Abstract
Aim: The relationship between carotid artery ultrasound findings and clinical outcomes in patients who undergo percutaneous coronary intervention (PCI) has not been completely elucidated.
Methods: This single-center retrospective study investigated 691 patients who underwent PCI and carotid ultrasound testing. Maximum carotid intima-media thickness (CIMT) was defined as the greatest CIMT at the maximally thick point among the common carotid artery, carotid bulb, and internal carotid artery. A carotid plaque was defined as vessel wall thickening with a CIMT ≥ 1.5 mm. The characteristics of carotid plaque (heterogeneity, calcification, or irregular/ulcerated surface) were evaluated visually. Patients were divided into those with and without heterogeneous carotid plaque (maximum CIMT ≥ 1.5 mm and heterogeneous texture). The endpoint was the incidence of a major adverse cardiovascular event (MACE) defined as a composite of cardiovascular (CV) death, myocardial infarction, and ischemic stroke.
Results: Among 691 patients, 309 were categorized as having a heterogeneous plaque. Patients with heterogeneous plaques were at a higher risk of MACE than those without (p=0.002). A heterogeneous plaque was independently associated with MACE after adjusting for covariates (hazard ratio [HR], 1.71; 95% confidence interval [CI], 1.01–2.90;p=0.046). Calcified or irregular/ulcerated plaques were correlated with a higher incidence of MACE, but both were not independently associated with MACE (HR, 1.35; 95% CI, 0.69–2.64,p=0.38 and HR, 0.98; 95% CI, 0.57–1.69;p=0.95, respectively).
Conclusion: The presence of a heterogeneous carotid plaque in patients who underwent PCI predicted future CV events. These patients may require more aggressive medical therapy and careful follow-up.
Keywords: Carotid plaque, Carotid intima-media thickness, Carotid artery ultrasound, Percutaneous coronary intervention, Coronary artery disease
Introduction
The management of coronary artery disease (CAD), including optimal medical therapy and revascularization, has dramatically progressed, and its prognosis has improved in the last few decades 1 , 2) . However, CAD remains a major cause of death worldwide 3 , 4) . To reduce CAD-related mortality rates, the primary prevention of CAD is obviously important; however, the secondary prevention or identification of high-risk subjects among those with established CAD is also essential. To assess atherosclerosis and cardiovascular (CV) disease risks, carotid artery ultrasound is usually performed, and the calculation of carotid intima-media thickness (CIMT) and assessment of carotid plaque height and characteristics are recommended 5 , 6) . Several studies have shown that CIMT or plaque height is a useful surrogate to predict CV events in patients without known CV disease or with intermediate CV disease risk 7 - 10) . In addition, heterogeneous plaques are reportedly correlated with plaque instability (e.g. intraplaque hemorrhage or ulceration) and poor clinical outcomes 11 - 13) . Thus, carotid artery ultrasound is a well-validated tool for the primary prevention of CAD and is used in clinical practice; however, the correlation between carotid artery ultrasound findings and clinical outcomes in patients with CAD, especially those who undergo percutaneous coronary intervention (PCI), has not been completely elucidated. It is important to establish how to apply carotid artery ultrasound results in clinical practice to address secondary prevention in this high-risk cohort. The present study aimed to investigate the relationship between carotid ultrasound findings, including CIMT and plaque characteristics, and CV events in patients with CAD who undergo PCI.
Methods
Patients
This was a single-center observational study. This study was approved by our institutional ethics committee and complied with the Declaration of Helsinki. A total of 691 patients were included in the study. Among patients who underwent PCI at Nagoya University Hospital between 2006 and 2020, those who underwent carotid artery ultrasound around the time of the index PCI were enrolled. Patients with previously implanted carotid artery stents were excluded from the analysis, but those with carotid artery stenosis were included. Their baseline characteristics, medications, laboratory and echocardiographic data, and PCI procedure data were obtained from their medical records. Written informed consent was obtained from all patients.
Carotid Artery Ultrasound
Carotid artery ultrasound testing was conducted according to the recommendations of the American Society of Echocardiography 5 , 6) . Two-dimensional ultrasound was performed by experienced sonographers. The bilateral common carotid artery (CCA), carotid bulbus, and internal carotid artery (ICA) were observed using longitudinal and short-axis planes. CIMT was defined as the distance from the leading edge of the lumen–intima interface to the leading edge of the media–adventitia interface in the far wall and the trailing edge of the lumen–intima interface to the trailing edge of the media–adventitia interface in the near wall.
CIMT was measured at the maximum thickness of the CCA, carotid bulbus, and ICA, and the greatest value was defined as maximum CIMT. Plaque was defined as focal or diffuse vessel wall thickening with a CIMT ≥ 1.5 mm. Maximum CIMT was used for analysis because maximum CIMT or maximum plaque height is reportedly associated with clinical outcomes 5 , 6) . If CIMT was ≥ 1.5 mm, plaque characteristics, including texture (homogeneous or heterogeneous echogenicity), calcification, and surface morphology (smooth, irregular, or ulcerated), were visually evaluated 5 , 14) . Here we especially focused on plaque heterogeneity, and heterogeneous plaque was defined as mixed lesion of hyper- (calcification), iso-, or hypoechoic area. Patients were divided into two groups according to the presence or absence of heterogeneous plaque: those with heterogeneous plaque (maximum CIMT ≥ 1.5 mm and heterogeneous texture) and those without heterogeneous plaque (maximum CIMT ＜1.5 mm or homogenous texture). In patients with multiple plaques, they were classified into the heterogeneous group if they had at least one heterogeneous plaque.
