Abstract
Aims: Although several antihypertensive agents reduced the carotid intima-media thickness (IMT), it remains unclear whether those agents affect the interadventitial diameter (IAD). We aimed to examine whether cilnidipine, an L/N-type calcium channel blocker, reduced the common carotid IMT or IAD in post-stroke hypertensive patients.
Methods: The common carotid IMT and IAD were measured at the start of cilnidipine treatment and 12 months from that. The changes in the mean max-IMT or IAD between baseline and the 12-month follow-up were evaluated and compared between the thick group (max-IMT ≥ 1.1 mm) and the normal group (max-IMT < 1.1 mm).
Results: A total of 603 post-stroke hypertensive subjects (mean age = 69.3 yr, 378 males) were included in the analysis. At baseline, IAD was increased stepwise according to the value of max-IMT (p for trend < 0.001). Among them, 326 subjects were followed up for 12 months. The mean max-IMT from baseline to 12 months did not change in the normal group (−0.01 mm, 95% confidence interval [CI] −0.03 to 0.01, n = 170), whereas a significant reduction was observed in the thick group (−0.09 mm, 95% CI −0.13 to −0.05, n = 156). The mean IAD was significantly reduced during the study period in the normal group (−0.14 mm, 95% CI −0.22 to −0.05) as well as in the thick group (−0.12 mm, 95% CI −0.21 to −0.03).
Conclusions: Cilnidipine promoted the regression of common carotid IMT in post-stroke hypertensive patients, especially in the thick group. Cilnidipine also reduced the IAD in both normal and thick groups.
Keywords: Cilnidipine, Carotid artery, Positive remodeling, Intima-media thickness, Post-stroke, hypertensive
Introduction
Atherosclerosis is a major cause of cardiovascular death. Several studies have investigated the indicators of carotid intima–media thickness (IMT) progression, because the common carotid IMT and its progression are considered as surrogate markers for atherosclerosis1–3). The progression of IMT was positively associated with the incident stroke4, 5). A high IMT also predicts a higher risk of stroke recurrence6, 7).
Therefore, several trials using antihypertensive or lipid-lowering agents have used the carotid IMT as a clinical endpoint8, 9). Although there is accumulating evidence for the association between carotid IMT and cerebral and cardiovascular events, the associations between carotid IMT regression and clinical outcomes are not conclusive10). More recently, several studies have reported that the common carotid interadventitial diameter (IAD) is associated with vascular risk factors, carotid IMT, left ventricular mass, and myocardial infarction11–13). In addition, Polak et al. showed that IAD was a stronger predictor of ischemic stroke than carotid IMT14). However, it remains unclear whether medical intervention reduces the carotid IAD.
The Carotid Atherosclerosis-Antihypertensive Treatment Trial, Effect of N-type Calcium Channel Blocker for Cerebrovascular Disease (CA-ATTEND) study is a 12-month, large-scale (n = 2,667), prospective postmarketing surveillance (PMS) study in which the efficacy and safety of cilnidipine were investigated in registered post-stroke hypertensive patients on the basis of pressure (BP) and atherosclerosis of the common carotid arteries15). Cilnidipine is a dual L/N-Type calcium channel blocker that can block not only L-type vascular calcium channels but also N-type calcium channels in the sympathetic nerves16).
In the present study, the effects of cilnidipine on the regression of atherosclerosis, estimated by the carotid IMT or IAD, were evaluated.
Materials and Methods
Study Design and Patients
The study design, patient characteristics, and main BP results of the CA-ATTEND study have been reported elsewhere15). This study was registered in the University Hospital Medical Information Network Clinical Trials Registry (UMIN000005523). This study was carried out according to the Good Post-marketing Study Practice established by the Ministry of Health, Labour and Welfare of Japan. Briefly, the subjects of this study were hypertensive patients with a history of stroke who newly began cilnidipine treatment between May 2011 and June 2013, and they were recruited from throughout Japan. The observational period was 12 months. The observation items included patient characteristics (sex, age, height, weight, stroke subtype, presence/absence and types of complications, laboratory data related to lifestyle-related disease, etc.), BP, and concomitant agents. The protocol was reviewed and accepted by the ethics committees of the Hiroshima University and by each site where this study was conducted when required from each committee. A written informed consent was not required since this was an observational study in daily medical practice, and not an interventional study.
Carotid Artery Measurements by Ultrasonography
Carotid ultrasonography and measurements on the image were performed according to the methods in the J-STARS Echo study17). Ultrasonography was performed before starting treatment and after 12 months of follow-up by expert sonographers. The authorization of qualified sonographers followed the standardized examination criteria in the J-STARS Echo study. Before recruiting the subjects, recorded image data of the common carotid artery of volunteers were submitted to the CA-ATTEND secretariat (CA-ATTEND Central Office, US-ism Co., Ltd., Tokyo, Japan). Participation in this study was allowed for only the sonographers who met the CA-ATTEND criteria, for example, providing scans that clearly showed the long and minor axis views of both common carotid arteries and clearly depicted the arteria vertebralis. Each patient was examined by the same sonographer with the same equipment (high-resolution B-mode ultrasound scanners). The expert sonographers recorded all scans as movies for more than five heart rates and sent them to the CA-ATTEND central office. All saved images were transferred to a personal computer for semi-automated measurements. To avoid interreader variability, all images were read by two of the three observers using the semi-automated digital measurement software (IntimaScope, Version 5.0 R; Media Cross Co, Ltd., Tokyo, Japan)18). Two independent observers determined the lumen diameter (LD), IAD, max-IMT, and mean-IMT of the far wall of every bilateral common carotid artery at end-diastole. The coefficients of correlation for the values between the two observers were 1.00 for the left max-IMT (p < 0.001), 0.99 for the left mean-IMT (p < 0.001), 0.98 for the left IAD (p < 0.001), 0.98 for the left LD (p < 0.001), 0.99 for the right max-IMT (p < 0.001), 0.99 for the right mean-IMT (p < 0.001), 0.99 for the right IAD (p < 0.001), and 0.98 for the right LD (p < 0.001).
We used the max-IMT, mean-IMT, IAD, and LD of the common carotid artery, on the side with the greater max-IMT, for the arteriosclerosis evaluation. Carotid plaque was generally defined as a lesion with a focal IMT of 1.1 mm or more in Japan19–23). Therefore, we divided subject into the thick group (max-IMT ≥ 1.1 mm) and the normal group (max-IMT < 1.1 mm). If subjects had the carotid plaques, we measured the max-IMT including it.
Statistical Analysis
The data are expressed as the mean ± standard deviation, mean (95% confidence interval [CI]), or median (25th to 75th percentiles). Fisher's exact test or Wilcoxon rank-sum test was used for categorical data, and t-tests were used for continuous data. Dunnett's test was used for multiple comparisons. The Jonckheere–Terpstra test was used for trend analysis. Analysis of covariance (ANCOVA) was used to verify differences in carotid ultrasonography parameters after adjustment for unbalanced baseline subject characteristics. Pearson correlation coefficients were employed to examine the relationships. Multiple linear regression analysis was used to examine the effects of the baseline characteristics (age, sex, smoking habit [current smoker + ex-smoker], dyslipidemia, and diabetes mellitus) or concomitant agents (angiotensin II [AII] receptor blockers [ARBs], statins, and antiplatelet agents) on the changes of the max-IMT or IAD. A p-value < 0.05 was considered statistically significant.
The primary outcome was the change in the mean common carotid max-IMT or IAD from baseline to 12 months, compared between the thick group (max-IMT ≥ 1.1 mm) and the normal group (max-IMT < 1.1 mm).
All statistical analyses were performed using a statistical software package (JMP, version 12.2.0; SAS Institute, Cary, NC, USA).
