stenosis of both internal carotid arteries (ICAs) (North American Symptomatic Carotid Endarterectomy Trial (NASCET) range: 30–99%). The degree of carotid stenosis was initially measured using B-mode and Doppler ultrasound, as described in the following section. In cases of borderline ultrasound, calculated degree of carotid stenosis (NASCET: 70±10%), patients underwent digital subtraction angiography (DSA) to further validate the grade of carotid stenosis.12 We excluded patients with: indications for intervention of both ICAs due to significant symptomatic or asymptomatic stenosis, autoimmune or life-threatening diseases, recently diagnosed/untreated hypothyroidism, osteoporosis, coronary artery disease or overt cardiac-origin symptoms, atrial fibrillation, liver (ALT>2.5 times higher than the upper normal limit) or renal (creatinine levels>2.0mgdl−1) impairment, ongoing use of lipid-lowering medications and contraindications to the use of statins or CAS. We finally enrolled 117 patients (47 men and 70 women) who were divided into two groups:

•Group A (N=48): Patients with recent stroke or TIA, ascribed to significant ipsilateral carotid stenosis (NASCET: >70%), underwent CAS of the culprit lesion. Those patients had simultaneously contralateral carotid stenosis without indications for revascularisation (NASCET: 30–69%). In addition to ultrasound examination, all patients of this group underwent pre-procedural DSA. The interventional procedures were performed under local anaesthesia, systemic heparinisation and cerebral device protection. ‘Technical success’ was defined as the ability of treating the stenosis with less than 30% residual stenosis. Neurological outcome was evaluated both at the end of the procedure and in the following 24h by a neurologist according to the National Institutes of Health Stroke Scale (NIHSS) and the modified Rankin Scale (mRS). Among CAS and CEA, we selected CAS performance as a routine procedure in our high-volume centres owing to the very low rates of peri- and post-procedural adverse events.10

•Group B (N=69): Patients with recent stroke or TIA attributed to ipsilateral carotid atherosclerosis and bilateral carotid stenosis, but without indications for revascularisation (NASCET: 30–69%).

The diagnosis of stroke/TIA and its relationship with ipsilateral carotid lesions was based on the comparative evaluation of medical history, neurological examination, brain computed tomography (CT) or magnetic resonance imaging (MRI), when CT findings were questionable. Patients of both groups were treated with atorvastatin for 6 months. Atorvastatin treatment initiated at the time of diagnosis and its dose was gradually titrated (10—80mg) to target LDL<100mgdl−1, at 6 weeks' intervals. Patients' compliance was closely monitoring by calculating the number of statin pills, already taken, every 2 months. It was considered effective if at least 90% of estimated study medication had been received. In addition, dual anti-platelet therapy (aspirin 100mg plus clopidogrel 75mg) started 3 days before the stenting procedure and continued for the whole duration of the study in group A, while group B received aspirin 100mg or clopidogrel 75mg throughout the study. The concomitant anti-hypertensive and hypoglycaemic medications remained unaltered, unless it was deemed medically necessary. At baseline, patients were given written dietary and exercise recommendations and smokers were encouraged to cease smoking.

Blood sampling, ultrasound of both carotids and anthropometrical parameters assessment, such as body mass index (BMI), waist-to-hip ratio (WHR) and blood pressure (BP), were performed at baseline and at the end of the study.13 We estimated the mean value of two consecutive measurements of BP with a 5-min interval. All participants had been kept in a sitting position for 15min before BP measurement.

This study was approved by the Committee on Research Ethics at our hospitals, in compliance with the ethical guidelines of the Declaration of Helsinki. All participants gave written informed consent prior to study entry.

Calculation of GSM Score and the Degree of Carotid Stenosis 

A carotid ultrasound examination was performed using a 7.5-MHz probe of an ultrasound scanner (General Electric Logiq700, Riverside, CA, USA). Only one operator, blinded to patients' clinical characteristics, performed all of the carotid scans at the beginning and at the end of the study. The procedure of carotid ultrasound examination and image analysis for GSM calculation has been previously described.7 Then, we calculated the GSM score of each carotid plaque contralateral to the brain infarct and the average value was considered for statistical analysis.