Clinical Outcomes
The endpoint of this study was the incidence of a major adverse cardiac event (MACE) defined as a composite of CV death, myocardial infarction (MI), and ischemic stroke during all follow-up period. CV death was defined as any death of a CV cause, sudden death, or death of unknown cause [15]. MI was defined as the presence of pathological and new Q waves on an electrocardiogram and/or an increase in creatine kinase myocardial band level to the upper limit of normal 15) . Ischemic stroke was defined as an acute episode of focal or global neurological dysfunction caused by brain, spinal cord, or retinal vascular injury as a result of an infarction 16) . Clinical follow-up was performed during routine clinical visits or via telephone interviews.
Statistical Analysis
All statistical analyses were performed using SPSS Statistics version 28 (IBM Corp, Armonk, NY, USA). Continuous variables are expressed as mean±standard deviation or median (interquartile range). Categorical variables are expressed as numbers and percentages. Continuous variables were compared using Student’s t-test or the Mann–Whitney U test, whereas categorical variables were compared using the chi-square or Fisher’s exact test. Time-to-event data were evaluated using the Kaplan–Meier method, and intergroup differences in the event rates were evaluated using the log-rank test. Cox proportional hazard regression analyses were performed to evaluate the associations between clinical events and variables. A multivariable Cox regression analysis was performed after adjusting for variables with p＜0.05 in the univariate analysis. Hazard ratios (HRs) are presented with 95% confidence intervals (CIs). Statistical significance was set at p＜0.05.
Results
The baseline characteristics of the 691 enrolled patients are shown in Table 1 . The median age was 70 (63–76) years. Of the 691 patients, 80.0% were men, 31.0% presented with acute coronary syndrome, 73.7% had dyslipidemia, and 85.4% received a statin at discharge. The median low density lipoprotein cholesterol level was 97 (78–122) mg/dL. Among 691 patients, 309 had a heterogeneous plaque. Patients with heterogeneous plaques were significantly older; more frequently had hypertension, diabetes mellitus, chronic kidney disease, and history of ischemic stroke, MI, and coronary artery bypass grafting; and had lower hemoglobin levels. In patients with heterogeneous plaques, low density lipoprotein cholesterol and triglyceride levels were significantly lower, and acute coronary syndrome was less frequently observed. Calcified or irregular/ulcerated plaque was more frequently observed in the heterogeneous group than in the homogeneous group.
Table 1. Characteristics of the patients.
| All N= 691 | Patients with heterogeneous plaque N= 309 | Patients without heterogeneous plaque N= 382 | P-valuea | |
|---|---|---|---|---|
| Age, years | 70 (63-76) | 72 (66-78) | 67 (60-74) | ＜0.001 |
| Body mass index, kg/m2 | 23.7 (21.5-26.3) | 23.4 (21.0-25.8) | 24.0 (21.7-26.6) | 0.02 |
| Men, n (%) | 553 (80.0%) | 251 (81.2%) | 302 (79.1%) | 0.48 |
| Hypertension, n (%) | 512 (74.1%) | 241 (78.0%) | 271 (70.9%) | 0.04 |
| Diabetes mellitus, n (%) | 322 (46.6%) | 159 (51.5%) | 163 (42.7%) | 0.02 |
| Dyslipidemia, n (%) | 509 (73.7%) | 215 (69.6%) | 294 (77.0%) | 0.03 |
| eGFR, mL/min/1.73 m2 | 64.6 (50.5-76.9) | 61.8 (45.9-74.4) | 66.6 (54.0-79.3) | ＜0.001 |
| eGFR＜60 mL/min/1.73 m2, n (%) | 274 (39.7%) | 140 (45.3%) | 134 (35.1%) | 0.006 |
| Dialysis, n (%) | 26 (3.8%) | 20 (6.5%) | 6 (1.6%) | ＜0.001 |
| Current Smoker, n (%) | 148 (21.4%) | 67 (21.8%) | 81 (21.2%) | 0.86 |
| Previous ischemic stroke | 104 (15.1%) | 60 (19.4%) | 44 (11.5%) | 0.004 |
| Previous MI, n (%) | 89 (12.9%) | 51 (16.5%) | 38 (9.9%) | 0.01 |
| Previous PCI, n (%) | 137 (19.8%) | 69 (22.3%) | 68 (17.8%) | 0.14 |
| Previous CABG, n (%) | 48 (6.9%) | 32 (10.4%) | 16 (4.2%) | 0.002 |
| ACS, n (%) | 214 (31.0%) | 82 (26.5%) | 132 (34.6%) | 0.02 |
| AMI, n (%) | 132 (19.1%) | 49 (15.9%) | 83 (21.7%) | 0.05 |
| UAP, n (%) | 82 (11.9%) | 33 (10.7%) | 49 (12.8%) | 0.39 |
| SAP, n (%) | 477 (69.0%) | 227 (73.5%) | 250 (65.4%) | 0.02 |
| Medication at discharge | ||||
| Antiplatelet agent, n (%) | 686 (99.3%) | 306 (99.0%) | 380 (99.5%) | 0.40 |
| ACE-i/ARB, n (%) | 422 (61.1%) | 193 (62.5%) | 229 (59.9%) | 0.50 |
| Ca blocker, n (%) | 276 (39.9%) | 129 (41.7%) | 147 (38.5%) | 0.38 |
| β blocker, n (%) | 263 (38.1%) | 122 (39.5%) | 141 (36.9%) | 0.49 |
| Statin, n (%) | 590 (85.4%) | 256 (82.8%) | 334 (87.4%) | 0.09 |
| Oral antidiabetic, n (%) | 208 (30.1%) | 106 (34.3%) | 102 (26.7%) | 0.03 |
| Insulin, n (%) | 73 (10.6%) | 30 (9.7%) | 43 (11.3%) | 0.51 |
| Total cholesterol, mg/dL | 172 (146-202) | 169 (142-195) | 176 (154-208) | ＜0.001 |
| HDL cholesterol, mg/dL | 45 (37-53) | 44 (36-53) | 45 (38-54) | 0.18 |
| LDL cholesterol, mg/dL | 97 (78-122) | 94 (76-114) | 100 (80-128) | 0.002 |
| Triglyceride, mg/dL | 120 (86-174) | 112 (82-164) | 127 (90-183) | 0.01 |
| HbA1c, % | 6.1 (5.8-6.8) | 6.2 (5.8-7.0) | 6.1 (5.8-6.7) | 0.08 |
| Hemoglobin, g/dL | 13.3 (11.8-14.7) | 12.9 (11.3-14.3) | 13.7 (12.3-15.0) | ＜0.001 |
| Ejection fraction, % | 63.6 (56.0-69.0) | 62.1 (54.0-68.3) | 64.0 (57.4-69.3) | 0.03 |
| Max CIMT, mm | 2.5 (1.8-3.1) | 2.9 (2.4-3.6) | 1.9 (1.4-2.7) | ＜0.001 |
| Calcified plaque, n (%) | 471 (68.2%) | 288 (93.2%) | 174 (45.5%) | ＜0.001 |
| Irregular or ulcerated plaque, n (%) | 238 (34.4%) | 178 (57.6%) | 58 (15.2%) | ＜0.001 |
a between the patients with and without heterogeneous carotid plaque
HDL; high density lipoprotein, LDL; low density lipoprotein, eGFR; estimated glomerular filtration rate, MI; myocardial infarction, PCI; percutaneous coronary intervention, CABG; coronary artery bypass grafting, ACS; acute coronary syndrome, AMI; acute myocardial infarction, UAP; unstable angina pectoris, SAP; stable angina pectoris, ACE-I; angiotensin converting enzyme inhibitor, ARB; angiotensin Ⅱ receptor blocker, CIMT; carotid intima-media thickness
During the median follow-up period of 1300 (541–2466) days, 63 patients developed MACE (36 in patients with heterogeneous plaque and 27 in patients without heterogeneous plaque). Patients with heterogeneous plaques had a significantly higher incidence of MACE (p=0.002) ( Fig.1 ) . The incidence of CV death was significantly higher, and that of ischemic stroke tended to be higher in patients with heterogeneous plaque, whereas that of MI did not differ significantly between the two groups. When the patients were divided into three groups, namely, patients without plaque (CIMT ＜1.5 mm), those with only homogeneous plaque, and those with heterogeneous plaque, those with heterogeneous plaque had the highest incidence of MACE ( Fig.2 ) . Patients with calcified plaques had a significantly higher incidence of MACE than those without calcified plaques (p=0.01). Patients with irregular/ulcerated plaques tended to have a higher incidence of MACE than those without irregular/ulcerated plaques, but the difference was not statistically significant (p=0.054) ( Fig.3 ) .
Fig.1.
Kaplan–Meier failure curves for MACE (a), CV death (b), MI (c), and ischemic stroke (d) in patients with and without heterogeneous carotid plaque
Fig.2.
Kaplan–Meier failure curves for MACE among patients without carotid plaque, with only homogeneous carotid plaque and with heterogeneous carotid plaque
Fig.3.
Kaplan–Meier failure curves for MACE in patients with and without calcified carotid plaque (a) and in those with and without irregular/ulcerated carotid plaque (b)
Univariate and multivariate Cox regression analyses of MACE are shown in Table 2 . Heterogeneous plaques were significantly associated with MACE after adjusting for covariates (HR, 1.71; 95% CI, 1.01–2.90; p=0.046). Meanwhile, maximum CIMT ≥ 1.5 mm was not independently associated with MACE (HR, 1.25; 95% CI, 0.52–2.97; p=0.62) ( Supplemental Table 1 ) . Calcified or irregular/ulcerated plaques were not independently associated with MACE (HR, 1.35; 95% CI, 0.69–2.64; p=0.38 and HR, 0.98; 95% CI, 0.57–1.69; p=0.95, respectively) ( Supplemental Tables 2 and 3 ) .
Table 2. Univariate and multivariate Cox regression analysis for MACE.
| Univariate | Multivariate | |||||
|---|---|---|---|---|---|---|
| HR | 95%CI | P-value | HR | 95%CI | P-value | |
| Heterogeneous carotid plaque | 2.20 | 1.33-3.66 | 0.002 | 1.71 | 1.01-2.90 | 0.046 |
| Max CIMT | 1.41 | 1.14-1.76 | 0.002 | |||
| Age | 1.04 | 1.01-1.06 | 0.02 | 1.01 | 0.98-1.04 | 0.47 |
| Body mass index | 0.94 | 0.87-.1.01 | 0.10 | |||
| Men | 0.67 | 0.38-1.16 | 0.15 | |||
| Hypertension | 1.47 | 0.76-2.81 | 0.25 | |||
| Diabetes mellitus | 1.75 | 1.05-2.91 | 0.03 | 1.49 | 0.89-2.49 | 0.14 |
| Dyslipidemia | 0.60 | 0.35-1.01 | 0.054 | |||
| eGFR＜60 mL/min/1.73 m2 | 2.79 | 1.67-4.66 | ＜0.001 | 2.16 | 1.25-3.71 | 0.005 |
| Dialysis | 6.43 | 3.16-13.09 | ＜0.001 | |||
| Current Smoker | 0.62 | 0.31-1.25 | 0.18 | |||
| Hemoglobin | 0.86 | 0.75-0.98 | 0.02 | 0.98 | 0.85-1.12 | 0.74 |
| Ejection fraction | 0.98 | 0.96-1.00 | 0.12 | |||
| Previous ischemic stroke | 3.65 | 2.18-6.12 | ＜0.001 | 2.77 | 1.63-4.73 | ＜0.001 |
| Previous MI | 0.76 | 0.33-1.76 | 0.52 | |||
| Previous PCI | 0.80 | 0.42-1.53 | 0.50 | |||
| Previous CABG | 1.23 | 0.49-3.08 | 0.66 | |||
| ACS | 1.42 | 0.84-2.39 | 0.19 | |||
| Medication at discharge | ||||||
| Antiplatelet agent | 0.19 | 0.03-1.40 | 0.10 | |||
| ACE-i / ARB | 1.33 | 0.77-2.28 | 0.31 | |||
| Ca blocker | 0.92 | 0.56-1.53 | 0.75 | |||
| β blocker | 1.56 | 0.95-2.58 | 0.08 | |||
| Statin | 0.45 | 0.26-0.79 | 0.005 | 0.60 | 0.34-1.05 | 0.07 |
| Oral antidiabetic | 1.08 | 0.63-1.84 | 0.78 | |||
| Insulin | 1.83 | 0.98-3.44 | 0.06 | |||
MACE; major adverse cardiovascular event, CIMT; carotid intima-media thickness, eGFR; estimated glomerular filtration rate, MI; myocardial infarction, PCI; percutaneous coronary intervention, CABG; coronary artery bypass grafting, ACS; acute coronary syndrome, ACE-I; angiotensin converting enzyme inhibitor, ARB; angiotensin Ⅱ receptor blocker
Supplemental Table 1. Multivariate Cox regression analysis for MACE (Model 2).
| Multivariate | |||
|---|---|---|---|
| HR | 95%CI | P-value | |
| Max CIMT ≥ 1.5 mm | 1.25 | 0.52-2.97 | 0.62 |
| Age | 1.02 | 0.99-1.05 | 0.31 |
| Diabetes mellitus | 1.47 | 0.87-2.47 | 0.15 |
| eGFR＜60 mL/min/1.73m2 | 2.20 | 1.28-3.79 | 0.004 |
| Hemoglobin | 0.97 | 0.85-1.11 | 0.66 |
| Previous ischemic stroke | 2.85 | 1.68-4.85 | ＜0.001 |
| Statin at discharge | 0.60 | 0.34-1.06 | 0.08 |
MACE; major adverse cardiovascular event, CIMT; carotid intima-media thickness, eGFR; estimated glomerular filtration rate
Supplemental Table 2. Multivariate Cox regression analysis for MACE (Model 3).
| Multivariate | |||
|---|---|---|---|
| HR | 95%CI | P-value | |
| Calcified plaque | 1.35 | 0.69-2.64 | 0.38 |
| Age | 1.01 | 0.99-1.04 | 0.35 |
| Diabetes mellitus | 1.46 | 0.87-2.45 | 0.16 |
| eGFR＜60 mL/min/1.73m2 | 2.15 | 1.25-3.72 | 0.006 |
| Hemoglobin | 0.98 | 0.85-1.12 | 0.72 |
| Previous ischemic stroke | 2.83 | 1.66-4.81 | ＜0.001 |
| Statin at discharge | 0.61 | 0.35-1.06 | 0.08 |
MACE; major adverse cardiovascular event, eGFR; estimated glomerular filtration rate
Supplemental Table 3. Multivariate Cox regression analysis for MACE (Model 4).
| Multivariate | |||
|---|---|---|---|
| HR | 95%CI | P-value | |
| Irregular / ulcerated plaque | 0.98 | 0.57-1.69 | 0.95 |
| Age | 1.02 | 0.99-1.05 | 0.27 |
| Diabetes mellitus | 1.48 | 0.88-2.49 | 0.14 |
| eGFR＜60 mL/min/1.73m2 | 2.24 | 1.30-3.84 | 0.004 |
| Hemoglobin | 0.97 | 0.84-1.11 | 0.63 |
| Previous ischemic stroke | 2.89 | 1.69-4.94 | ＜0.001 |
| Statin at discharge | 0.60 | 0.34-1.05 | 0.08 |
MACE; major adverse cardiovascular event, eGFR; estimated glomerular filtration rate
Discussion
This study showed a correlation between carotid artery ultrasound findings and clinical outcomes in patients who underwent PCI. To the best of our knowledge, this is the first study showing the clinical significance of a visually evaluated heterogeneous carotid plaque in patients with PCI. Patients with heterogeneous plaques (maximum CIMT ≥ 1.5 mm and visually evaluated heterogeneous texture) had a higher incidence of MACE (CV death, MI, and ischemic stroke). The presence of heterogeneous plaques independently predicted MACE after adjustments for covariates, whereas maximum CIMT only did not. Patients with calcified or irregular/ulcerated plaques were significantly or tended to be at higher risk of MACE; however, calcified or irregular/ulcerated plaques were not independent predictors of MACE.
Carotid atherosclerosis reflects systemic atherosclerosis, including that of the coronary arteries 17) . Assessing carotid atherosclerosis is useful for predicting future CV disease risk 5 , 6) . CIMT, carotid plaque, and plaque characteristics are important indicators of carotid atherosclerosis. For measuring CIMT, it is recommended to obtain images of distal 1 cm of the far wall of each CCA (not at the maximally thick point in any segment of the carotid artery) 6) . Many studies have shown a relationship between CIMT and future CV events 6) . In patients without known CV disease, CIMT was significantly associated with MI, stroke, and CV death 18 - 21) . However, a meta-analysis showed no additional value of CIMT measurement to the Framingham Risk Score, a widely used CV risk prediction tool, for predicting CV events 22) . Consequently, the American Heart Association/American College of Cardiology and European Society of Cardiology guidelines do not recommend routine CIMT measurements in risk assessments 23 , 24) . In contrast, carotid plaque, defined as atherosclerotic focal thickening protruding into the lumen or atherosclerotic diffuse vessel wall thickening with a CIMT ≥ 1.5 mm in any segment of the carotid artery, reflects atherosclerosis more strongly than CIMT and is useful for risk assessments 5) . Measuring maximal plaque height is recommended because several studies have demonstrated an association with clinical outcomes 8 - 10) . A meta-analysis of population-based studies reported that carotid plaque, compared with CIMT, was a stronger predictor of a future MI 25) . Moreover, in patients with CAD, carotid plaque was a better predictor of CV events than CIMT 26) . Considering this evidence, we measured the maximum CIMT at the maximally thick point in the bilateral CCA, carotid bulbus, and ICA (not distal 1 cm of the CCA).
Heterogeneous plaques are reportedly correlated with intraplaque hemorrhage, ulceration, and lipid core, indicating carotid plaque vulnerability 12 , 13) . A recent study showed that histologically evaluated vulnerable carotid plaques were associated with future CV events 27) . Echolucent (hypoechoic) plaques are also considered to indicate carotid plaque vulnerability. Previous studies reported that echolucent plaques, which were quantitatively evaluated by grayscale median or integrated backscatter, were associated with future CV events 28 - 31) . The quantitative evaluation of carotid plaques is certainly effective, but it takes time and might be difficult to adapt to clinical practice. Furthermore, clear cut-off values have not yet been determined 5) . In the current study, we visually evaluated plaque heterogeneity as a simple assessment of plaque characteristics. Shimoda et al. reported that visually evaluated heterogeneous carotid plaques are associated with the risk of CV diseases in subjects without known CV disease 11) . These results suggest the utility of visual assessment of carotid plaque heterogeneity. In the present study, the presence of heterogeneous plaque had a greater impact on the prediction of MACE than maximum CIMT alone. In addition, patients with heterogeneous plaques had a higher incidence of MACE than those with homogeneous plaques. It is important to assess carotid plaque volume and quality, as a previous study also reported that the combination of CIMT and plaque characteristics was effective for outcome prediction 30) .
Several studies have investigated the correlation between carotid ultrasound findings and CV events in patients with CAD 29 - 33) . Echolucent carotid plaques evaluated by integrated backscatter are reportedly associated with future CV events in patients with CAD 29 - 31) . However, the relationship between carotid ultrasound findings and future risks in patients undergoing PCI has not been completely elucidated. Although the association between CIMT and in-stent restenosis has been reported 34 , 35) , few studies have investigated the relationship between carotid ultrasound findings and hard clinical outcomes 36 - 38) . This study targeted patients who underwent PCI and showed the association between maximum CIMT, visually assessed plaque characteristics, and hard MACE (CV death, MI, and stroke) with a median follow-up period of 3.5 years. Our results suggest that patients with PCI with heterogeneous plaques might benefit from more aggressive managements such as strict optimal medication therapy.
Calcified or irregular/ulcerated plaques were significantly or tended to be related to MACE, but they were not independent predictors in our study. Nonin et al. reported that carotid plaque calcification length is associated with a composite of cardiac death and acute MI, whereas plaque irregularity is associated with a composite of cardiac death, acute MI, and coronary revascularization in patients who underwent coronary stent implantation 36) . This inconsistency may be partially because of differences in the methods used to evaluate plaque characteristics. They quantitatively measured the calcification length and defined an irregular surface as surface irregularity ＞0.4 mm; meanwhile, we only evaluated them visually. Thus, a quantitative evaluation might be better for assessing the calcification or surface morphology of carotid plaques.
In the current study, the prevalence of hypertension and diabetes mellitus was higher in the heterogeneous group, but that of dyslipidemia was higher in the homogenous group. A previous study reported that lipid-lowering therapy brought stabilization of carotid plaque 39) . Therefore, characteristics of carotid plaque might have been already affected at the time of PCI among patients with dyslipidemia.
This study had several limitations. First, this was a single-center retrospective study with a limited number of patients. Second, ultrasound data regarding hypoechoic plaques, mobile plaques, plaque volume, and the number of plaques were not available. Third, the endpoint of ischemic stroke might include cardiogenic cerebral embolization, which might be less related to carotid plaque than other atherosclerotic infarctions. However, in clinical practice, it is often difficult to completely distinguish cardiogenic embolization from atherosclerotic infarction, including artery-to-artery embolization. Fourth, this study included patients who underwent PCI during an extended period; therefore, characteristics such as PCI and medical therapy might have varied. The utility of carotid ultrasound for risk estimation in patients who receive contemporary PCI and medication therapy should be investigated in the future.
Conclusion
In patients with CAD undergoing PCI, the presence of heterogeneous carotid plaque was independently associated with the risk of MACE, including CV death, MI, and ischemic stroke. Such patients may require more aggressive medical therapy and careful follow-up.
Acknowledgements:
This work was supported by a grant from Grant-in-Aid for Scientific Research (KAKENHI) (No.19K17591) of the Ministry of Education, Culture, Sports, Science and Technology (MEXT) and Japanese Society for the Promotion of Science (JSPA).
Grant Support:
None.
Conflicts of interest:
Hideki Ishii received lecture fees from Astellas Pharma Inc, AstraZeneca, Daiichi Sankyo Inc, MSD. Toyoaki Murohara received lecture fees from Bayer Pharmaceutical Co LTD, Daiichi Sankyo Co Ltd, Dainippon Sumitomo Pharma Co Ltd, Kowa Co Ltd, MSD, Mitsubishi Tanabe Pharma Corp, Nippon Boehringer Ingelheim Co Ltd, Novartis Pharma Kabushiki Kaisha, Pfizer Japan Inc, Sanofi-aventis, Takeda Pharmaceutical Co Ltd. Toyoaki Murohara received unrestricted research grants from Daiichi Sankyo Co Ltd, Dainippon Sumitomo Pharma Co Ltd, Kowa Co Ltd, MSD, Mitsubishi Tanabe Pharma Corp, Nippon Boehringer Ingelheim Co Ltd, Novartis Pharma Kabushiki Kaisha, Pfizer Japan Inc, Sanofi-aventis, Takeda Pharmaceutical Co Ltd, Astellas Pharma Inc, Otsuka Pharmaceutical Co Ltd, Teijin Pharma Ltd. All other authors have reported that they have no relationships relevant to the contents of this paper to disclose.
Footnote
All authors take responsibility for all aspects of the reliability and freedom from bias of the data presented and their discussed interpretation.
References
- 1).Kogame N, Ono M, Kawashima H, Tomaniak M, Hara H, Leipsic J, Andreini D, Collet C, Patel MR, Tu S, Xu B, Bourantas CV, Lerman A, Piek JJ, Davies JE, Escaned J, Wijns W, Onuma Y and Serruys PW: The Impact of Coronary Physiology on Contemporary Clinical Decision Making. JACC Cardiovasc Interv, 2020; 13: 1617-1638 [DOI] [PubMed] [Google Scholar]
- 2).Kawashima H, Serruys PW, Ono M, Hara H, O’Leary N, Mack MJ, Holmes DR, Morice MC, Head SJ, Kappetein AP, Thuijs D, Milojevic M, Noack T, Mohr FW, Davierwala PM, Sharif F, McEvoy JW, Onuma Y and Investigators SES: Impact of Optimal Medical Therapy on 10-Year Mortality After Coronary Revascularization. J Am Coll Cardiol, 2021; 78: 27-38 [DOI] [PubMed] [Google Scholar]
- 3).Mozaffarian D, Benjamin EJ, Go AS, Arnett DK, Blaha MJ, Cushman M, de Ferranti S, Despres JP, Fullerton HJ, Howard VJ, Huffman MD, Judd SE, Kissela BM, Lackland DT, Lichtman JH, Lisabeth LD, Liu S, Mackey RH, Matchar DB, McGuire DK, Mohler ER, 3rd, Moy CS, Muntner P, Mussolino ME, Nasir K, Neumar RW, Nichol G, Palaniappan L, Pandey DK, Reeves MJ, Rodriguez CJ, Sorlie PD, Stein J, Towfighi A, Turan TN, Virani SS, Willey JZ, Woo D, Yeh RW, Turner MB, American Heart Association Statistics C and Stroke Statistics S: Heart disease and stroke statistics--2015 update: a report from the American Heart Association. Circulation, 2015; 131: e29-322 [Google Scholar]
- 4).Nichols M, Townsend N, Scarborough P and Rayner M: Cardiovascular disease in Europe 2014: epidemiological update. Eur Heart J, 2014; 35: 2950-2959 [DOI] [PubMed] [Google Scholar]
- 5).Johri AM, Nambi V, Naqvi TZ, Feinstein SB, Kim ESH, Park MM, Becher H and Sillesen H: Recommendations for the Assessment of Carotid Arterial Plaque by Ultrasound for the Characterization of Atherosclerosis and Evaluation of Cardiovascular Risk: From the American Society of Echocardiography. J Am Soc Echocardiogr, 2020; 33: 917-933 [DOI] [PubMed] [Google Scholar]
- 6).Stein JH, Korcarz CE, Hurst RT, Lonn E, Kendall CB, Mohler ER, Najjar SS, Rembold CM, Post WS and American Society of Echocardiography Carotid Intima-Media Thickness Task F: Use of carotid ultrasound to identify subclinical vascular disease and evaluate cardiovascular disease risk: a consensus statement from the American Society of Echocardiography Carotid Intima-Media Thickness Task Force. Endorsed by the Society for Vascular Medicine. J Am Soc Echocardiogr, 2008; 21: 93-111; quiz 189-190 [DOI] [PubMed] [Google Scholar]
- 7).Nambi V, Chambless L, Folsom AR, He M, Hu Y, Mosley T, Volcik K, Boerwinkle E and Ballantyne CM: Carotid intima-media thickness and presence or absence of plaque improves prediction of coronary heart disease risk: the ARIC (Atherosclerosis Risk In Communities) study. J Am Coll Cardiol, 2010; 55: 1600-1607 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8).Johri AM, Behl P, Hetu MF, Haqqi M, Ewart P, Day AG, Parfrey B and Matangi MF: Carotid Ultrasound Maximum Plaque Height-A Sensitive Imaging Biomarker for the Assessment of Significant Coronary Artery Disease. Echocardiography, 2016; 33: 281-289 [DOI] [PubMed] [Google Scholar]
- 9).Adams A, Bojara W and Schunk K: Early Diagnosis and Treatment of Coronary Heart Disease in Asymptomatic Subjects With Advanced Vascular Atherosclerosis of the Carotid Artery (Type III and IV b Findings Using Ultrasound) and Risk Factors. Cardiol Res, 2018; 9: 22-27 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 10).Sillesen H, Sartori S, Sandholt B, Baber U, Mehran R and Fuster V: Carotid plaque thickness and carotid plaque burden predict future cardiovascular events in asymptomatic adult Americans. Eur Heart J Cardiovasc Imaging, 2018; 19: 1042-1050 [DOI] [PubMed] [Google Scholar]
- 11).Shimoda S, Kitamura A, Imano H, Cui R, Muraki I, Yamagishi K, Umesawa M, Sankai T, Hayama-Terada M, Kubota Y, Shimizu Y, Okada T, Kiyama M and Iso H: Associations of Carotid Intima-Media Thickness and Plaque Heterogeneity With the Risks of Stroke Subtypes and Coronary Artery Disease in the Japanese General Population: The Circulatory Risk in Communities Study. J Am Heart Assoc, 2020; 9: e017020 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 12).Reilly LM, Lusby RJ, Hughes L, Ferrell LD, Stoney RJ and Ehrenfeld WK: Carotid plaque histology using real-time ultrasonography. Clinical and therapeutic implications. Am J Surg, 1983; 146: 188-193 [DOI] [PubMed] [Google Scholar]
- 13).Bos D, Arshi B, van den Bouwhuijsen QJA, Ikram MK, Selwaness M, Vernooij MW, Kavousi M and van der Lugt A: Atherosclerotic Carotid Plaque Composition and Incident Stroke and Coronary Events. J Am Coll Cardiol, 2021; 77: 1426-1435 [DOI] [PubMed] [Google Scholar]
- 14).Cao JJ, Arnold AM, Manolio TA, Polak JF, Psaty BM, Hirsch CH, Kuller LH and Cushman M: Association of carotid artery intima-media thickness, plaques, and C-reactive protein with future cardiovascular disease and all-cause mortality: the Cardiovascular Health Study. Circulation, 2007; 116: 32-38 [DOI] [PubMed] [Google Scholar]
- 15).Thygesen K, Alpert JS, Jaffe AS, Chaitman BR, Bax JJ, Morrow DA, White HD and Executive Group on behalf of the Joint European Society of Cardiology /American College of Cardiology /American Heart Association /World Heart Federation Task Force for the Universal Definition of Myocardial I: Fourth Universal Definition of Myocardial Infarction (2018). Circulation, 2018; 138: e618-e651 [DOI] [PubMed] [Google Scholar]
- 16).Hicks KA, Mahaffey KW, Mehran R, Nissen SE, Wiviott SD, Dunn B, Solomon SD, Marler JR, Teerlink JR, Farb A, Morrow DA, Targum SL, Sila CA, Hai MTT, Jaff MR, Joffe HV, Cutlip DE, Desai AS, Lewis EF, Gibson CM, Landray MJ, Lincoff AM, White CJ, Brooks SS, Rosenfield K, Domanski MJ, Lansky AJ, McMurray JJV, Tcheng JE, Steinhubl SR, Burton P, Mauri L, O’Connor CM, Pfeffer MA, Hung HMJ, Stockbridge NL, Chaitman BR, Temple RJ and Standardized Data Collection for Cardiovascular Trials I: 2017 Cardiovascular and Stroke Endpoint Definitions for Clinical Trials. Circulation, 2018; 137: 961-972 [DOI] [PubMed] [Google Scholar]
- 17).Poredos P and Jezovnik MK: Preclinical carotid atherosclerosis as an indicator of polyvascular disease: a narrative review. Ann Transl Med, 2021; 9: 1204 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 18).Chambless LE, Heiss G, Folsom AR, Rosamond W, Szklo M, Sharrett AR and Clegg LX: Association of coronary heart disease incidence with carotid arterial wall thickness and major risk factors: the Atherosclerosis Risk in Communities (ARIC) Study, 1987-1993. Am J Epidemiol, 1997; 146: 483-494 [DOI] [PubMed] [Google Scholar]
- 19).Chambless LE, Folsom AR, Clegg LX, Sharrett AR, Shahar E, Nieto FJ, Rosamond WD and Evans G: Carotid wall thickness is predictive of incident clinical stroke: the Atherosclerosis Risk in Communities (ARIC) study. Am J Epidemiol, 2000; 151: 478-487 [DOI] [PubMed] [Google Scholar]
- 20).Lorenz MW, von Kegler S, Steinmetz H, Markus HS and Sitzer M: Carotid intima-media thickening indicates a higher vascular risk across a wide age range: prospective data from the Carotid Atherosclerosis Progression Study (CAPS). Stroke, 2006; 37: 87-92 [DOI] [PubMed] [Google Scholar]
- 21).O’Leary DH, Polak JF, Kronmal RA, Manolio TA, Burke GL and Wolfson SK, Jr.: Carotid-artery intima and media thickness as a risk factor for myocardial infarction and stroke in older adults. Cardiovascular Health Study Collaborative Research Group. N Engl J Med, 1999; 340: 14-22 [DOI] [PubMed] [Google Scholar]
- 22).Den Ruijter HM, Peters SA, Anderson TJ, Britton AR, Dekker JM, Eijkemans MJ, Engstrom G, Evans GW, de Graaf J, Grobbee DE, Hedblad B, Hofman A, Holewijn S, Ikeda A, Kavousi M, Kitagawa K, Kitamura A, Koffijberg H, Lonn EM, Lorenz MW, Mathiesen EB, Nijpels G, Okazaki S, O’Leary DH, Polak JF, Price JF, Robertson C, Rembold CM, Rosvall M, Rundek T, Salonen JT, Sitzer M, Stehouwer CD, Witteman JC, Moons KG and Bots ML: Common carotid intima-media thickness measurements in cardiovascular risk prediction: a meta-analysis. JAMA, 2012; 308: 796-803 [DOI] [PubMed] [Google Scholar]
- 23).Andrus B and Lacaille D: 2013 ACC/AHA guideline on the assessment of cardiovascular risk. J Am Coll Cardiol, 2014; 63: 2886 [DOI] [PubMed] [Google Scholar]
- 24).Visseren FLJ, Mach F, Smulders YM, Carballo D, Koskinas KC, Back M, Benetos A, Biffi A, Boavida JM, Capodanno D, Cosyns B, Crawford C, Davos CH, Desormais I, Di Angelantonio E, Franco OH, Halvorsen S, Hobbs FDR, Hollander M, Jankowska EA, Michal M, Sacco S, Sattar N, Tokgozoglu L, Tonstad S, Tsioufis KP, van Dis I, van Gelder IC, Wanner C, Williams B, Group ESCSD and Societies ESCNC: 2021 ESC Guidelines on cardiovascular disease prevention in clinical practice. Eur Heart J, 2021; 42: 3227-3337 [Google Scholar]
- 25).Inaba Y, Chen JA and Bergmann SR: Carotid plaque, compared with carotid intima-media thickness, more accurately predicts coronary artery disease events: a meta-analysis. Atherosclerosis, 2012; 220: 128-133 [DOI] [PubMed] [Google Scholar]
- 26).Held C, Hjemdahl P, Eriksson SV, Bjorkander I, Forslund L and Rehnqvist N: Prognostic implications of intima-media thickness and plaques in the carotid and femoral arteries in patients with stable angina pectoris. Eur Heart J, 2001; 22: 62-72 [DOI] [PubMed] [Google Scholar]
- 27).Goncalves I, Sun J, Tengryd C, Nitulescu M, Persson AF, Nilsson J and Edsfeldt A: Plaque Vulnerability Index Predicts Cardiovascular Events: A Histological Study of an Endarterectomy Cohort. J Am Heart Assoc, 2021; 10: e021038 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 28).Wohlin M, Sundstrom J, Andren B, Larsson A and Lind L: An echolucent carotid artery intima-media complex is a new and independent predictor of mortality in an elderly male cohort. Atherosclerosis, 2009; 205: 486-491 [DOI] [PubMed] [Google Scholar]
- 29).Honda O, Sugiyama S, Kugiyama K, Fukushima H, Nakamura S, Koide S, Kojima S, Hirai N, Kawano H, Soejima H, Sakamoto T, Yoshimura M and Ogawa H: Echolucent carotid plaques predict future coronary events in patients with coronary artery disease. J Am Coll Cardiol, 2004; 43: 1177-1184 [DOI] [PubMed] [Google Scholar]
- 30).Hirano M, Nakamura T, Kitta Y, Sano K, Kodama Y, Kobayashi T, Fujioka D, Saito Y, Yano T, Watanabe K, Watanabe Y, Kawabata K, Obata JE and Kugiyama K: Assessment of carotid plaque echolucency in addition to plaque size increases the predictive value of carotid ultrasound for coronary events in patients with coronary artery disease and mild carotid atherosclerosis. Atherosclerosis, 2010; 211: 451-455 [DOI] [PubMed] [Google Scholar]
- 31).Uematsu M, Nakamura T, Sugamata W, Kitta Y, Fujioka D, Saito Y, Kawabata K, Obata JE, Watanabe Y, Watanabe K and Kugiyama K: Echolucency of carotid plaque is useful for assessment of residual cardiovascular risk in patients with chronic coronary artery disease who achieve LDL-C goals on statin therapy. Circ J, 2014; 78: 151-158 [DOI] [PubMed] [Google Scholar]
- 32).Park HW, Kim WH, Kim KH, Yang DJ, Kim JH, Song IG, Kwon TG and Bae JH: Carotid plaque is associated with increased cardiac mortality in patients with coronary artery disease. Int J Cardiol, 2013; 166: 658-663 [DOI] [PubMed] [Google Scholar]
- 33).Yuk HB, Park HW, Jung IJ, Kim WH, Kim KH, Yang DJ, Park YH, Kim YK, Song IG and Bae JH: Analysis of Carotid Ultrasound Findings on Cardiovascular Events in Patients with Coronary Artery Disease during Seven-Year Follow-Up. Korean Circ J, 2015; 45: 28-37 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 34).Kitta Y, Obata JE, Takano H, Nakamura T, Kodama Y, Fujioka D, