Journal of Atherosclerosis and Thrombosis Vol. 22, No. 2
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Original Article
Progression of Intracranial Major Artery Stenosis is Associated with Baseline Carotid and Intracranial Atherosclerosis Heisuke Mizukami, Takahiro Shimizu, Futaba Maki, Makoto Shiraishi and Yasuhiro Hasegawa Department of Internal Medicine, Division of Neurology, St. Marianna University School of Medicine, Kanagawa, Japan
Aim: Intracranial atherosclerotic major artery stenosis (IMAS) is associated with a high risk of ischemic stroke. Carotid ultrasound (US) has been widely used to evaluate an individual’s atherosclerotic burden, but no information is available on whether the carotid US findings are associated with IMAS progression. The aim of the present study was to identify the associations among traditional risk factors, the duplex carotid US findings and IMAS progression in patients with varying degrees of carotid atherosclerosis. Methods: All patients who underwent a set of imaging studies (MRI, MRA and carotid US) in our outpatient clinic were screened. A total of 101 patients with a mean age of 75.0±10.6 years, who received the same imaging studies with a mean interval of two years, were studied. In each patient, the extent of stenosis of three arteries (both middle cerebral arteries [MCAs] and the basilar artery [BA]) was classified into five grades. The total score of the three arteries was calculated as the global stenosis score (GSS). The progression of IMAS was defined as worsening of stenosis by ≥ 1 grade on final MRA. The maximum IMT (maxIMT), plaque findings and carotid stenosis were measured by carotid US. A multivariate stepwise logistic regression analysis was used to identify independent predictors of IMAS progression. Results: Follow-up MRA revealed IMAS progression in 12 patients (11.9%). The logistic regression analysis demonstrated that the baseline GSS (p = 0.008) and carotid stenosis ≥ 70% on the baseline carotid US (p = 0.023) were significantly associated with IMAS progression. Conclusions: The baseline severity of intracranial and extracranial atherosclerosis was significantly associated with the progression of IMAS. J Atheroscler Thromb, 2015; 22:183-190. Key words: Carotid ultrasound, Intima-media thickness, Intracranial atherosclerosis, Magnetic resonance angiography, Stenosis
Introduction Intracranial atherosclerotic major artery stenosis (IMAS) is associated with a high risk of ischemic stroke, and the incidence of IMAS is known to be higher in Asian, Black, and Hispanic populations than in Caucasians 1-4). The progression or regression of IMAS can be evaluated noninvasively by transcranial Address for correspondence: Heisuke Mizukami, Department of Internal Medicine, Division of Neurology, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku Kawasaki-city, Kanagawa 216-8511, Japan E-mail: [email protected] Received: May 19, 2014 Accepted for publication: July 31, 2014
Doppler ultrasound (TCD) or magnetic resonance angiography (MRA). Several clinical studies have been conducted using the presence of changes in serial TCD or MRA as a surrogate marker, with adjustment for traditional risk factors as confounders 5-10), but the predictors of IMAS progression have not yet been determined. The carotid intima-media thickness (IMT) and carotid stenosis measured by carotid ultrasound (US) have been widely used to evaluate an individual’s atherosclerotic burden. Recent studies suggest that traditional risk factors may explain ≈11% of the variance in carotid IMT 11), while the IMT and plaque may reflect different genetic and biological aspects of atherogenesis 12-15). No information is available about
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whether the IMT and carotid stenosis similarly affect intracranial atherosclerosis. To elucidate the associations among the baseline IMT, carotid stenosis and the IMAS progression, patients who underwent follow-up evaluations of both intracranial and extracranial atherosclerosis using MRA and carotid US were analyzed. The aim of this study was to identify the associations among traditional risk factors, the duplex carotid ultrasound (US) findings and IMAS progression. Methods Study Population All patients who underwent a set of imaging studies (MRI, MRA and carotid US) and underwent the same imaging studies for a follow-up evaluation of atherosclerosis in our outpatient clinic between September 2005 and April 2012 were screened. There were 224 patients who met these criteria. In this study, 133 patients who underwent a follow-up imaging study two years (±6 months) after the initial evaluation were selected for the analysis. A total of 19 patients with a poor carotid US study were excluded because of calcified plaques or complete occlusion, as were as 13 patients who underwent carotid endarterectomy or carotid stenting within two years after the initial examination. Finally, 101 patients (69 men; average age 75.0±10.6 years) were examined. The most common reason for the follow-up imaging study was routine follow-up for patients with stroke or TIA (n = 48, 47.5%). In 53 patients without a history of stroke or TIA, the follow-up