Based on peak systolic velocity (PSV) and ICA/CCA PSV ratio thresholds,14 ICA stenosis was initially categorised to the following groups: <50%, 50–69%, >70%, near occlusion and total occlusion. Then, we calculated the highest degree of carotid stenosis in each patient using B-mode imaging. For this purpose, we compared the diameter of the minimal residual lumen (at the point of tightest ICA stenosis) and the diameter of the normal ICA lumen distal to the bulb on longitudinal and transverse images using colour-flow imaging.15 This is a well-validated procedure in our laboratory and the results match Doppler ultrasound findings. To get comparable images during the second ultrasound examination, the stored baseline images of each patient were simultaneously showed to the operator on a computer screen.

Blood Parameters 

Blood samples were collected after an overnight fast at the beginning (preoperatively in group A) and at the end of the study. Lipid parameters and fasting plasma glucose (FPG) were immediately determined using standard enzymatic methods (Olympus AU560, Hamburg, Germany). The rest of blood samples were centrifuged at 5000×g for 7min, and serum was stored at −80°C, until analysis in the same assay. Measurements of HbA1c were made by high-performance liquid chromatography (Menarini Diagnostics, Florence, Italy). We used Quantikine enzyme-immunoassay (EIA) kits to assay serum OPN (R&D Systems Inc., Minneapolis, MN, USA) and OPG (Metra, San Diego, CA, USA) levels. The intra- and inter-assay coefficients of variance (CVs) were 2.6% and 5.7% for OPN and 7% and 6.8% for OPG, respectively. High-sensitivity C-reactive protein (hsCRP) was measured by a nephelometric assay (Dade Behrin, BNII, Marburg, Germany).

Statistical Analysis 

Data are expressed as mean and ± standard deviation (SD). Normality of distribution was assessed by Kolmogorov–Smirnov test. Comparisons of parametric parameters within and between groups were analysed by paired samples and Student's t-test, respectively. Chi-square test was used for categorical data. To test correlations between the changes of OPN, OPG and GSM throughout the study, Pearson's correlation was used. Standard multiple regression analysis assessed the dependent association of changes in GSM with the changes of the rest of significant parameters. All analyses were carried out by SPSS 13.0 software package (SPSS Inc., Chicago, IL, USA). Two-tailed p<0.05 was considered as statistically significant.

Back to Article Outline

Results 

Patients' characteristics at baseline 

Baseline clinical characteristics of the groups are shown in Table 1, Table 2. In general, four patients had major complications and discontinued the study. Two patients in group A developed reversible stroke early after intervention, while in group B, one patient underwent coronary angioplasty due to angina pectoris and one patient experienced stroke. Thereby, 46 and 67 patients in groups A and B, respectively, completed the entire study and their data were analysed. Among smokers, only seven patients in group A and three patients in group B ceased smoking throughout the study despite our intensive encouragement. The large number of statin-free patients with carotid stenosis entering our study could be attributed to their low compliance with their physicians’ recommendations, despite the high incidence of concomitant diabetes or hypertension. Unfortunately, the usage of statins in primary and secondary cardiovascular disease prevention is not widely accepted by patients without overt cardiovascular diseases. In general, patients without overt clinical cardiovascular symptoms or with unknown carotid stenosis are predominantly under-treated. No adverse event related to atorvastatin usage was recorded throughout the study, while satisfactory ultrasound images, proper for computer analysis, were obtained in all participants.

Table 1. Baseline characteristics of the patients.
Group AGroup Bp-Value
Number4667-
Male/Female16/3029/39NS
Active smoking, n17 (36.96%)20 (29.41%)NS
Diabetes mellitus, n17 (36.96%)21 (30.88%)NS
Hypertension, n35 (76.09%)46 (67.65%)NS
Age (y)66.76±7.3164.91±10.360.437
Diabetes duration (y)a5.75±4.17.34±4.310.318
hsCRP (mg/L)6.61±2.695.91±20.391
Osteopontin (ng/ml)84.74±41.9179.3±25.880.507
Osteoprotegerin (pmol/L)8.86±3.479.05±2.650.687
GSM score74.1±28.2670.47±27.830.739

Data are mean±SD. Group A, CAS+atorvastatin therapy; Group B, atorvastatin therapy; n, number of patients; y, years; NS, non-significant.

aComparison between groups for diabetes duration was performed only in the diabetic subgroups.

Table 2. Time course of clinical and biochemical parameters during CAS plus atorvastatin treatment or atorvastatin treatment in both groups.
Group A (N=46)Group B (N=67)P
Baseline6 monthsBaseline6 months
BMI (kg/m2)29.58±328.92±4.129.61±4.7429.34±4.750.295
WHR0.95±0.080.94±0.090.96±0.080.95±0.080.625
SBP (mmHg)132.7±13.47128.68±17.47130±19.23126.06±16.350.540
DBP (mmHg)77.03±7.3173.42±1079.06±11.5877.16±10.950.852
HbA1c (%)a6.48±1.485.97±0.51*6.37±1.086.03±1.12*0.415
FPG (mg/dl)135.8±46110.4±31.8126.7±40.4120.5±38.60.123
TChol (mg/dl)223±48.33165.21±29.32*233.36±47.59170.11±46.13*0.351
TG (mg/dl)165.81±94.86102.42±75.17*156.63±59.64133.08±57.6*0.466
HDL-C (mg/dl)39.47±9.6344.77±11.29*44.98±10.7446.96±13.030.115
LDL-C (mg/dl)150.37±37.8599.96±20.38*157.04±4396.53±27.95*0.528
WBC (cells/μL)7397.6±1717.66188.9±1983.9*7541.1±2182.67096.4±2131.1*0.260
Carotid stenosis (%)b46.66±7.2846.89±6.1346.04±7.9646.31±8.150.775

Data are mean±SD. SBP, systolic blood pressure; DBP, diastolic blood pressure; FPG, fasting plasma glucose; TChol, Total cholesterol; TG, Triglycerides; HDL-C, high-density lipoprotein-Cholesterol; LDL-C, low-density lipoprotein-Cholesterol; WBC, white blood cells. P-values of changes of variables between groups.

*p<0.05 change of variables within groups.

aComparison within and between groups for HbA1c was performed only in the diabetic subgroups.

bThe degree of carotid stenosis contralateral to symptomatic carotid atherosclerotic lesions.

At baseline, no significant differences were detected between groups (Table 1, Table 2). The anti-hypertensive medications were modified in 13 patients (group A: eight, group B: five) to target systolic/diastolic BP <140/90mmHg, during the study. The dosage of anti-diabetic medications was up-titrated in eight patients (group A: three, group B: five), due to uncontrolled hyperglycaemia (HbA1c>7%). The afore-mentioned changes explain the slight decrease in BP and the significant down-regulation in HbA1c, within both groups (A: p=0.009, B: p=0.002).

Effects of Atorvastatin Treatment 

As illustrated in Table 2, there was an equivalent improvement in almost all lipid parameters within both groups after atorvastatin treatment (p<0.05). There was no significant difference in changes in lipids between groups. Upon examining white blood cell (WBC) count, a significant decrease from baseline values occurred within groups A (p=0.005) and B (p=0.042); however, the treatment difference between groups was negligible (p=0.260). The degree of the contralateral carotid stenosis remained unaltered over time in both groups (p>0.05).

CAS plus 6-month atorvastatin treatment resulted in considerable down-regulation in OPN, OPG and hsCRP levels from baseline (p<0.001). Similarly, atorvastatin treatment significantly suppressed OPN (p=0.003), OPG (p<0.001) and hsCRP (p=0.020), levels within group B. The magnitude of change in OPN (p=0.035), OPG (p=0.029) and hsCRP (p=0.045) was significantly greater in group A versus group B. GSM score of the carotid lesions contralateral to the brain infarct was significantly increased within both groups (p<0.01). Notably, the relative increment in GSM score was more pronounced in group A rather than group B (p=0.041) (Fig. 1).

  • View full-size image.
  • Figure 1 

    Serum levels of osteopontin, osteoprotegerin and hsCRP and GSM score values at baseline and at the end of the study. P1, difference of variables within groups; P2, difference of changes of variables between groups.

Correlations 

We further assessed the correlations between the changes of the contralateral GSM score and the changes of the rest of variables, across the study. We found the GSM score increment to be inversely associated with the reduction in OPN (r=−0.286; p=0.014), OPG (r=−0.411; p=0.011) and low-density lipoprotein-cholesterol (LDL-C) (r=−0.234; p=0.041). After standard multiple regression analysis OPN, OPG and LDL-C remained in the model as independent predictors of GSM improvement (R2=0.399; p=0.028).

Back to Article Outline

Discussion 

The present 6-month, open-label, prospective study demonstrated a significant decline in novel cardiovascular risk factors such as OPN, OPG and hsCRP after combined treatment with ispilateral CAS plus intensive atorvastatin therapy in patients with bilateral carotid stenosis. Besides, after combined treatment, we found that the afore-mentioned favourable effects were associated with enhanced contralateral carotid plaque stability.

The current study extended our previous work7 by reporting statin-induced suppression of serum OPN, OPG and hsCRP levels in patients with significant carotid stenosis, which is of clinical importance. Looking for the underlying mechanisms, previous investigators have suggested the inhibition of mevalonate pathway and protein prenylation to mediate OPN and OPG suppression.16 Although lipid lowering contributes to improved cardiovascular outcomes, accumulating evidence supports the lipid-independent cardio-protective effects of statins over the long term.8 Concerning the strong relationship of vascular calcification inhibitors with cardiovascular diseases and carotid-related symptomatology,3 the atorvastatin-induced suppression of OPN and OPG provides an alternative, ‘pleiotropic’ mechanism by which statins could reduce cardiovascular risk.

Inflammatory and endothelial-related biomolecules show an acute rise after stenting procedure; most of them usually return to baseline levels in the long term.17, 18 In our trial, we found the end-study values of OPN, OPG and hsCRP below the baseline levels in both groups, but the amount of their reduction was significantly greater after combined treatment compared with conservatively treated patients. Although the latter effects were predominantly attributed to atorvastatin administration in our statin-naïve patients, this is the first study demonstrating an adjunctive improvement of cardiovascular risk profile after combined treatment with CAS and statin. Atherosclerosis is a diffuse process, wide-spread on the whole artery tree and each atherosclerotic lesion constitutes the source of numerous atherogenic biomolecules entering blood circulation.19, 20 Therefore, we postulated statin treatment and atherosclerotic plaque compression on the arterial wall, during CAS, to have restricted cardiovascular biomolecules invasion in circulation. Future studies will investigate the time-course changes of biomarkers after CAS and the clinical sequels.

We and other investigators have recently reported the statin-induced increase in carotid plaque echogenicity.7, 21 In the present study, intensive atorvastatin therapy significantly increased from baseline the GSM score of the atherosclerotic plaques contralateral to the cerebral infarct. Most importantly, their echogenicity increased to a greater extent after combined treatment with ipsilateral CAS plus 6-month intensive atorvastatin treatment than atorvastatin alone. There is evidence that statins targeting the systemic risk factors and the triggered pathways have the potential to attenuate the whole atherosclerotic progression and plaque vulnerability at multiple sites of early or advanced atherosclerotic lesions.22, 23 In our study, the inverse relationship between contralateral GSM score and OPN, OPG and LDL changes supports the latter hypothesis. Another plausible explanation for the additional benefits of CAS over 6-month period derives from the local factors, such as shear stress, vessel anatomy or haemodynamics, which are crucial for atherosclerosis progression and may alter after unilateral carotid revascularisation.24 Endothelial dysfunction, inflammatory cells infiltration, lipid deposition, oxidative stress and calcium clustering contribute to local lesion formation.25 Advanced atherosclerotic plaques act as dynamic sources of inflammatory and calcification mediators entering blood circulation. Plaque-derived biomolecules further precipitate atherosclerotic lesions destabilisation.26 Thus, CAS might have attenuated the latter phenomenon via atherosclerotic plaque destruction and suppression of circulating risk factors, adding more benefits in intact plaques' stability. Longer studies in larger samples will shed more light on the underlying mechanisms and will confirm the clinical efficacy of CAS plus concomitant statin treatment.

Despite the bilateral symmetry of carotid atherosclerosis, the role of surveillance of the contralateral carotid artery remains still unclear.27 Previous studies have suggested surveillance of contralateral carotid stenosis to add little benefit in ischaemic attack prevention.28 Perhaps that benefit was underestimated since those studies evaluated lumen narrowing, and were unable to identify vulnerable plaque composition.29, 30 Moreover, bilateral carotid disease, independent of its severity, is associated with higher rates of ischaemic events in other arterial territories, outlining the systemic predisposition to plaque vulnerability.31 In agreement with previous studies, we strongly suggest that carotid plaque morphology contralateral to the symptomatic carotid stenosis reflects atherosclerosis progressionas a diffuse disease, and its monitoring could provide an indication of anti-atherogenic therapy efficacy.32

Our symptomatic patients with significant ipsilateral carotid stenosis greatly profited from combined treatment with CAS and statin in terms of cardiovascular risk profile and contralateral plaque stability. It is still unknown whether those positive results could be extended to symptomatic patients with moderate carotid stenosis (<70%). Regarding the degree of carotid stenosis as the mainstay of patients' selection, current guidelines underline that carotid intervention is probably indicated in symptomatic patients with stenosis 50–69%.10 Perhaps, selection criteria other than lumen narrowing classification, such as cardiovascular biomarkers and imaging features of plaque texture, could identify ‘vulnerable’ patients, at high risk for a cardiovascular event, but with haemodynamically non-significant carotid stenoses who benefit most from carotid revascularisation. The observed improvement of cardiovascular risk profile and contralateral carotid plaque stability outlines the efficacy of combined pharmaceutical and interventional treatment. Unfortunately, most trials focus on the comparative evaluation of different therapeutic strategies of high-risk patients. Our study supports the multifactorial treatment as the most effective approach of cardiovascular risk reduction.

The present study has some shortcomings that should be considered. First, the limited study duration and the modest sample size did not allow us to draw conclusions on the differences in the long-term cardiovascular events between treatment groups. Nevertheless, GSM score constitutes a valid index of carotid plaque vulnerability, strongly associated with cerebrovascular events.1 Perhaps the observed significant correlations of GSM might have been stronger in a larger study population. Second, a small proportion of participants had its concomitant medication modified, which might have influenced our results. Exclusion of these patients from statistical analysis yielded slight changes in the final outcomes. Furthermore, the interventional group received dual anti-platelet therapy compared with the single anti-platelet agent administration to the conservative treatment group. Regarding the anti-inflammatory properties of anti-platelet agents, this might have somehow biased the effects attributed to the stenting procedure and should be taken into consideration. Finally, our study was confined to hsCRP and vascular calcification inhibitors. Probably, more systemic factors could account for our findings.

In conclusion, ispilateral CAS plus intensive atorvastatin therapy compared with atorvastatin therapy alone was associated with enhanced carotid plaque stability contralateral to symptomatic carotid stenosis to a greater extent than atorvastin therapy alone. Amelioration of LDL and vascular calcification inhibitors levels seemed to mediate the afore-mentioned favourable effects. Prospective studies will determine whether the degree of carotid stenosis is an adequately valid criterion for carotid revascularisation in symptomatic patients.

Back to Article Outline

Conflicts of Interest 

None.

Back to Article Outline

Funding 

The project was co-funded by the European Social Fund and National Resources – (EPEAEK II, PYTHAGORAS II), the joint research and technology project ‘Hellas-Slovenia’ the Ministry for Development, General Secretariat for Research & Technology, and the research project ‘KAPODISTRIAS II’ (University of Athens, Greece). Nikolaos P.E. Kadoglou was funded by the Alexander S. Onassis Public Benefit Foundation.

Back to Article Outline

Acknowledgements 

The technical support of Christos P.E. Kadoglou and Ioulia Vitta is gratefully acknowledged. The content of this article was presented at the Annual Meeting of the European Society for Vascular Surgery, Oslo, Norway, 2009.

Back to Article Outline

References 

  1. Effenberger I, Sabeti S, Mlekusch W, Schlager O, Dick P, Puchner S, et al. Increasing carotid plaque echolucency is predictive of cardiovascular events in high-risk patients. Radiology. 2008;248:1050–1055
  2. Lal BK, Hobson RW, Pappas PJ, Kubicka R, Hameed M, Chakhtoura EY, et al. Pixel distribution analysis of B-mode ultrasound scan images predicts histologic features of atherosclerotic carotid plaques. J Vasc Surg. 2002;35:1210–1217
  3. Kadoglou NP, Gerasimidis T, Golemati S, Kapelouzou A, Karayannacos PE, Liapis CD. The relationship between serum levels of vascular calcification inhibitors and carotid plaque vulnerability. J Vasc Surg. 2008;47:55–62
  4. Scatena M, Liaw L, Giachelli CM. Osteopontin: a multifunctional molecule regulating chronic inflammation and vascular disease. Arterioscler Thromb Vasc Biol. 2007;27:2302–2309
  5. Golledge J, McCann M, Mangan S, Lam A, Karan M. Osteoprotegerin and osteopontin are expressed at high concentrations within symptomatic carotid atherosclerosis. Stroke. 2004;35:1636–1641
  6. Kiechl S, Schett G, Wenning G, Redlich K, Oberhollenzer M, Mayr A, et al. Osteoprotegerin is a risk factor for progressive atherosclerosis and cardiovascular disease. Circulation. 2004;109:2175–2180
  7. Kadoglou NP, Gerasimidis T, Moumtzouoglou A, Kapelouzou A, Sailer N, Fotiadis G, et al. Intensive lipid-lowering therapy ameliorates novel calcification markers and GSM score in patients with carotid stenosis. Eur J Vasc Endovasc Surg. 2008;35:661–668
  8. Athyros VG, Kakafika AI, Tziomalos K, Karagiannis A, Mikhailidis DP. Pleiotropic effects of statins–clinical evidence. Curr Pharm Des. 2009;15:479–489
  9. Dembowski E, Davidson MH. A review of lipid management in primary and secondary prevention. J Cardiopulm Rehabil Prev. 2009;29:2–12
  10. Liapis CD, Bell PR, Mikhailidis D, Sivenius J, Nicolaides A, Fernandes e Fernandes J, et al. ESVS guidelines. Invasive treatment for carotid stenosis: indications, techniques. Eur J Vasc Endovasc Surg. 2009;37(4 Suppl):1–19
  11. Perler BA. The effect of statin medications on perioperative and long-term outcomes following carotid endarterectomy or stenting. Semin Vasc Surg. 2007;20:252–258
  12. Bucek RA, Puchner S, Haumer M, Rand T, Minar E, Lammer J. Grading of internal carotid artery stenosis: can CTA overcome the confusion?. J Endovasc Ther. 2006;13:443–450
  13. Kadoglou NP, Iliadis F, Angelopoulou N, Sailer N, Fotiadis G, Voliotis K, et al. Cardiorespiratory capacity is associated with favourable cardiovascular risk profile in patients with Type 2 diabetes. J Diabetes Complications. 2009;23:160–166
  14. Grant EG, Benson CB, Moneta GL, Alexandrov AV, Baker JD, Bluth EI, et al. Carotid artery stenosis: gray-scale and Doppler US diagnosis–Society of Radiologists in Ultrasound Consensus Conference. Radiology. 2003;229:340–346
  15. Griffiths GD, Razzaq R, Farrell A, Ashleigh R, Charlesworth D. Variability in measurement of internal carotid artery stenosis by arch angiography and duplex ultrasonography–time for a reappraisal?. Eur J Vasc Endovasc Surg. 2001;21:130–136
  16. Takemoto M, Kitahara M, Yokote K, Asaumi S, Take A, Saito Y, et al. NK-104, a 3-hydroxy-3-methylglutaryl coenzyme A reductase inhibitor, reduces osteopontin expression by rat aortic smooth muscle cells. Br J Pharmacol. 2001;133:83–88
  17. Garg R, Tellez A, Alviar C, Granada J, Kleiman NS, Lev EI. The effect of percutaneous coronary intervention on inflammatory response and endothelial progenitor cell recruitment. Catheter Cardiovasc Interv. 2008;72:205–209
  18. Lee WL, Sheu WH, Liu TJ, Lee WJ, Tsao CR, Ju YH, et al. The short-/intermediate-term changes in novel vascular inflammatory markers after angioplasty plus stenting in patients with symptomatic advanced systemic arterial diseases. Atherosclerosis. 2004;176:125–132
  19. Arauz A, Hoyos L, Zenteno M, Mendoza R, Alexanderson E. Carotid plaque inflammation detected by 18F-fluorodeoxyglucose-positron emission tomography. Pilot study. Clin Neurol Neurosurg. 2007;109:409–412
  20. Handberg A, Skjelland M, Michelsen AE, Sagen EL, Krohg-Sørensen K, Russell D, et al. Soluble CD36 in plasma is increased in patients with symptomatic atherosclerotic carotid plaques and is related to plaque instability. Stroke. 2008;39:3092–3095
  21. Yamagami H, Sakaguchi M, Furukado S, Hoshi T, Abe Y, Hougaku H, et al. Statin therapy increases carotid plaque echogenicity in hypercholesterolemic patients. Ultrasound Med Biol. 2008;34:1353–1359
  22. Spagnoli LG, Bonanno E, Sangiorgi G, Mauriello A. Role of inflammation in atherosclerosis. J Nucl Med. 2007;48:1800–1815
  23. Weintraub HS. Identifying the vulnerable patient with rupture-prone plaque. Am J Cardiol. 2008;101(12A):3F–10F
  24. Järvilehto M, Tuohimaa P. Vasa vasorum hypoxia: initiation of atherosclerosis. Med Hypotheses. 2009;73:40–41
  25. Insull W. The pathology of atherosclerosis: plaque development and plaque responses to medical treatment. Am J Med. 2009;122(1 Suppl):S3–S14
  26. Hallow KM, Taylor WR, Rachev A, Vito RP. Markers of inflammation collocate with increased wall stress in human coronary arterial plaque. Biomech Model Mechanobiol. 2009;[Epub ahead of print]
  27. Adams GJ, Simoni DM, Bordelon CB, Vick GW, Kimball KT, Insull W, et al. Bilateral symmetry of human carotid artery atherosclerosis. Stroke. 2002;33:2575–2580
  28. Naylor AR, John T, Howlett J, Gillespie I, Allan P, Ruckley CV. Fate of the non-operated carotid artery after contralateral endarterectomy. Br J Surg. 1995;82:44–48
  29. Fisher M, Paganini-Hill A, Martin A, Cosgrove M, Toole JF, Barnett HJ, et al. Carotid plaque pathology: thrombosis, ulceration, and stroke pathogenesis. Stroke. 2005;36:253–257
  30. Ballotta E, Da Giau G, Meneghetti G, Barbon B, Militello C, Baracchini C. Progression of atherosclerosis in asymptomatic carotid arteries after contralateral endarterectomy: a 10-year prospective study. J Vasc Surg. 2007;45:516–522
  31. Touzé E, Warlow CP, Rothwell PM. Risk of coronary and other nonstroke vascular death in relation to the presence and extent of atherosclerotic disease at the carotid bifurcation. Stroke. 2006;37:2904–2909
  32. Tang T, Howarth SP, Miller SR, Trivedi R, Graves MJ, King-Im JU, et al. Assessment of inflammatory burden contralateral to the symptomatic carotid stenosis using high-resolution ultrasmall, superparamagnetic iron oxide-enhanced MRI. Stroke. 2006;37:2266–2270

☆ Presented at the XXIII Annual Meeting 3–6 September 2009, European Society for Vascular Surgery, Oslo, Norway.

PII: S1078-5884(09)00580-2

doi:10.1016/j.ejvs.2009.11.013

European Journal of Vascular & Endovascular Surgery
Volume 39, Issue 3 , Pages 258-265, March 2010

Article Tools

* Image Usage & Resolution