Results
Demographic Data and Baseline Max-IMT or IAD
In the CA-ATTEND study, 2,667 patients were registered in 314 hospitals. Of those hospitals, 81 hospitals with trained sonographers recruited the subjects (n = 618) with a baseline evaluation of IMT for CA-ATTEND Echo Study. Among them, 15 patients were excluded because they did not have carotid diameter evaluations. The remaining 603 subjects were included in the analysis. The characteristics of the 603 subjects are shown in Table 1. The mean age was 69.3 yr, and male patients accounted for 62.7% of the subjects. The mean office systolic BP and diastolic BP were 152.7 and 84.3 mmHg, respectively. In the thick group, the subjects were older than those in the normal group; the incidence of dyslipidemia, diabetes mellitus, coronary artery disease, and cerebral infarction was higher; and the incidence of subarachnoid hemorrhage was lower. The diastolic office BP was lower, and glycated hemoglobin (HbA1c) was higher in the thick group. The coadministration ratio of statins or antiplatelet agents was higher in the thick group. The other baseline patient characteristics were not different between the thick and normal groups. The baseline mean max-IMT was 1.20 mm (95% CI 1.17 to 1.24, n = 603), and baseline IAD was 8.07 mm (95% CI 8.00 to 8.15, n = 603). The relationships between laboratory data and max-IMT or IAD are shown in Supplementary Figs. 1 and 2. The baseline max-IMT and baseline IAD were positively associated with age (r = 0.17, p < 0.001, n = 603; and r = 0.20, p < 0.001, n = 603, respectively) and negatively with estimated glomerular filtration rate (r = −0.14, p = 0.005, n = 388; and r = −0.17, p = 0.001, n = 388, respectively). Additionally, the baseline IAD was positively associated with body mass index (r = 0.11, p = 0.021, n = 451). All subjects were divided into quartiles on the basis of the baseline max-IMT values. IAD was increased stepwise according to the value of max-IMT (p for trend < 0.001, n = 603, Fig. 1). However, no association with LD was observed in these quartiles (p for trend = 0.074, n = 603).
Table 1. Baseline characteristics of subjects.
| Factors | Total (n = 603) | Normal group (max-IMT < 1.1 mm) (n = 302) | Thick group (max-IMT ≥ 1.1 mm) (n = 301) | p value |
|---|---|---|---|---|
| Age, years | 69.3 ± 10.5 | 68.0 ± 11.4 | 70.7 ± 9.2 | 0.002 |
| Male, n (%) | 378 (62.7) | 187 (61.9) | 191 (63.5) | 0.736 |
| BMI, kg/m2 | 23.5 ± 3.4 (n = 451) | 23.3 ± 3.3 (n = 225) | 23.7 ± 3.5 (n = 226) | 0.213 |
| mRS score | 1 (0 to 2) | 1 (0 to 2) | 1 (0 to 2) | 0.466 |
| Concomitant disease | ||||
| Dyslipidemia, n (%) | 295 (48.9) | 133 (44.0) | 162 (53.8) | 0.018 |
| Diabetes mellitus, n (%) | 120 (19.9) | 50 (16.6) | 70 (23.3) | 0.042 |
| Coronary artery disease, n (%) | 38 (6.3) | 11 (3.6) | 27 (9.0) | 0.007 |
| Stroke historya | ||||
| Cerebral infarction, n (%) | 475 (78.8) | 221 (73.2) | 254 (84.4) | 0.001 |
| Small vessel occlusion, n (%) | 230 (38.1) | 109 (36.1) | 121 (40.2) | 0.315 |
| Large artery atherosclerosis, n (%) | 170 (28.2) | 70 (23.2) | 100 (33.2) | 0.007 |
| Cardioembolism, n (%) | 26 (4.3) | 15 (5.0) | 11 (3.7) | 0.548 |
| Others, n (%) | 52 (8.6) | 28 (9.3) | 24 (8.0) | 0.664 |
| Cerebral hemorrhage, n (%) | 94 (15.6) | 49 (16.2) | 45 (15.0) | 0.736 |
| SAH, n (%) | 46 (7.6) | 35 (11.6) | 11 (3.7) | < 0.001 |
| Smoking habitb | 279 (46.3) | 131 (43.4) | 148 (49.2) | 0.165 |
| Drinking habit | 220 (36.5) | 108 (35.8) | 112 (37.2) | 0.735 |
| Daily dose of cilnidipine, mg/day | 10.2 ± 3.1 | 10.0 ± 2.9 | 10.5 ± 3.3 | 0.056 |
| Anti-hypertensives | ||||
| ARBs, n (%) | 226 (37.5) | 108 (35.8) | 118 (39.2) | 0.401 |
| CCBs, n (%) | 49 (8.1) | 21 (7.0) | 28 (9.3) | 0.301 |
| ACE inhibitors, n (%) | 20 (3.3) | 9 (3.0) | 11 (3.7) | 0.658 |
| Diuretics, n (%) | 48 (8.0) | 30 (9.9) | 18 (6.0) | 0.097 |
| Statins, n (%) | 195 (32.3) | 77 (25.5) | 118 (39.2) | < 0.001 |
| Antiplatelet agents, n (%) | 324 (53.7) | 146 (48.3) | 178 (59.1) | 0.009 |
| Warfarin, n (%) | 25 (4.1) | 14 (4.6) | 11 (3.7) | 0.684 |
| Office systolic BP, mmHg | 152.7 ± 23.3 (n = 553) | 152.6 ± 23.5 (n = 277) | 152.8 ± 23.1 (n = 276) | 0.912 |
| Office diastolic BP, mmHg | 84.3 ± 14.6 (n = 550) | 85.9 ± 15.3 (n = 277) | 82.7 ± 13.8 (n = 273) | 0.012 |
| Office pulse rate, beats/min | 77.5 ± 13.8 (n = 478) | 77.3 ± 14.7 (n = 238) | 77.6 ± 12.8 (n = 240) | 0.861 |
| eGFR, mL/min/1.73 m2 | 68.2 ± 19.5 (n = 388) | 69.7 ± 21.5 (n = 202) | 66.6 ± 17.0 (n = 186) | 0.110 |
| HbA1c, % | 6.1 ± 0.9 (n = 270) | 6.0 ± 0.8 (n = 137) | 6.2 ± 1.0 (n = 133) | 0.030 |
| Total cholesterol, mg/dL | 191.8 ± 36.5 (n = 325) | 190.3 ± 37.8 (n = 169) | 193.5 ± 35.1 (n = 156) | 0.429 |
| HDL cholesterol, mg/dL | 55.0 ± 14.9 (n = 323) | 55.3 ± 14.7 (n = 163) | 54.6 ± 15.1 (n = 160) | 0.644 |
| LDL cholesterol, mg/dL | 112.4 ± 31.8 (n = 318) | 109.7 ± 31.2 (n = 165) | 115.3 ± 32.3 (n = 153) | 0.114 |
Data are shown as the number of subjects (%), the mean ± SD, or median (25th to 75th percentiles).
The clinical subtype of stroke included cases in which more than one subtype of stroke was recorded in the same patient.
Smoking habit, current smoker, and ex-smoker.
Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BMI, body mass index; BP, blood pressure; CCBs, calcium channel blockers; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein; mRS, modified Rankin scale; SAH, subarachnoid hemorrhage.
Supplementary Fig. 1.
The associations between baseline max-IMT and patient characteristics.
A. The association between max-IMT and age.
B. The association between max-IMT and office systolic blood pressure (BP).
C. The association between max-IMT and office pulse rate.
D. The association between max-IMT and body mass index (BMI).
E. The association between max-IMT and estimated glomerular filtration rate (eGFR).
F. The association between max-IMT and glycated hemoglobin (HbA1c).
G. The association between max-IMT and total cholesterol.
H. The association between max-IMT and low-density lipoprotein (LDL) cholesterol.
I. The association between max-IMT and high-density lipoprotein (HDL) cholesterol.
Pearson's correlation coefficients (r) and the associated p values are shown.
Abbreviation: IMT, intima-media thickness.
Supplementary Fig. 2.
The associations between baseline IAD and patient characteristics.
A. The association between IAD and age.
B. The association between IAD and office systolic blood pressure (BP).
C. The association between IAD and office pulse rate.
D. The association between IAD and body mass index (BMI).
E. The association between IAD and estimated glomerular filtration rate (eGFR).
F. The association between IAD and glycated hemoglobin (HbA1c).
G. The association between IAD and total cholesterol.
H. The association between IAD and low-density lipoprotein (LDL) cholesterol.
I. The association between IAD and high-density lipoprotein (HDL) cholesterol.
Pearson's correlation coefficients (r) and the associated p values are shown.
Abbreviation: IAD, interadventitial diameter.
Fig. 1.
Changes in IAD and LD at the quartile of max-IMT in the carotid arteries.
The increasing trend of LD or IAD in the quartile of max-IMT was analyzed using the Jonckheere–Terpstra test. The difference in IAD was calculated using Dunnett's test. *p < 0.05, **p < 0.01, ***p < 0.001 vs. < 0.95 mm group.
Abbreviations: CI, confidence interval; IAD, interadventitial diameter; IMT, intima-media thickness; LD, lumen diameter.
Changes in Max-IMT or IAD
Among the 603 subjects evaluated, 326 subjects had carotid ultrasonography at 12 months of follow-up. The subjects with follow-up had some considerable differences from the subjects without follow-up (Supplementary Table 1). The subjects with follow-up had a lower modified Rankin scale score at enrollment. The proportion of subjects with antiplatelet agents was high, and warfarin was low in the subjects with follow-up. Additionally, the subjects with follow-up had lower office systolic BP, diastolic BP, and HbA1c. In 326 subjects who had follow-up carotid ultrasonography, changes in IMT and carotid diameters were evaluated (Table 2). The characteristics of 326 subjects, 170 subjects in the normal group and 156 subjects in the thick group, are shown in Supplementary Table 2. The mean change in max-IMT, mean-IMT, and IAD from baseline to 12 months were −0.05 mm (95% CI −0.07 to −0.03, n = 326), −0.03 mm (95% CI −0.05 to −0.02, n = 326), and −0.13 mm (95% CI −0.19 to −0.07, n = 326), respectively. However, the mean LD did not decrease significantly (−0.06 mm, 95% CI −0.13 to 0.00, n = 326). The change in max-IMT from baseline to 12 months after cilnidipine treatment was negatively correlated with baseline max-IMT (r = −0.21, p < 0.001, n = 326, Supplementary Fig. 3A). The change in IAD from baseline to 12 months after cilnidipine treatment was also negatively correlated with baseline IAD (r = −0.36, p < 0.001, n = 326, Supplementary Fig. 3B).
Supplementary Table 1. Baseline characteristics of subjects with and without follow-up.
| Factors | Subjects with follow-up (n = 326) | Subjects without follow-up (n = 277) | p value |
|---|---|---|---|
| Age, years | 69.1 ± 9.6 | 69.6 ± 11.4 | 0.527 |
| Male, n (%) | 209 (64.1) | 169 (61.0) | 0.448 |
| BMI, kg/m2 | 23.5 ± 3.2 (n = 261) | 23.5 ± 3.7 (n = 190) | 0.927 |
| mRS score | 1 (0 to 1.25) | 1 (0 to 2) | 0.011 |
| Concomitant disease | |||
| Dyslipidemia, n (%) | 171 (52.5) | 124 (44.8) | 0.061 |
| Diabetes mellitus, n (%) | 57 (17.5) | 63 (22.7) | 0.125 |
| Coronary artery disease, n (%) | 20 (6.1) | 18 (6.5) | 0.868 |
| Stroke historya | |||
| Cerebral infarction, n (%) | 257 (78.8) | 218 (78.7) | 1.000 |
| Small vessel occlusion, n (%) | 129 (39.6) | 101 (36.5) | 0.450 |
| Large artery atherosclerosis, n (%) | 97 (29.8) | 73 (26.4) | 0.365 |
| Cardioembolism, n (%) | 8 (2.5) | 18 (6.5) | 0.016 |
| Others, n (%) | 25 (7.7) | 27 (9.7) | 0.385 |
| Cerebral hemorrhage, n (%) | 46 (14.1) | 48 (17.3) | 0.311 |
| SAH, n (%) | 30 (9.2) | 16 (5.8) | 0.125 |
| Smoking habitb | 155 (47.5) | 124 (44.8) | 0.513 |
| Drinking habit | 112 (34.4) | 108 (39.0) | 0.270 |
| Daily dose of cilnidipine, mg/day | 10.3 ± 3.0 | 10.2 ± 3.2 | 0.622 |
| Anti-hypertensives | |||
| ARBs, n (%) | 117 (35.9) | 109 (39.4) | 0.399 |
| CCBs, n (%) | 28 (8.6) | 21 (7.6) | 0.765 |
| ACE inhibitors, n (%) | 11 (3.4) | 9 (3.2) | 1.000 |
| Diuretics, n (%) | 20 (6.1) | 28 (10.1) | 0.096 |
| Statins, n (%) | 113 (34.7) | 82 (29.6) | 0.191 |
| Antiplatelet agents, n (%) | 190 (58.3) | 134 (48.4) | 0.017 |
| Warfarin, n (%) | 8 (2.5) | 17 (6.1) | 0.038 |
| Office systolic BP, mmHg | 150.6 ± 21.6 (n = 299) | 155.1 ± 24.9 (n = 254) | 0.025 |
| Office diastolic BP, mmHg | 83.0 ± 13.9 (n = 298) | 85.8 ± 15.3 (n = 252) | 0.027 |
| Office pulse rate, beats/min | 77.2 ± 13.6 (n = 263) | 77.8 ± 14.1 (n = 215) | 0.614 |
| eGFR, mL/min/1.73 m2 | 66.9 ± 17.7 (n = 223) | 70.0 ± 21.6 (n = 165) | 0.117 |
| HbA1c, % | 6.0 ± 0.7 (n = 173) | 6.4 ± 1.2 (n = 97) | < 0.001 |
| Total cholesterol, mg/dL | 194.6 ± 38.2 (n = 200) | 187.5 ± 33.3 (n = 125) | 0.087 |
| HDL cholesterol, mg/dL | 55.3 ± 14.5 (n = 194) | 54.4 ± 15.4 (n = 129) | 0.563 |
| LDL cholesterol, mg/dL | 113.2 ± 33.5 (n = 187) | 111.3 ± 29.3 (n = 131) | 0.604 |
Data are shown as the number of subjects (%), the mean ± SD, or median (25th to 75th percentiles).
The clinical subtype of stroke included cases in which more than one subtype of stroke was recorded in the same subject.
Smoking habit, current smoker, and ex-smoker.
Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BMI, body mass index; BP, blood pressure; CCBs, calcium channel blockers; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein; mRS, modified Rankin scale; SAH, subarachnoid hemorrhage.
Table 2. Baseline and follow-up carotid measures.
| Total (n = 326) | Normal group (max-IMT < 1.1 mm) (n = 170) | Thick group (max-IMT ≥ 1.1 mm) (n = 156) | Difference | p value | ||
|---|---|---|---|---|---|---|
| Max-IMT (mm) | ||||||
| Baseline | 1.18 (1.14 to 1.22) | 0.93 (0.92 to 0.95) | 1.45 (1.38 to 1.51) | |||
| 12 months | 1.13 (1.08 to 1.17) | 0.92 (0.90 to 0.94) | 1.35 (1.28 to 1.43) | |||
| Mean change | −0.05 (−0.07 to −0.03) | −0.01 (−0.03 to 0.01) | −0.09 (−0.13 to −0.05) | −0.08 | < 0.001 | |
| Mean-IMT (mm) | ||||||
| Baseline | 0.91 (0.88 to 0.94) | 0.77 (0.75 to 0.78) | 1.07 (1.03 to 1.11) | |||
| 12 months | 0.88 (0.85 to 0.90) | 0.76 (0.74 to 0.77) | 1.01 (0.97 to 1.05) | |||
| Mean change | −0.03 (−0.05 to −0.02) | −0.01 (−0.03 to 0.00) | −0.06 (−0.08 to −0.04) | −0.05 | 0.001 | |
| IAD (mm) | ||||||
| Baseline | 8.04 (7.93 to 8.14) | 7.85 (7.70 to 8.00) | 8.24 (8.09 to 8.39) | |||
| 12 months | 7.91 (7.80 to 8.01) | 7.71 (7.58 to 7.84) | 8.12 (7.97 to 8.27) | |||
| Mean change | −0.13 (−0.19 to −0.07) | −0.14 (−0.22 to −0.05) | −0.12 (−0.21 to −0.03) | 0.02 | 0.799 | |
| LD (mm) | ||||||
| Baseline | 6.53 (6.43 to 6.64) | 6.46 (6.32 to 6.60) | 6.61 (6.47 to 6.76) | |||
| 12 months | 6.47 (6.37 to 6.57) | 6.41 (6.28 to 6.54) | 6.54 (6.39 to 6.69) | |||
| Mean change | −0.06 (−0.13 to 0.00) | −0.05 (−0.14 to 0.04) | −0.08 (−0.17 to 0.02) | −0.02 | 0.723 |
Data are shown as the mean and 95% confidence interval or mean only.
Abbreviations: IAD, interadventitial diameter; IMT, intima-media thickness; LD, lumen diameter.
Supplementary Table 2. Baseline characteristics of subjects in the normal and thick groups.
| Factors | Total (n = 326) | Normal group (max-IMT < 1.1 mm) (n = 170) | Thick group (max-IMT ≥ 1.1 mm) (n = 156) | p value |
|---|---|---|---|---|
| Age, years | 69.1 ± 9.6 | 68.1 ± 10.3 | 70.2 ± 8.6 | 0.052 |
| Male, n (%) | 209 (64.1) | 106 (62.4) | 103 (66.0) | 0.563 |
| BMI, kg/m2 | 23.5 ± 3.2 (n = 261) | 23.4 ± 3.0 (n = 133) | 23.6 ± 3.4 (n = 128) | 0.495 |
| mRS score | 1 (0 to 1.25) | 1 (0 to 1) | 1 (0 to 2) | 0.451 |
| Concomitant disease | ||||
| Dyslipidemia, n (%) | 171 (52.5) | 81 (47.6) | 90 (57.7) | 0.076 |
| Diabetes mellitus, n (%) | 57 (17.5) | 20 (11.8) | 37 (23.7) | 0.005 |
| Coronary artery disease, n (%) | 20 (6.1) | 5 (2.9) | 15 (9.6) | 0.019 |
| Stroke historya | ||||
| Cerebral infarction, n (%) | 257 (78.8) | 125 (73.5) | 132 (84.6) | 0.015 |
| Small vessel occlusion, n (%) | 129 (39.6) | 62 (36.5) | 67 (42.9) | 0.258 |
| Large artery atherosclerosis, n (%) | 97 (29.8) | 43 (25.3) | 54 (34.6) | 0.070 |
| Cardioembolism, n (%) | 8 (2.5) | 5 (2.9) | 3 (1.9) | 0.725 |
| Others, n (%) | 25 (7.7) | 16 (9.4) | 9 (5.8) | 0.298 |
| Cerebral hemorrhage, n (%) | 46 (14.1) | 23 (13.5) | 23 (14.7) | 0.753 |
| SAH, n (%) | 30 (9.2) | 24 (14.1) | 6 (3.8) | 0.002 |
| Smoking habitb | 155 (47.5) | 75 (44.1) | 80 (51.3) | 0.222 |
| Drinking habit | 112 (34.4) | 58 (34.1) | 54 (34.6) | 1.000 |
| Daily dose of cilnidipine, mg/day | 10.3 ± 3.0 | 10.0 ± 2.8 | 10.6 ± 3.2 | 0.080 |
| Anti-hypertensives | ||||
| ARBs, n (%) | 117 (35.9) | 57 (33.5) | 60 (38.5) | 0.358 |
| CCBs, n (%) | 28 (8.6) | 12 (7.1) | 16 (10.3) | 0.328 |
| ACE inhibitors, n (%) | 11 (3.4) | 5 (2.9) | 6 (3.8) | 0.763 |
| Diuretics, n (%) | 20 (6.1) | 12 (7.1) | 8 (5.1) | 0.498 |
| Statins, n (%) | 113 (34.7) | 47 (27.6) | 66 (42.3) | 0.007 |
| Antiplatelet agents, n (%) | 190 (58.3) | 87 (51.2) | 103 (66.0) | 0.007 |
| Warfarin, n (%) | 8 (2.5) | 5 (2.9) | 3 (1.9) | 0.725 |
| Office systolic BP, mmHg | 150.6 ± 21.6 (n = 299) | 151.2 ± 21.5 (n = 155) | 150.0 ± 21.9 (n = 144) | 0.627 |
| Office diastolic BP, mmHg | 83.0 ± 13.9 (n = 298) | 85.0 ± 14.7 (n = 155) | 80.9 ± 12.7 (n = 143) | 0.009 |
| Office pulse rate, beats/min | 77.2 ± 13.6 (n = 263) | 76.5 ± 13.8 (n = 135) | 77.9 ± 13.4 (n = 128) | 0.401 |
| eGFR, mL/min/1.73 m2 | 66.9 ± 17.7 (n = 223) | 67.7 ± 19.4 (n = 119) | 66.0 ± 15.5 (n = 104) | 0.481 |
| HbA1c, % | 6.0 ± 0.7 (n = 173) | 5.8 ± 0.5 (n = 91) | 6.1 ± 0.8 (n = 82) | 0.010 |
| Total cholesterol, mg/dL | 194.6 ± 38.2 (n = 200) | 192.6 ± 40.8 (n = 108) | 196.8 ± 35.1 (n = 92) | 0.440 |
| HDL cholesterol, mg/dL | 55.3 ± 14.5 (n = 194) | 56.0 ± 14.2 (n = 101) | 54.6 ± 14.9 (n = 93) | 0.501 |
| LDL cholesterol, mg/dL | 113.2 ± 33.5 (n = 187) | 109.8 ± 33.8 (n = 101) | 117.2 ± 32.9 (n = 86) | 0.134 |
Data are shown as the number of subjects (%), the mean ± SD or median (25th to 75th percentiles).
The clinical subtype of stroke included cases in which more than one subtype of stroke was recorded in the same subject.
Smoking habit, current smoker, and ex-smoker.
Abbreviations: ACE inhibitors, angiotensin-converting enzyme inhibitors; ARBs, angiotensin receptor blockers; BMI, body mass index; BP, blood pressure; CCBs, calcium channel blockers; eGFR, estimated glomerular filtration rate; HbA1c, glycated hemoglobin; HDL, high-density lipoprotein; IMT, intima-media thickness; LDL, low-density lipoprotein; mRS, modified Rankin scale; SAH, subarachnoid hemorrhage.
Supplementary Fig. 3A.
The association between the changes in max-IMT and baseline max-IMT.
Pearson's correlation coefficient (r) and the associated p value are shown for all subjects (n = 326).
Abbreviation: IMT, intima-media thickness.
Supplementary Fig. 3B. The association between the changes in IAD and baseline IAD.
Pearson's correlation coefficient (r) and the associated p value are shown for all subjects (n = 326).
Abbreviation: IAD, interadventitial diameter.
The mean max-IMT from baseline to 12 months did not change in the normal group (−0.01 mm, 95% CI −0.03 to 0.01, n = 170), whereas a significant reduction was observed in the thick group (−0.09 mm, 95% CI −0.13 to −0.05, n = 156) but not LD (−0.08 mm, 95% CI −0.17 to 0.02, n = 156, Table 2). The mean IAD from baseline to 12 months significantly decreased in both groups (thick group −0.12 mm, 95% CI −0.21 to −0.03; normal group −0.14 mm, 95% CI −0.22 to −0.15). There was a significant difference in the change in mean max-IMT between the thick and normal groups (mean difference between groups −0.08 mm, p < 0.001). A significant difference was also shown in the mean mean-IMT between the two groups (mean difference between groups −0.05 mm, p = 0.001). No differences between groups were observed in the mean IAD and LD. These differences between the two groups were not affected by statistical adjustment for each of the baseline subject characteristics that differed between the groups (ANCOVA, data not shown).
Office systolic BP decreased markedly in both groups (thick group −16.0 mmHg, 95% CI −19.9 to −12.0, n = 126; normal group −19.5 mmHg, 95% CI −23.2 to −15.7, n = 145), and its reductions were not different between both groups (mean difference between groups 3.5 mmHg, 95% CI −1.9 to 8.9). There was no significant association between decrease in max-IMT and reduction in systolic BP in all subjects (r = −0.07, p = 0.278, n = 271). Any significant relationship was also not observed between decrease in IAD and reduction in systolic BP in all subjects (r = 0.05, p = 0.403, n = 271).
Combined Action of Cilnidipine with Concomitant Agents in the Change of Max-IMT or IAD
To evaluate the effects of concomitant agents (ARBs, statins, and antiplatelet agents) on the reduction in max-IMT or IAD, multivariate regression analysis was used. After adjustment for age, sex, smoking habit, dyslipidemia, diabetes mellitus, statins, and antiplatelet agents, ARBs was the only independent determinant on the reduction in max-IMT in the thick group but not in all subjects (Table 3). After addition of angiotensin-converting enzyme inhibitors to ARBs as covariate, the result of multivariate regression analysis was not different from that of ARBs only on the reduction in max-IMT in the thick group (estimates of beta coefficient −0.106, 95% CI −0.185 to −0.027, p = 0.009). In the thick group, the decrease in the mean max-IMT was −0.16 mm (95% CI −0.23 to −0.09) in subjects taking ARBs (n = 60) and −0.05 mm (95% CI −0.09 to −0.01) in subjects not taking ARBs (n = 96); the difference in the reduction between the two groups was 0.11 mm (95% CI 0.03 to 0.18).
Table 3. Multiple linear regression analysis for change in max-IMT or IAD.
| Covariates | max-IMT |
|||||
|---|---|---|---|---|---|---|
| Total (n = 326) |
Thick group (n = 156) |
|||||
| Estimates of beta coefficient | 95% CI | p value | Estimates of beta coefficient | 95% CI | p value | |
| Age | 0.001 | −0.002 to 0.003 | 0.555 | 0.002 | −0.003 to 0.006 | 0.508 |
| Sex (male) | 0.036 | −0.019 to 0.090 | 0.199 | 0.070 | −0.031 to 0.170 | 0.174 |
| Smokinga | −0.047 | −0.099 to 0.005 | 0.077 | −0.044 | −0.139 to 0.051 | 0.360 |
| Dyslipidemia | 0.017 | −0.041 to 0.074 | 0.568 | 0.062 | −0.046 to 0.170 | 0.256 |
| Diabetes Mellitus | −0.014 | −0.072 to 0.044 | 0.635 | 0.004 | −0.088 to 0.096 | 0.931 |
| ARBs | −0.042 | −0.088 to 0.003 | 0.067 | −0.112 | −0.192 to −0.033 | 0.006 |
| Statins | −0.018 | −0.078 to 0.042 | 0.549 | −0.073 | −0.179 to 0.034 | 0.181 |
| Antiplatelet agents | −0.010 | −0.054 to 0.035 | 0.675 | −0.018 | −0.099 to 0.063 | 0.664 |
| Covariates | IAD |
|||||
|---|---|---|---|---|---|---|
| Total (n = 326) |
Thick group (n = 156) |
|||||
| Estimates of beta coefficient | 95% CI | p value | Estimates of beta coefficient | 95% CI | p value | |
| Age | 0.001 | −0.005 to 0.008 | 0.714 | −0.684 | −1.467 to 0.099 | 0.086 |
| Sex (male) | 0.080 | −0.083 to 0.244 | 0.334 | 0.006 | −0.005 to 0.017 | 0.274 |
| Smokinga | −0.047 | −0.203 to 0.109 | 0.552 | 0.156 | −0.082 to 0.395 | 0.198 |
| Dyslipidemia | 0.123 | −0.047 to 0.294 | 0.156 | 0.001 | −0.223 to 0.226 | 0.991 |
| Diabetes Mellitus | 0.021 | −0.152 to 0.193 | 0.814 | 0.188 | −0.068 to 0.444 | 0.148 |
| ARBs | 0.009 | −0.127 to 0.144 | 0.898 | 0.108 | −0.111 to 0.326 | 0.333 |
| Statins | −0.131 | −0.309 to 0.048 | 0.151 | −0.010 | −0.199 to 0.179 | 0.916 |
| Antiplatelet agents | 0.080 | −0.054 to 0.214 | 0.239 | −0.233 | −0.485 to 0.019 | 0.070 |
Smoking: current smoker+ ex-smoker.
Abbreviations: ARBs, angiotensin II U receptor blockers; CI, confidence interval; IAD, interadventitial diameter; IMT, intima-media thickness.
Discussion
We have found that cilnidipine, an L/N-type calcium channel blocker, promoted the regression of carotid IMT in post-stroke hypertensive patients in the thick group during 12 months. In addition, there was a significant reduction in IAD in any post-stroke hypertensive patients taking cilnidipine. Although the relevance between carotid IMT regression and clinical outcomes has not yet been concluded, the accumulation of medical outcomes as to what kind of medical intervention can reduce carotid IMT or IAD is important in carotid arteriosclerosis treatment.
Compensatory enlargement of the artery, which reflects vascular remodeling, is recognized as an important adaptive process in early atherosclerosis24). This positive remodeling is characterized by increases in IMT and IAD25). A wider IAD was associated with an increased IMT in the present study. Additionally, the baseline max-IMT, mean-IMT, and IAD were greater in the thick group than in the normal group. In this study, no change in baseline LD was observed with increasing max-IMT. Several studies also reported that the LD remained constant with increasing IMT of the carotid artery25–28). Our findings of baseline carotid artery ultrasonographic parameters might reflect that the carotid artery in the thick group was experiencing the positive remodeling characteristic of early atherosclerosis. After 12 months of treatment with cilnidipine, a significant reduction in mean max-IMT was observed in the thick group, whereas no significant change was observed in the normal group, and the difference was significant between the groups. In the Prospective Randomized Evaluation of the Vascular Effects of Norvasc Trial, the L-type calcium channel blocker, amlodipine, significantly inhibited the progression of common carotid artery atherosclerosis in 825 participants with coronary artery disease29). Kaneshiro et al. reported that after 12 months of treatment with cilnidipine, the common carotid max-IMT decreased in a small number of hypertensive patients (n = 50)30). However, to the best of our knowledge, few studies have investigated the effects of calcium channel blockers on the progression of carotid IMT in post-stroke hypertensive patients. No group differences were observed in the change in office systolic BP, even though the thick group experienced a greater reduction in max-IMT. Therefore, the decrease in office systolic BP is not associated with the reduction in max-IMT. The decrease in max-IMT did not accompany changes in LD in the present study. Because a lowered BP leads lower wall tension and apparently increases the IMT in the carotid arteries31), “a true regression” in vascular mass by antihypertensive agents is defined as a decrease in IMT unrelated to a change in LD in a report from American Society of Echocardiography and Society for Vascular Medicine and Biology32). Therefore, we believe that a true regression of early atherosclerosis in the common carotid artery after 12 months of cilnidipine treatment was observed in the thick group.
More recently, some studies showed that the IAD of the common carotid artery was associated with ischemic stroke as well as cardiovascular events. It was shown that the IAD was a stronger predictor of ischemic stroke than carotid IMT from the results of the Multi-Ethnic Study of Atherosclerosis14). On the other hand, Eigenbrodt et al. reported that the presence of both a large IAD and large a IMT was the strongest predictor of stroke incidence in the general population33). In this study, we separately analyzed the effects of cilnidipine on IAD. The significant decreases in mean IAD after 12 months of cilnidipine treatment were shown not only in the thick group but also in all subjects. No linear relationship was observed between a reduction of IAD and a decrease in office systolic BP in all subjects. Only a few studies have investigated the association between medical interventions and carotid IAD34, 35). Cooper et al. showed that the common carotid IAD as well as IMT decreased with weight loss intervention in severely obese adults34). Lloyd et al. reported that estrogen replacement therapy decreased common carotid IAD in overweight or obese post-menopausal women35). Because there have been few studies evaluating the effects of agents for lifestyle-related diseases on carotid IAD in a high-risk population, further accumulation of evidence for medical intervention is needed to establish the therapeutic position of IAD in carotid atherosclerosis.
ARBs36–38), statins39, 40), and antiplatelet agents41) have been reported to promote the regression or inhibition of progression of the IMT in the common carotid artery, and the effects of these agents have also been reported in the meta-analysis8, 42–44). In the present study, these agents were coadministered in approximately one-third to one-half of subjects in the thick group. Therefore, the effects of the concomitant agents (ARBs, statins, and antiplatelet agents) on the regression of the max-IMT were investigated to clarify their combined action with cilnidipine by using multiple linear regression analysis. The association between the coadministration of ARBs and the decrease in the max-IMT remained statistically significant after adjustment for other concomitant agents in the thick group but not in all subjects. It seems that the combination of ARBs and cilnidipine will be essential in the regression of atherosclerosis of the common carotid artery in post-stroke hypertensive patients. Interestingly, there was no association between the coadministration of ARBs and the decrease in IAD in not only all subjects but also the thick group. Moreover, the decrease in IAD was observed in both normal and thick groups, and the decrease in max-IMT was shown only in the thick group. Kawamoto et al. reported that common carotid enlargement may reflect the ability of adaptive remodeling to atherosclerosis before plaque formation45). Therefore, from our results, the pathophysiology of IAD enlargement and increase of IMT may be different in common carotid arteries of post-stroke hypertensive patients.
A few studies have found that N-type calcium channels are distributed not only in sympathetic nerve ends46) but also in podocytes47), adrenal cortex48), pancreatic alpha cells49), and endothelial cells50). In aortic endothelial cell lines, cilnidipine suppressed the production of AII-induced reactive oxygen species through blocking N-type calcium channels50). However, the pathophysiological roles of N-type calcium channels, which can be inhibited by cilnidipine, have not been elucidated in carotid artery plaque or adventitia. Further studies are needed to clarify the pharmacological actions of triple-blocking AII receptors, and N-type and L-type calcium channels in the atherosclerotic carotid artery. In the future, larger-scale and longer-term randomized, controlled trials are needed to establish the clinical usefulness of cilnidipine for reversing the progression of carotid atherosclerosis in hypertensive patients with stroke.
This study had certain limitations. At first, the PMS study had no control group. Therefore, a relative evaluation of the efficacy of cilnidipine was not possible. Second, the large proportion of subjects did not have a carotid ultrasonography at 12 months of follow-up. Additionally, there were several factors that were different between the subjects with follow-up and the subjects without follow-up. These factors may cause a considerable selection bias. Third, we could not analyze the effects of antidiabetic agents on max-IMT or IAD. Since many kinds of antidiabetic agents were used in this study, the number of patients for each agent and its combination was small, which was inconvenient for analysis. Finally, we could not evaluate the BP change in all subjects with follow-up carotid ultrasonography. Therefore, the associations between decrease in max-IMT or IAD and reduction of systolic BP might be affected by selection bias.
Conclusion
In conclusion, as a result of the ultrasonographic investigation of the common carotid artery of 326 post-stroke hypertensive subjects undergoing cilnidipine treatment, the reduction in the max-IMT at 12 months was observed only in the thick group (max-IMT ≥ 1.1 mm) but not the normal group (max-IMT < 1.1 mm). The reduction in IAD was observed in both groups. The treatment with cilnidipine, an L/N-type calcium channel blocker, promoted the regression of carotid atherosclerosis in post-stroke hypertensive patients.
Acknowledgments
We express our sincere gratitude to the 97 participating medical institutions and 152 physicians that provided these valuable data.
Conflicts of Interest
Naohisa Hosomi reports an honorarium from Mochida Pharmaceutical Co., Ltd. Hirofumi Maruyama reports grants from Daiichi Sankyo Co., Ltd. Masayasu Matsumoto reports grants from Takeda Pharmaceutical Co., Ltd., Sanofi K.K., Mochida Pharma ceutical Co., Ltd., Otsuka Pharmaceutical, and Daiichi Sankyo Co., Ltd. and honoraria from Sanofi K.K., Bayer Health Care, and Daiichi Sankyo Co., Ltd. The other authors declare no conflicts of interest. Tsukasa Teshima, Hitoshi Sugii, and Noriyuki Suzuki are employees of Mochida Pharmaceutical Co., Ltd. Shinobu Nagahama and Yoshiki Kurose are employees of EA Pharma Co., Ltd.
Financial Support
The present study was funded by Ajinomoto Pharmaceuticals Co., Ltd. and Mochida Pharmaceutical Co., Ltd. The name of Ajinomoto Pharmaceuticals Co., Ltd. was changed to EA Pharma Co., LTD since April 2016.
Author Contributions
T.N. and N.H. wrote the introduction, methods, results, and discussion.
S.A., N.S., and S.N. contributed to the discussion.
T.T and H.S. collected the data.
Y.K. analyzed the results under the guidance of medical professionals, M.M. and N.H.
N.H., H.M., and M.M. reviewed/edited the manuscript and contributed to the discussion.
References
- 1). Nezu T, Hosomi N, Aoki S, Matsumoto M. Carotid Intima-Media Thickness for Atherosclerosis. J Atheroscler Thromb 2016; 23: 18-31 [DOI] [PubMed] [Google Scholar]
- 2). Huang L-C, Lin R-T, Chen C-F, Chen C-H, Hank Juo S-H, Lin H-F. Predictors of Carotid Intima-Media Thickness and Plaque Progression in a Chinese Population. J Atheroscler Thromb 2016; 23: 940-949 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3). Herder M, Johnsen SH, Arntzen KA, Mathiesen EB. Risk Factors for Progression of Carotid Intima-Media Thickness and Total Plaque Area. Stroke 2012; 43 http://stroke.ahajournals.org/content/43/7/1818.long Accessed 4 September 2017 [DOI] [PubMed] [Google Scholar]
- 4). Polak JF, Pencina MJ, O'Leary DH, D'Agostino RB. Common carotid artery intima-media thickness progression as a predictor of stroke in multi-ethnic study of atherosclerosis. Stroke 2011; 42: 3017-3021 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 5). Baldassarre D, Veglia F, Hamsten A, Humphries SE, Rauramaa R, de Faire U, Smit AJ, Giral P, Kurl S, Mannarino E, Grossi E, Paoletti R, Tremoli E. Progression of carotid intima-media thickness as predictor of vascular events: results from the IMPROVE study. Arterioscler Thromb Vasc Biol 2013; 33: 2273-2279 [DOI] [PubMed] [Google Scholar]
- 6). Tsivgoulis G, Vemmos K, Papamichael C, Spengos K, Manios E, Stamatelopoulos K, Vassilopoulos D, Zakopoulos N. Common carotid artery intima-media thickness and the risk of stroke recurrence. Stroke 2006; 37: 1913-1916 [DOI] [PubMed] [Google Scholar]
- 7). Talelli P, Terzis G, Katsoulas G, Chrisanthopoulou A, Ellul J. Recurrent stroke: The role of common carotid artery intima-media thickness. J Clin Neurosci 2007; 14: 1067-1072 [DOI] [PubMed] [Google Scholar]
- 8). Huang Y, Li W, Dong L, Li R, Wu Y. Effect of statin therapy on the progression of common carotid artery intima-media thickness: an updated systematic review and meta-analysis of randomized controlled trials. J Atheroscler Thromb 2013; 20: 108-121 [DOI] [PubMed] [Google Scholar]
- 9). Wang JG, Staessen JA, Li Y, Van Bortel LM, Nawrot T, Fagard R, Messerli FH, Safar M. Carotid intima-media thickness and antihypertensive treatment: A meta-analysis of randomized controlled trials. Stroke 2006; 37: 1933-1940 [DOI] [PubMed] [Google Scholar]
- 10). Costanzo P, Perrone-Filardi P, Vassallo E, Paolillo S, Cesarano P, Brevetti G, Chiariello M. Does carotid intima-media thickness regression predict reduction of cardiovascular events?: A meta-analysis of 41 randomized trials. J Am Coll Cardiol 2010; 56: 2006-2020 [DOI] [PubMed] [Google Scholar]
- 11). Polak JF, Wong Q, Johnson WC, Bluemke DA, Harrington A, O'Leary DH, Yanez ND. Associations of cardiovascular risk factors, carotid intima-media thickness and left ventricular mass with inter-adventitial diameters of the common carotid artery: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2011; 218: 344-349 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12). Eigenbrodt ML, Sukhija R, Rose KM, Tracy RE, Couper DJ, Evans GW, Bursac Z, Mehta JL. Common carotid artery wall thickness and external diameter as predictors of prevalent and incident cardiac events in a large population study. Cardiovasc Ultrasound 2007; 5: 11. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 13). Baldassarre D, Hamsten A, Veglia F, de Faire U, Humphries SE, Smit AJ, Giral P, Kurl S, Rauramaa R, Mannarino E, Grossi E, Paoletti R, Tremoli E, IMPROVE Study Group Measurements of carotid intima-media thickness and of interadventitia common carotid diameter improve prediction of cardiovascular events: results of the IMPROVE (Carotid Intima Media Thickness [IMT] and IMT-Progression as Predictors of Vascular Events in a high risk European population. J Am Coll Cardiol 2012; 60: 1489-1499 [DOI] [PubMed] [Google Scholar]
- 14). Polak JF, Sacco RL, Post WS, Vaidya D, Kweku Arnan M, O'Leary DH. Incident stroke is associated with common carotid artery diameter and not common carotid artery intima-media thickness. Stroke 2014; 45: 1442-1446 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 15). Aoki S, Hosomi N, Nezu T, Teshima T, Sugii H, Nagahama S, Kurose Y, Maruyama H, Matsumoto M. Blood pressure control with cilnidipine treatment in Japanese post-stroke hypertensive patients: the CA-ATTEND study. Clin Exp Hypertens 2017; 39: 225-234 [DOI] [PubMed] [Google Scholar]
- 16). Takahara A. Cilnidipine: a new generation Ca channel blocker with inhibitory action on sympathetic neurotransmitter release. Cardiovasc Ther 2009; 27: 124-139 [DOI] [PubMed] [Google Scholar]
- 17). Toyoda K, Minematsu K, Yasaka M, Nagai Y, Hosomi N, Origasa H, Kitagawa K, Uchiyama S, Koga M, Matsumoto M. The Japan Statin Treatment Against Recurrent Stroke (J-STARS) Echo Study: Rationale and Trial Protocol. J Stroke Cerebrovasc Dis 2017; 26: 595-599 [DOI] [PubMed] [Google Scholar]
- 18). Yanase T, Nasu S, Mukuta Y, Shimizu Y, Nishihara T, Okabe T, Nomura M, Inoguchi T, Nawata H. Evaluation of a new carotid intima-media thickness measurement by B-mode ultrasonography using an innovative measurement software, intimascope. Am J Hypertens 2006; 19: 1206-1212 [DOI] [PubMed] [Google Scholar]
- 19). Katakami N, Yamasaki Y, Kosugi K, Waki H, Matsuhisa M, Kajimoto Y, Masuyama T, Hori M. Tissue characterization identifies subjects with high risk of cardiovascular diseases. Diabetes Res Clin Pract 2004; 63: 93-102 [DOI] [PubMed] [Google Scholar]
- 20).The joint committee of ‘The japan academy of neurosonology’ and ‘The japan society of embolus detection and treatment’ on guideline for neurosonology, carotid ultrasound examination. Neurosonology 2006; 19: 49-69 [Google Scholar]
- 21). Kasami R, Kaneto H, Katakami N, Sumitsuji S, Yamasaki K, Kuroda T, Tachibana K, Yasuda T, Kuroda A, Matsuoka T, Matsuhisa M, Shimomura I. Relationship between carotid intima-media thickness and the presence and extent of coronary stenosis in type 2 diabetic patients with carotid atherosclerosis but without history of coronary artery disease. Diabetes Care 2011; 34: 468-470 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 22). Okimoto H, Ishigaki Y, Koiwa Y, Hinokio Y, Ogihara T, Suzuki S, Katagiri H, Ohkubo T, Hasegawa H, Kanai H, Oka Y. A novel method for evaluating human carotid artery elasticity: Possible detection of early stage atherosclerosis in subjects with type 2 diabetes. Atherosclerosis 2008; 196: 391-397 [DOI] [PubMed] [Google Scholar]
- 23). Nezu T, Hosomi N, Aoki S, Kubo S, Araki M, Mukai T, Takahashi T, Maruyama H, Higashi Y, Matsumoto M. Endothelial dysfunction is associated with the severity of cerebral small vessel disease. Hypertens Res 2015; 38: 291-297 [DOI] [PubMed] [Google Scholar]
- 24). Glagov S, Weisenberg E, Zarins CK, Stankunavicius R, Kolettis GJ. Compensatory enlargement of human atherosclerotic coronary arteries. N Engl J Med 1987; 316: 1371-1375 [DOI] [PubMed] [Google Scholar]
- 25). Polak JF, Kronmal RA, Tell GS, O'Leary DH, Savage PJ, Gardin JM, Rutan GH, Borhani NO. Compensatory increase in common carotid artery diameter. Relation to blood pressure and artery intima-media thickness in older adults. Cardiovascular Health Study. Stroke 1996; 27: 2012-2015 [DOI] [PubMed] [Google Scholar]
- 26). Henry RMA, Kostense PJ, Dekker JM, Nijpels G, Heine RJ, Kamp O, Bouter LM, Stehouwer CDA. Carotid Arterial Remodeling: A Maladaptive Phenomenon in Type 2 Diabetes but Not in Impaired Glucose Metabolism: The Hoorn Study. Stroke 2004; 35: 671-676 [DOI] [PubMed] [Google Scholar]
- 27). Terry JG, Tang R, Espeland MA, Davis DH, Vieira JLC, Mercuri MF, Crouse JR. Carotid arterial structure in patients with documented coronary artery disease and disease-free control subjects. Circulation 2003; 107: 1146-1151 [DOI] [PubMed] [Google Scholar]
- 28). Kato M, Dote K, Habara S, Takemoto H, Goto K, Nakaoka K. Clinical implications of carotid artery remodeling in acute coronary syndrome: ultrasonographic assessment of positive remodeling. J Am Coll Cardiol 2003; 42: 1026-1032 [DOI] [PubMed] [Google Scholar]
- 29). Pitt B, Byington RP, Furberg CD, Hunninghake DB, Mancini GB, Miller ME, Riley W. Effect of amlodipine on the progression of atherosclerosis and the occurrence of clinical events. PREVENT Investigators. Circulation 2000; 102: 1503-1510 [DOI] [PubMed] [Google Scholar]
- 30). Kaneshiro Y, Ichihara A, Sakoda M, Kurauchi A, Takemitsu T, Itoh H. Cilnidipine and Telmisartan Similarly Improves Vascular Damage in Hypertensive Patients. Clin Med Insights Cardiol 2007; 1: 1-11 [Google Scholar]
- 31). Hosomi N, Mizushige K, Ohyama H, Takahashi T, Kitadai M, Hatanaka Y, Matsuo H, Kohno M, Koziol JA. Angiotensin-converting enzyme inhibition with enalapril slows progressive intima-media thickening of the common carotid artery in patients with non-insulin-dependent diabetes mellitus. Stroke 2001; 32: 1539-1545 [DOI] [PubMed] [Google Scholar]
- 32). Roman MJ, Naqvi TZ, Gardin JM, Gerhard-Herman M, Jaff M, Mohler E. American society of echocardiography report. Clinical application of noninvasive vascular ultrasound in cardiovascular risk stratification: a report from the American Society of Echocardiography and the Society for Vascular Medicine and Biology. Vasc Med 2006; 11: 201-211 [DOI] [PubMed] [Google Scholar]
- 33). Eigenbrodt ML, Evans GW, Rose KM, Bursac Z, Tracy RE, Mehta JL, Couper DJ. Bilateral common carotid artery ultrasound for prediction of incident strokes using intima-media thickness and external diameter: an observational study. Cardiovasc Ultrasound 2013; 11: 22. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34). Cooper JN, Columbus ML, Shields KJ, Asubonteng J, Meyer ML, Sutton-Tyrrell K, Goodpaster BH, DeLany JP, Jakicic JM, Barinas-Mitchell E. Effects of an intensive behavioral weight loss intervention consisting of caloric restriction with or without physical activity on common carotid artery remodeling in severely obese adults. Metabolism 2012; 61: 1589-1597 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 35). Lloyd KD, Barinas-Mitchell E, Kuller LH, Mackey RH, Wong EA, Sutton-Tyrrell K. Common carotid artery diameter and cardiovascular risk factors in overweight or obese postmenopausal women. Int J Vasc Med 2012; 2012: 169323. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36). Ariff B, Zambanini A, Vamadeva S, Barratt D, Xu Y, Sever P, Stanton A, Hughes A, Thom S. Candesartan- and atenolol-based treatments induce different patterns of carotid artery and left ventricular remodeling in hypertension. Stroke 2006; 37: 2381-2384 [DOI] [PubMed] [Google Scholar]
- 37). Ono H, Minatoguchi S, Watanabe K, Yamada Y, Mizukusa T, Kawasaki H, Takahashi H, Uno T, Tsukamoto T, Hiei K, Fujiwara H. Candesartan decreases carotid intima-media thickness by enhancing nitric oxide and decreasing oxidative stress in patients with hypertension. Hypertens Res 2008; 31: 271-279 [DOI] [PubMed] [Google Scholar]
- 38). Sonoda M, Aoyagi T, Takenaka K, Uno K, Nagai R. A one-year study of the antiatherosclerotic effect of the angiotensin-II receptor blocker losartan in hypertensive patients. A comparison with angiotension-converting enzyme inhibitors. Int Heart J 2008; 49: 95-103 [DOI] [PubMed] [Google Scholar]
- 39). Crouse JR, Raichlen JS, Riley WA, Evans GW, Palmer MK, O'Leary DH, Grobbee DE, Bots ML. Effect of rosuvastatin on progression of carotid intima-media thickness in low-risk individuals with subclinical atherosclerosis: the METEOR Trial. JAMA 2007; 297: 1344-1353 [DOI] [PubMed] [Google Scholar]
- 40). Smilde TJ, van Wissen S, Wollersheim H, Trip MD, Kastelein JJ, Stalenhoef AF. Effect of aggressive versus conventional lipid lowering on atherosclerosis progression in familial hypercholesterolaemia (ASAP): a prospective, randomised, double-blind trial. Lancet 2001; 357: 577-581 [DOI] [PubMed] [Google Scholar]
- 41). Shinoda-Tagawa T, Yamasaki Y, Yoshida S, Kajimoto Y, Tsujino T, Hakui N, Matsumoto M, Hori M. A phosphodiesterase inhibitor, cilostazol, prevents the onset of silent brain infarction in Japanese subjects with Type II diabetes. Diabetologia 2002; 45: 188-194 [DOI] [PubMed] [Google Scholar]
- 42). Kang S, Wu Y, Li X. Effects of statin therapy on the progression of carotid atherosclerosis: a systematic review and meta-analysis. Atherosclerosis 2004; 177: 433-442 [DOI] [PubMed] [Google Scholar]
- 43). Tropeano A, Saleh N, Hawajri N, Macquin-Mavier I, Maison P. Do all antihypertensive drugs improve carotid intima-media thickness? A network meta-analysis of randomized controlled trials. Fundam Clin Pharmacol 2011; 25: 395-404 [DOI] [PubMed] [Google Scholar]
- 44). Geng D-F, Deng J, Jin D-M, Wu W, Wang J-F. Effect of cilostazol on the progression of carotid intima-media thickness: a meta-analysis of randomized controlled trials. Atherosclerosis 2012; 220: 177-183 [DOI] [PubMed] [Google Scholar]
- 45). Kawamoto R, Tomita H, Oka Y, Ohtsuka N. Association between risk factors and carotid enlargement. Intern Med 2006; 45: 503-509 [DOI] [PubMed] [Google Scholar]
- 46). Uhrenholt TR, Nedergaard OA. Calcium channels involved in noradrenaline release from sympathetic neurones in rabbit carotid artery. Pharmacol Toxicol 2003; 92: 226-233 [DOI] [PubMed] [Google Scholar]
- 47). Fan Y-Y, Kohno M, Nakano D, Ohsaki H, Kobori H, Suwarni D, Ohashi N, Hitomi H, Asanuma K, Noma T, Tomino Y, Fujita T, Nishiyama A. Cilnidipine suppresses podocyte injury and proteinuria in metabolic syndrome rats: possible involvement of N-type calcium channel in podocyte. J Hypertens 2010; 28: 1034-1043 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 48). Aritomi S, Wagatsuma H, Numata T, Uriu Y, Nogi Y, Mitsui A, Konda T, Mori Y, Yoshimura M. Expression of N-type calcium channels in human adrenocortical cells and their contribution to corticosteroid synthesis. Hypertens Res 2011; 34: 193-201 [DOI] [PubMed] [Google Scholar]
- 49). De Marinis YZ, Salehi A, Ward CE, Zhang Q, Abdulkader F, Bengtsson M, Braha O, Braun M, Ramracheya R, Amisten S, Habib AM, Moritoh Y, Zhang E, Reimann F, Rosengren AH, Shibasaki T, Gribble F, Renström E, Seino S, Eliasson L, Rorsman P. GLP-1 Inhibits and Adrenaline Stimulates Glucagon Release by Differential Modulation of N- and L-Type Ca2+ Channel-Dependent Exocytosis. Cell Metab 2010; 11: 543-553 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 50). Nishida M, Ishikawa T, Saiki S, Sunggip C, Aritomi S, Harada E, Kuwahara K, Hirano K, Mori Y, Kim-Mitsuyama S. Voltage-dependent N-type Ca2+ channels in endothelial cells contribute to oxidative stress-related endothelial dysfunction induced by angiotensin II in mice. Biochem Biophys Res Commun 2013; 434: 210-216 [DOI] [PubMed] [Google Scholar]