imaging study was performed to evaluate asymptomatic carotid stenosis in 28 patients with IMAS (n = 10) or without IMAS (n = 18). Thus, all patients had varying degrees of carotid atherosclerosis, but IMAS was not observed in 70 patients (69%) at baseline. This study was conducted in a single hospital, and the study protocol was approved by the St. Marianna University Bioethics Committee. Clinical Data Collection The background factors and laboratory test values for each patient were evaluated at the baseline and follow-up examinations. The definitions of risk factors were as follows: Hypertension was defined as ≥ 2 blood pressure measurements of ≥ 140/90 mmHg, or a previous diagnosis of hypertension and the use of antihypertensive agents. Abnormal lipid metabolism was defined as total cholesterol ≥ 220 mg/dL, neutral fat levels ≥ 1 50 mg/dL, HDL cholesterol ＜ 40 mg/dL or the use of oral agents. Diabetes was considered to be
present if the patient showed fasting blood glucose levels ≥ 126 mg/dL and a HbA1c value ≥ 6.5%, or if treatment for diabetes was being administered. Using information from the medical records at baseline, the patients were classified as non-smokers or smokers. Non-smokers included never-smokers who had never smoked in their lifetime and ex-smokers who had previously smoked. Smokers were defined as current smokers at baseline. Chronic kidney disease (CKD) was defined by decreased kidney function (characterized by a reduced estimated glomerular filtration rate [eGFR] ＜ 60 mL/min/1.73 m2), kidney damage characterized by albuminuria or proteinuria for more than three months or as CKD diagnosed before entry into this study 16). Evaluation of Stenosis and the Progression of Atherosclerotic Lesions MRI and MRA were performed using an Excelart (1.5T, Toshiba Medical Co., Tokyo, Japan) or an Achieva Nova Dual (1.5T, Phillips Co., Tokyo, Japan) scanner. MRA was performed using a three-dimensional time-of-flight gradient-echo technique for the intracranial arteries. After completion of all data collection in all participants, baseline and follow-up MRA images were examined by three experienced stroke neurologists who were blinded to the patients’ clinical information. The extent of stenosis of three arteries (both middle cerebral arteries (MCAs) and the basilar artery) in each patient was classified into fives grades: 0 (normal; no signal reduction), 1 (mild; signal reduction ＜ 50%), 2 (moderate; signal reduction ＞ 50%), 3 (severe; focal signal loss with the presence of a distal MCA signal) and 4 (occlusion) 7-9, 17). The stenosis grade was decided by agreement between at least two neurologists. When there was no agreement, the stenosis was graded by consensus after reassessment of the MRA images. The total score for the three arteries on the baseline MRA images was calculated as the baseline global stenosis score. Progression was defined as worsening of stenosis by one or more grades on final MRA, whereas regression was defined as an improvement of stenosis by one or more grades compared with the findings of baseline MRA. Patients with IMAS progression in at least one vessel were classified as the progression (＋) group, and the other patients were classified as the progression (−) group. Fluid-attenuated inversion recovery (FLAIR) images were used to assess the severity of white matter changes according to the Fazekas classification system 18). This widely used scale rates DWML and PVWML separately using a four-point scale for each, with WMLs scored from 0 (absent) to 3 (marked
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Table 1. The patients’ characteristics
Men, n (%) Age, years Body mass index, kg/m2 Comorbidity, n (%) Hypertension Dyslipidemia Diabetes mellitus Current smoker Chronic kidney disease Atrial fibrillation Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Baseline Rankin score ＞ 1, n (%) History of stroke, n (%) Ischemic stroke TIA Lacunar Atherothrombotic Cardioembolic Other Brain hemorrhage Total cholesterol, mg/dL Triglycerides, mg/dL HDL cholesterol, mg/dL LDL cholesterol, mg/dL Blood glucose, mg/dL† HbA1c, % Current medications, n (%) Statin Antiplatelet Aspirin Cilostazol Thienopyridine§ Dual anti-platelet therapy
Progression group (n = 12)
No progression group (n = 89)
p value
11 (91.7) 74.6±10.0 22.4±2.9
58 (65.2) 72.7±10.7 22.8±3.9
0.097＊ 0.580 0.762
10 (83.3) 9 (75.0) 6 (50.0) 5 (41.7) 2 (16.7) 1 (8.3) 140.6±15.0 80.3±15.5 3 (25.0)
73 (82.0) 58 (65.2) 42 (47.2) 26 (29.2) 20 (22.4) 8 (9.0) 135.9±21.8 75.0±12.5 38 (42.7)
1.000＊ 0.746＊ 1.000＊ 0.506＊ 1.000＊ 1.000＊ 0.533 0.244 0.351＊
9 (75.0) 1 (8.3) 4 (33.3) 2 (16.7) 1 (8.3) 1 (8.3) 0 (0) 183.6±37.4 150.8±131.4 48.9±16.2 107.0±28.8 142.8±75.0 6.55±1.94
38 (42.7) 5 (5.6) 20 (22.5) 11 (12.4) 0 (0) 2 (2.2) 1 (1.1) 184.8±38.0 133.0±78.9 49.5±16.7 106.9±33.7 127.5±47.3 5.86±1.31
0.035＊
5 (41.7) 10 (83.3) 8 (66.7) 1 (8.3) 2 (16.7) 2 (16.7)
41 (46.0) 53 (59.6) 36 (40.4) 6 (6.7) 22 (24.7) 10 (11.2)
1.000＊ 0.202＊ 0.121＊ 1.000＊ 0.726＊ 0.632＊
0.881＊ 0.928 0.541 0.911 0.994 0.379 0.151
†
Incidental carotid or intracranial major artery stenosis, ＊χ2 test, §Clopidogrel and ticlopyridine are combined as Thienopyridine. The values are the means±SD.
abnormality). These assessments were performed independently by two trained neurologists who were blinded to the clinical data; good reliability was achieved (κ coefficient = 0.97). Carotid US with a 7.5-MHz linear probe (SSA770A Aplio or SSA-660A Xario, Toshiba Medical Co., Tokyo, Japan, and HDI-3000, Hitachi Co., Tokyo, Japan) was performed within five months before or after the MRI examination. Both common carotids, as well as the internal and external carotid arteries, were examined by expert neurologists following a standard-
ized protocol. The maximum IMT (maxIMT) was measured in the posterior wall of each carotid artery as the distance between the leading edge of the first and second echogenic lines. The larger maxIMT of the two carotid arteries was used for further analysis. When carotid plaque was observed, the %area stenosis was assessed, and the plaque morphology was evaluated based on its echogenicity on grey-scale images (isoechoic, hyperechoic or hypoechoic). The surface morphology was also recorded as smooth, ulcerative or movable. The following were accepted as the charac-
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Table 2. The changes in laboratory findings between the baseline and follow-up examinations Changes in laboratory findings during the follow-up period HbA1c, % FBS, mg/dL Diastolic blood pressure, mmHg TChol, mg/dL TG, mg/dL LDL, mg/dL HDL, mg/dL CRP, mg/dL
Progression n = 12 −0.65±1.68 −12.33±64.58 −3.49±15.23 −10.94±39.38 −42.34±123.47 −4.97±36.61 −0.97±14.63 −0.03±0.14
No progression n = 89
p value
0.01±0.99 3.85±50.41 −0.16±13.99 −10.93±37.40 −8.71±83.71 −8.79±31.74 0.19±13.11 0.05±0.39
0.230 0.333 0.463 0.999 0.238 0.712 0.785 0.517
The values are the means±SD.
teristics of unstable stenoses on ultrasound imaging: stenosis ≥ 70%, presence of ulcerations on the surface of the plaque and a hypoechoic (or mixed echo plaque) structure of the atherosclerotic plaque, in accordance with the accepted definition of unstable plaques 19-22). Statistical Analyses The patients with and without IMAS progression were compared. The characteristics of the subjects are reported as the means and standard deviations (SD) unless otherwise indicated, and categorical variables are presented as absolute and relative frequencies. Univariate analyses were conducted using χ2 or Fisher exact tests, the unpaired Student’s t -test or the Mann-Whitney U test, as appropriate. To identify the potential variables related to IMAS progression, these variables were classified into two types: baseline variables (i.e., general demographics, risk factors, severity of baseline IMAS, MRI white matter lesions and carotid US findings) and variables during therapy (i.e., changes in laboratory data, MRI and carotid US findings). To identify independent variables to predict IMAS progression, the two types of variables were each entered into a univariate logistic regression model, and potential factors that were not significant (p ＞ 0.1) in the univariate analyses were sequentially deleted from the full logistic regression models using a forward stepwise inclusion method to yield odds ratios (ORs) and 95% confidence intervals (CI) for independent predictors of IMAS progression. Goodness of fit (Hosmer-Lemeshow) tests were used to evaluate the fitness of the logistic regression models. All statistical analyses were performed using the IBM SPSS for Windows version 19.0 software program (IBM Inc. Japan, Tokyo, Japan).
Results The baseline characteristics of the study patients and changes in the laboratory findings during the follow-up period are shown in Tables 1 and 2. There were no significant differences between the two groups except for a history of ischemic stroke (p = 0.035). The baseline and follow-up findings on carotid US and MRI are shown in Table 3. The follow-up periods were similar between the groups. The mean maxIMT was higher in the progression group than in the nonprogression group, but the difference was not significant. In the follow-up carotid US study, the frequency of patients with carotid stenosis (area stenosis ＞ 70%) was significantly higher in the progression group than in the non-progression group (p = 0.021). The GSS was significantly greater in patients with IMAS progression than in patients without IMAS progression. There were no significant differences in the Fazekas visual scores between the two groups (Table 3). In 84 patients, the stenosis grades of both the MCA and basilar artery were stable for two years. In 11 patients, one of the three major cerebral arteries progressed, and the other two arteries were stable. In five patients, one vessel regressed, and the other vessels were stable. One patient showed progression in the right MCA from grade 0 to grade 2, regression in the left MCA from grade 3 to grade 2 and the basilar artery was stable. This patient was categorized as belonging to the progression group because of the increase in the GSS from 3 to 4. The changes in the MRA findings during the two-year follow-up period in each group are shown in Table 4. The multivariate stepwise logistic regression analysis using the baseline clinical findings in Table 1 and the baseline imaging findings in Table 3 demonstrate that the baseline GSS and an area of stenosis ≥ 70% in carotid US were independent predictors of IMAS pro-
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Table 3. The carotid US and MRI findings at the baseline and follow-up examinations
Carotid Doppler ultrasonography Mean follow-up period (months) maxIMT (mm) Baseline Follow-up Increase/year Hypoechoic plaque, n (%) Baseline Follow-up Carotid stenosis ≥ 70%, n (%) Baseline Follow-up MRI and MRA findings Mean follow-up period (month) Global stenosis score Baseline Follow-up White matter lesion Baseline PVH Baseline DSWMH Follow-up PVH Follow-up DSWMH
Progression n = 12
No progression n = 89
p value
22.9±10.1
23.1±9.6
0.948
3.38±0.88 3.88±1.42 0.433±0.867
2.97±1.46 3.24±1.52 0.134±0.542
0.187 0.173 0.102
1 (8.3) 1 (8.3)
4 (4.5) 5 (5.6)
0.476 0.541
5 (41.7) 8 (66.7)
21 (23.6) 27 (30.3)
0.288 0.021
22.0±9.5
23.0±9.2
0.728
1.50±1.38 2.58±1.31
0.42±1.01 0.33±0.80
0.000＊ 0.032＊
1.63±0.92 0.88±0.84 1.67±1.07 1.08±1.08
1.04±0.96 0.76±0.79 1.16±1.08 0.85±0.94
0.079＊ 0.647＊ 0.101＊ 0.481＊
＊
PVH, periventricular hyperintensity; DSWMH, deep subcortical white matter hyperintensity. Mann-Whitney’s U test
gression. The changes in laboratory and imaging findings shown in Tables 2 and 3 were then added to the regression model, and stepwise logistic regression analyses were performed. None of the serial changes in laboratory and imaging parameters was selected by the stepwise logistic regression, and the GSS and an area of stenosis ≥ 70% remained significant (p = 0.008 and p = 0.023, Table 5). The adjusted OR of each GSS was relatively similar, ranging from 18.58 to 25.12, and these values were larger than those for carotid stenosis (OR 10.35, 95%CI 1.38-77.80). Discussion The present study demonstrated that carotid stenosis ( ＞ 70%) and IMAS (GSS ≥ 1) at baseline were independent predictors of IMAS progression. Although the IMT has been widely used as a surrogate marker of the atherosclerotic burden in clinical practice 23-27), neither the baseline maxIMT nor the annual increase in the maxIMT was associated with IMAS progression. This discrepancy may be partially explained by the fact that the IMT and carotid stenosis may reflect different phases of atherosclerosis. The IMT may repre-
sent the subclinical early atherosclerotic process, while carotid stenosis by plaque formation may represent a later phase of atherosclerosis. Recently, Rundek et al. demonstrated that traditional risk factors are not major contributors to the variance in the carotid IMT, implying that the IMT is a separate phenotype from carotid plaque, with different underlying biological and genetic factors 11). The adjusted ORs of the presence of IMAS at baseline for IMAS progression were similar among patients with different GSS values, ranging from 18.58 to 25.12, and they were around two-fold the value of carotid stenosis (OR, 10.35). We previously reported the greater importance of the baseline severity of IMAS and the proinflammatory state evaluated by the interleukin-6 concentration compared to the conventional risk factors in a small number of patients with repeat MRA 9). Recently, conflicting results were reported by Kim et al; they found that a high severity of baseline IMAS independently predicted future regression by repeat MRA with a follow-up period of seven months 28). This discrepancy should be carefully interpreted because of the differences in the background characteristics of the study patients. The pres-
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Table 4. The changes in the magnetic resonance angiographic findings during the follow-up Progression n = 12
No progression n = 89
p value
1 (8.3) 7 (58.3) 4 (33.3)
1 (1.1) 88 (98.9) 0 (0)
0.225 0.000 0.000
0 (0) 8 (66.7) 4 (33.3)
1 (1.1) 88 (98.9) 0 (0)
1.000 0.001 0.000
0 (0) 8 (66.7) 4 (33.3)
3 (3.4) 86 (96.6) 0 (0)
1.000 0.003 0.000
Right MCA, n (%) Regression Stationary Progression Left MCA, n (%) Regression Stationary Progression BA, n (%) Regression Stationary Progression MCA, middle cerebral artery; BA, basilar artery
Table 5. The results of the final stepwise multivariate logistic regression model for IMAS progression
Severity of IMAS GSS = 0 GSS = 1 GSS = 2 GSS ≥ 3 Carotid stenosis ＞ 70%
Unadjusted OR
Adjusted OR
Reference 15.69 17.00 17.00 2.47
Reference 22.35 18.58 25.12 10.35
95% CI
p value 0.008
ent study included patients not only with IMAS, but also without IMAS at baseline, with a follow-up period of two years. MRA is a well-validated technique to evaluate intracranial vascular stenosis, and the sensitivity and specificity for the correct diagnosis of intracranial stenosis have been reported to be 70% and 99%, respectively 29). However, the MRA findings might change dynamically due to the flow void effect 30) in patients with severe vascular stenosis, even with only slight changes in stenosis or hemodynamic factors. The natural course of IMAS has been studied by several imaging modalities, such as conventional angiography, TCD and MRA. In contrast to the natural course of carotid plaques, the regression of intracranial atheromatous lesions was frequently observed in these longitudinal studies, implying that IMAS lesions are dynamic. Regression was observed in 20% in a study with repeated conventional angiography at an average interval of 26.7 months 31), 7.7% in a study using serial TCD monitoring at an average interval of 27 months 1) and 15.4-30.2% in studies using MRA at an
3.27-154.33 1.57-220.38 2.40-263.58 1.38-77.80
0.002 0.021 0.007 0.023
average interval of six to seven months 7, 8). It may be reasonable to use serial MRA findings as a surrogate marker of the effects of pharmacologic intervention, because the regression of IMAS is detectable by this noninvasive method within a relatively short period. A study of cilostazol and aspirin versus aspirin alone demonstrated that cilostazol may prevent IMAS progression 8), and a study of dual antiplatelet therapy using aspirin/cilostazol versus aspirin/clopidogrel showed similar effects on preventing IMAS progression 7). A randomized, controlled study of simvastatin versus placebo demonstrated no significant effects on IMAS progression over two years 32). However, it should be kept in mind that it may not be accurate to assess the effects of pharmacological intervention by adjusting only for traditional risk factors as confounders. The present study is associated with several potential limitations. First, the relatively small sample size may have resulted in a type Ⅱ error; the weak but significantly associated factors might have been overlooked because of the insufficient statistical power.
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Second, the present study was retrospective, and the cohort included both symptomatic and asymptomatic IMAS. Caution may be needed when calculating the size of the study population for a randomized study using the present data. Conclusion In conclusion, the presence of severe intracranial and/or extracranial vascular stenosis is an important predictor of the progression of IMAS. These factors should be considered as confounders in clinical studies using the presence of changes in MRA findings as a surrogate endpoint. Conflicts of Interest Yasuhiro Hasegawa has received fees for promotional materials from Nippon Boehringer Ingelheim Company, Bristol-Myers Squibb Company, Sanofi K.K, Mitsubishi Tanabe Pharma Corporation, Bayer Yakuhin, Ltd. and Otsuka Pharma Co., Ltd.
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Original Article
Progression of Intracranial Major Artery Stenosis is Associated with Baseline Carotid and Intracranial Atherosclerosis Heisuke Mizukami, Takahiro Shimizu, Futaba Maki, Makoto Shiraishi and Yasuhiro Hasegawa Department of Internal Medicine, Division of Neurology, St. Marianna University School of Medicine, Kanagawa, Japan
Aim: Intracranial atherosclerotic major artery stenosis (IMAS) is associated with a high risk of ischemic stroke. Carotid ultrasound (US) has been widely used to evaluate an individual’s atherosclerotic burden, but no information is available on whether the carotid US findings are associated with IMAS progression. The aim of the present study was to identify the associations among traditional risk factors, the duplex carotid US findings and IMAS progression in patients with varying degrees of carotid atherosclerosis. Methods: All patients who underwent a set of imaging studies (MRI, MRA and carotid US) in our outpatient clinic were screened. A total of 101 patients with a mean age of 75.0±10.6 years, who received the same imaging studies with a mean interval of two years, were studied. In each patient, the extent of stenosis of three arteries (both middle cerebral arteries [MCAs] and the basilar artery [BA]) was classified into five grades. The total score of the three arteries was calculated as the global stenosis score (GSS). The progression of IMAS was defined as worsening of stenosis by ≥ 1 grade on final MRA. The maximum IMT (maxIMT), plaque findings and carotid stenosis were measured by carotid US. A multivariate stepwise logistic regression analysis was used to identify independent predictors of IMAS progression. Results: Follow-up MRA revealed IMAS progression in 12 patients (11.9%). The logistic regression analysis demonstrated that the baseline GSS (p = 0.008) and carotid stenosis ≥ 70% on the baseline carotid US (p = 0.023) were significantly associated with IMAS progression. Conclusions: The baseline severity of intracranial and extracranial atherosclerosis was significantly associated with the progression of IMAS. J Atheroscler Thromb, 2015; 22:183-190. Key words: Carotid ultrasound, Intima-media thickness, Intracranial atherosclerosis, Magnetic resonance angiography, Stenosis
Introduction Intracranial atherosclerotic major artery stenosis (IMAS) is associated with a high risk of ischemic stroke, and the incidence of IMAS is known to be higher in Asian, Black, and Hispanic populations than in Caucasians 1-4). The progression or regression of IMAS can be evaluated noninvasively by transcranial Address for correspondence: Heisuke Mizukami, Department of Internal Medicine, Division of Neurology, St. Marianna University School of Medicine, 2-16-1 Sugao Miyamae-ku Kawasaki-city, Kanagawa 216-8511, Japan E-mail: [email protected] Received: May 19, 2014 Accepted for publication: July 31, 2014
Doppler ultrasound (TCD) or magnetic resonance angiography (MRA). Several clinical studies have been conducted using the presence of changes in serial TCD or MRA as a surrogate marker, with adjustment for traditional risk factors as confounders 5-10), but the predictors of IMAS progression have not yet been determined. The carotid intima-media thickness (IMT) and carotid stenosis measured by carotid ultrasound (US) have been widely used to evaluate an individual’s atherosclerotic burden. Recent studies suggest that traditional risk factors may explain ≈11% of the variance in carotid IMT 11), while the IMT and plaque may reflect different genetic and biological aspects of atherogenesis 12-15). No information is available about
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whether the IMT and carotid stenosis similarly affect intracranial atherosclerosis. To elucidate the associations among the baseline IMT, carotid stenosis and the IMAS progression, patients who underwent follow-up evaluations of both intracranial and extracranial atherosclerosis using MRA and carotid US were analyzed. The aim of this study was to identify the associations among traditional risk factors, the duplex carotid ultrasound (US) findings and IMAS progression. Methods Study Population All patients who underwent a set of imaging studies (MRI, MRA and carotid US) and underwent the same imaging studies for a follow-up evaluation of atherosclerosis in our outpatient clinic between September 2005 and April 2012 were screened. There were 224 patients who met these criteria. In this study, 133 patients who underwent a follow-up imaging study two years (±6 months) after the initial evaluation were selected for the analysis. A total of 19 patients with a poor carotid US study were excluded because of calcified plaques or complete occlusion, as were as 13 patients who underwent carotid endarterectomy or carotid stenting within two years after the initial examination. Finally, 101 patients (69 men; average age 75.0±10.6 years) were examined. The most common reason for the follow-up imaging study was routine follow-up for patients with stroke or TIA (n = 48, 47.5%). In 53 patients without a history of stroke or TIA, the follow-up imaging study was performed to evaluate asymptomatic carotid stenosis in 28 patients with IMAS (n = 10) or without IMAS (n = 18). Thus, all patients had varying degrees of carotid atherosclerosis, but IMAS was not observed in 70 patients (69%) at baseline. This study was conducted in a single hospital, and the study protocol was approved by the St. Marianna University Bioethics Committee. Clinical Data Collection The background factors and laboratory test values for each patient were evaluated at the baseline and follow-up examinations. The definitions of risk factors were as follows: Hypertension was defined as ≥ 2 blood pressure measurements of ≥ 140/90 mmHg, or a previous diagnosis of hypertension and the use of antihypertensive agents. Abnormal lipid metabolism was defined as total cholesterol ≥ 220 mg/dL, neutral fat levels ≥ 1 50 mg/dL, HDL cholesterol ＜ 40 mg/dL or the use of oral agents. Diabetes was considered to be
present if the patient showed fasting blood glucose levels ≥ 126 mg/dL and a HbA1c value ≥ 6.5%, or if treatment for diabetes was being administered. Using information from the medical records at baseline, the patients were classified as non-smokers or smokers. Non-smokers included never-smokers who had never smoked in their lifetime and ex-smokers who had previously smoked. Smokers were defined as current smokers at baseline. Chronic kidney disease (CKD) was defined by decreased kidney function (characterized by a reduced estimated glomerular filtration rate [eGFR] ＜ 60 mL/min/1.73 m2), kidney damage characterized by albuminuria or proteinuria for more than three months or as CKD diagnosed before entry into this study 16). Evaluation of Stenosis and the Progression of Atherosclerotic Lesions MRI and MRA were performed using an Excelart (1.5T, Toshiba Medical Co., Tokyo, Japan) or an Achieva Nova Dual (1.5T, Phillips Co., Tokyo, Japan) scanner. MRA was performed using a three-dimensional time-of-flight gradient-echo technique for the intracranial arteries. After completion of all data collection in all participants, baseline and follow-up MRA images were examined by three experienced stroke neurologists who were blinded to the patients’ clinical information. The extent of stenosis of three arteries (both middle cerebral arteries (MCAs) and the basilar artery) in each patient was classified into fives grades: 0 (normal; no signal reduction), 1 (mild; signal reduction ＜ 50%), 2 (moderate; signal reduction ＞ 50%), 3 (severe; focal signal loss with the presence of a distal MCA signal) and 4 (occlusion) 7-9, 17). The stenosis grade was decided by agreement between at least two neurologists. When there was no agreement, the stenosis was graded by consensus after reassessment of the MRA images. The total score for the three arteries on the baseline MRA images was calculated as the baseline global stenosis score. Progression was defined as worsening of stenosis by one or more grades on final MRA, whereas regression was defined as an improvement of stenosis by one or more grades compared with the findings of baseline MRA. Patients with IMAS progression in at least one vessel were classified as the progression (＋) group, and the other patients were classified as the progression (−) group. Fluid-attenuated inversion recovery (FLAIR) images were used to assess the severity of white matter changes according to the Fazekas classification system 18). This widely used scale rates DWML and PVWML separately using a four-point scale for each, with WMLs scored from 0 (absent) to 3 (marked
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Table 1. The patients’ characteristics
Men, n (%) Age, years Body mass index, kg/m2 Comorbidity, n (%) Hypertension Dyslipidemia Diabetes mellitus Current smoker Chronic kidney disease Atrial fibrillation Systolic blood pressure, mmHg Diastolic blood pressure, mmHg Baseline Rankin score ＞ 1, n (%) History of stroke, n (%) Ischemic stroke TIA Lacunar Atherothrombotic Cardioembolic Other Brain hemorrhage Total cholesterol, mg/dL Triglycerides, mg/dL HDL cholesterol, mg/dL LDL cholesterol, mg/dL Blood glucose, mg/dL† HbA1c, % Current medications, n (%) Statin Antiplatelet Aspirin Cilostazol Thienopyridine§ Dual anti-platelet therapy
Progression group (n = 12)
No progression group (n = 89)
p value
11 (91.7) 74.6±10.0 22.4±2.9
58 (65.2) 72.7±10.7 22.8±3.9
0.097＊ 0.580 0.762
10 (83.3) 9 (75.0) 6 (50.0) 5 (41.7) 2 (16.7) 1 (8.3) 140.6±15.0 80.3±15.5 3 (25.0)
73 (82.0) 58 (65.2) 42 (47.2) 26 (29.2) 20 (22.4) 8 (9.0) 135.9±21.8 75.0±12.5 38 (42.7)
1.000＊ 0.746＊ 1.000＊ 0.506＊ 1.000＊ 1.000＊ 0.533 0.244 0.351＊
9 (75.0) 1 (8.3) 4 (33.3) 2 (16.7) 1 (8.3) 1 (8.3) 0 (0) 183.6±37.4 150.8±131.4 48.9±16.2 107.0±28.8 142.8±75.0 6.55±1.94
38 (42.7) 5 (5.6) 20 (22.5) 11 (12.4) 0 (0) 2 (2.2) 1 (1.1) 184.8±38.0 133.0±78.9 49.5±16.7 106.9±33.7 127.5±47.3 5.86±1.31
0.035＊
5 (41.7) 10 (83.3) 8 (66.7) 1 (8.3) 2 (16.7) 2 (16.7)
41 (46.0) 53 (59.6) 36 (40.4) 6 (6.7) 22 (24.7) 10 (11.2)
1.000＊ 0.202＊ 0.121＊ 1.000＊ 0.726＊ 0.632＊
0.881＊ 0.928 0.541 0.911 0.994 0.379 0.151
†
Incidental carotid or intracranial major artery stenosis, ＊χ2 test, §Clopidogrel and ticlopyridine are combined as Thienopyridine. The values are the means±SD.
abnormality). These assessments were performed independently by two trained neurologists who were blinded to the clinical data; good reliability was achieved (κ coefficient = 0.97). Carotid US with a 7.5-MHz linear probe (SSA770A Aplio or SSA-660A Xario, Toshiba Medical Co., Tokyo, Japan, and HDI-3000, Hitachi Co., Tokyo, Japan) was performed within five months before or after the MRI examination. Both common carotids, as well as the internal and external carotid arteries, were examined by expert neurologists following a standard-
ized protocol. The maximum IMT (maxIMT) was measured in the posterior wall of each carotid artery as the distance between the leading edge of the first and second echogenic lines. The larger maxIMT of the two carotid arteries was used for further analysis. When carotid plaque was observed, the %area stenosis was assessed, and the plaque morphology was evaluated based on its echogenicity on grey-scale images (isoechoic, hyperechoic or hypoechoic). The surface morphology was also recorded as smooth, ulcerative or movable. The following were accepted as the charac-
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Table 2. The changes in laboratory findings between the baseline and follow-up examinations Changes in laboratory findings during the follow-up period HbA1c, % FBS, mg/dL Diastolic blood pressure, mmHg TChol, mg/dL TG, mg/dL LDL, mg/dL HDL, mg/dL CRP, mg/dL
Progression n = 12 −0.65±1.68 −12.33±64.58 −3.49±15.23 −10.94±39.38 −42.34±123.47 −4.97±36.61 −0.97±14.63 −0.03±0.14
No progression n = 89
p value
0.01±0.99 3.85±50.41 −0.16±13.99 −10.93±37.40 −8.71±83.71 −8.79±31.74 0.19±13.11 0.05±0.39
0.230 0.333 0.463 0.999 0.238 0.712 0.785 0.517
The values are the means±SD.
teristics of unstable stenoses on ultrasound imaging: stenosis ≥ 70%, presence of ulcerations on the surface of the plaque and a hypoechoic (or mixed echo plaque) structure of the atherosclerotic plaque, in accordance with the accepted definition of unstable plaques 19-22). Statistical Analyses The patients with and without IMAS progression were compared. The characteristics of the subjects are reported as the means and standard deviations (SD) unless otherwise indicated, and categorical variables are presented as absolute and relative frequencies. Univariate analyses were conducted using χ2 or Fisher exact tests, the unpaired Student’s t -test or the Mann-Whitney U test, as appropriate. To identify the potential variables related to IMAS progression, these variables were classified into two types: baseline variables (i.e., general demographics, risk factors, severity of baseline IMAS, MRI white matter lesions and carotid US findings) and variables during therapy (i.e., changes in laboratory data, MRI and carotid US findings). To identify independent variables to predict IMAS progression, the two types of variables were each entered into a univariate logistic regression model, and potential factors that were not significant (p ＞ 0.1) in the univariate analyses were sequentially deleted from the full logistic regression models using a forward stepwise inclusion method to yield odds ratios (ORs) and 95% confidence intervals (CI) for independent predictors of IMAS progression. Goodness of fit (Hosmer-Lemeshow) tests were used to evaluate the fitness of the logistic regression models. All statistical analyses were performed using the IBM SPSS for Windows version 19.0 software program (IBM Inc. Japan, Tokyo, Japan).
Results The baseline characteristics of the study patients and changes in the laboratory findings during the follow-up period are shown in Tables 1 and 2. There were no significant differences between the two groups except for a history of ischemic stroke (p = 0.035). The baseline and follow-up findings on carotid US and MRI are shown in Table 3. The follow-up periods were similar between the groups. The mean maxIMT was higher in the progression group than in the nonprogression group, but the difference was not significant. In the follow-up carotid US study, the frequency of patients with carotid stenosis (area stenosis ＞ 70%) was significantly higher in the progression group than in the non-progression group (p = 0.021). The GSS was significantly greater in patients with IMAS progression than in patients without IMAS progression. There were no significant differences in the Fazekas visual scores between the two groups (Table 3). In 84 patients, the stenosis grades of both the MCA and basilar artery were stable for two years. In 11 patients, one of the three major cerebral arteries progressed, and the other two arteries were stable. In five patients, one vessel regressed, and the other vessels were stable. One patient showed progression in the right MCA from grade 0 to grade 2, regression in the left MCA from grade 3 to grade 2 and the basilar artery was stable. This patient was categorized as belonging to the progression group because of the increase in the GSS from 3 to 4. The changes in the MRA findings during the two-year follow-up period in each group are shown in Table 4. The multivariate stepwise logistic regression analysis using the baseline clinical findings in Table 1 and the baseline imaging findings in Table 3 demonstrate that the baseline GSS and an area of stenosis ≥ 70% in carotid US were independent predictors of IMAS pro-
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Table 3. The carotid US and MRI findings at the baseline and follow-up examinations
Carotid Doppler ultrasonography Mean follow-up period (months) maxIMT (mm) Baseline Follow-up Increase/year Hypoechoic plaque, n (%) Baseline Follow-up Carotid stenosis ≥ 70%, n (%) Baseline Follow-up MRI and MRA findings Mean follow-up period (month) Global stenosis score Baseline Follow-up White matter lesion Baseline PVH Baseline DSWMH Follow-up PVH Follow-up DSWMH
Progression n = 12
No progression n = 89
p value
22.9±10.1
23.1±9.6
0.948
3.38±0.88 3.88±1.42 0.433±0.867
2.97±1.46 3.24±1.52 0.134±0.542
0.187 0.173 0.102
1 (8.3) 1 (8.3)
4 (4.5) 5 (5.6)
0.476 0.541
5 (41.7) 8 (66.7)
21 (23.6) 27 (30.3)
0.288 0.021
22.0±9.5
23.0±9.2
0.728
1.50±1.38 2.58±1.31
0.42±1.01 0.33±0.80
0.000＊ 0.032＊
1.63±0.92 0.88±0.84 1.67±1.07 1.08±1.08
1.04±0.96 0.76±0.79 1.16±1.08 0.85±0.94
0.079＊ 0.647＊ 0.101＊ 0.481＊
＊
PVH, periventricular hyperintensity; DSWMH, deep subcortical white matter hyperintensity. Mann-Whitney’s U test
gression. The changes in laboratory and imaging findings shown in Tables 2 and 3 were then added to the regression model, and stepwise logistic regression analyses were performed. None of the serial changes in laboratory and imaging parameters was selected by the stepwise logistic regression, and the GSS and an area of stenosis ≥ 70% remained significant (p = 0.008 and p = 0.023, Table 5). The adjusted OR of each GSS was relatively similar, ranging from 18.58 to 25.12, and these values were larger than those for carotid stenosis (OR 10.35, 95%CI 1.38-77.80). Discussion The present study demonstrated that carotid stenosis ( ＞ 70%) and IMAS (GSS ≥ 1) at baseline were independent predictors of IMAS progression. Although the IMT has been widely used as a surrogate marker of the atherosclerotic burden in clinical practice 23-27), neither the baseline maxIMT nor the annual increase in the maxIMT was associated with IMAS progression. This discrepancy may be partially explained by the fact that the IMT and carotid stenosis may reflect different phases of atherosclerosis. The IMT may repre-
sent the subclinical early atherosclerotic process, while carotid stenosis by plaque formation may represent a later phase of atherosclerosis. Recently, Rundek et al. demonstrated that traditional risk factors are not major contributors to the variance in the carotid IMT, implying that the IMT is a separate phenotype from carotid plaque, with different underlying biological and genetic factors 11). The adjusted ORs of the presence of IMAS at baseline for IMAS progression were similar among patients with different GSS values, ranging from 18.58 to 25.12, and they were around two-fold the value of carotid stenosis (OR, 10.35). We previously reported the greater importance of the baseline severity of IMAS and the proinflammatory state evaluated by the interleukin-6 concentration compared to the conventional risk factors in a small number of patients with repeat MRA 9). Recently, conflicting results were reported by Kim et al; they found that a high severity of baseline IMAS independently predicted future regression by repeat MRA with a follow-up period of seven months 28). This discrepancy should be carefully interpreted because of the differences in the background characteristics of the study patients. The pres-
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Table 4. The changes in the magnetic resonance angiographic findings during the follow-up Progression n = 12
No progression n = 89
p value
1 (8.3) 7 (58.3) 4 (33.3)
1 (1.1) 88 (98.9) 0 (0)
0.225 0.000 0.000
0 (0) 8 (66.7) 4 (33.3)
1 (1.1) 88 (98.9) 0 (0)
1.000 0.001 0.000
0 (0) 8 (66.7) 4 (33.3)
3 (3.4) 86 (96.6) 0 (0)
1.000 0.003 0.000
Right MCA, n (%) Regression Stationary Progression Left MCA, n (%) Regression Stationary Progression BA, n (%) Regression Stationary Progression MCA, middle cerebral artery; BA, basilar artery
Table 5. The results of the final stepwise multivariate logistic regression model for IMAS progression
Severity of IMAS GSS = 0 GSS = 1 GSS = 2 GSS ≥ 3 Carotid stenosis ＞ 70%
Unadjusted OR
Adjusted OR
Reference 15.69 17.00 17.00 2.47
Reference 22.35 18.58 25.12 10.35
95% CI
p value 0.008
ent study included patients not only with IMAS, but also without IMAS at baseline, with a follow-up period of two years. MRA is a well-validated technique to evaluate intracranial vascular stenosis, and the sensitivity and specificity for the correct diagnosis of intracranial stenosis have been reported to be 70% and 99%, respectively 29). However, the MRA findings might change dynamically due to the flow void effect 30) in patients with severe vascular stenosis, even with only slight changes in stenosis or hemodynamic factors. The natural course of IMAS has been studied by several imaging modalities, such as conventional angiography, TCD and MRA. In contrast to the natural course of carotid plaques, the regression of intracranial atheromatous lesions was frequently observed in these longitudinal studies, implying that IMAS lesions are dynamic. Regression was observed in 20% in a study with repeated conventional angiography at an average interval of 26.7 months 31), 7.7% in a study using serial TCD monitoring at an average interval of 27 months 1) and 15.4-30.2% in studies using MRA at an
3.27-154.33 1.57-220.38 2.40-263.58 1.38-77.80
0.002 0.021 0.007 0.023
average interval of six to seven months 7, 8). It may be reasonable to use serial MRA findings as a surrogate marker of the effects of pharmacologic intervention, because the regression of IMAS is detectable by this noninvasive method within a relatively short period. A study of cilostazol and aspirin versus aspirin alone demonstrated that cilostazol may prevent IMAS progression 8), and a study of dual antiplatelet therapy using aspirin/cilostazol versus aspirin/clopidogrel showed similar effects on preventing IMAS progression 7). A randomized, controlled study of simvastatin versus placebo demonstrated no significant effects on IMAS progression over two years 32). However, it should be kept in mind that it may not be accurate to assess the effects of pharmacological intervention by adjusting only for traditional risk factors as confounders. The present study is associated with several potential limitations. First, the relatively small sample size may have resulted in a type Ⅱ error; the weak but significantly associated factors might have been overlooked because of the insufficient statistical power.
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Second, the present study was retrospective, and the cohort included both symptomatic and asymptomatic IMAS. Caution may be needed when calculating the size of the study population for a randomized study using the present data. Conclusion In conclusion, the presence of severe intracranial and/or extracranial vascular stenosis is an important predictor of the progression of IMAS. These factors should be considered as confounders in clinical studies using the presence of changes in MRA findings as a surrogate endpoint. Conflicts of Interest Yasuhiro Hasegawa has received fees for promotional materials from Nippon Boehringer Ingelheim Company, Bristol-Myers Squibb Company, Sanofi K.K, Mitsubishi Tanabe Pharma Corporation, Bayer Yakuhin, Ltd. and Otsuka Pharma Co., Ltd.
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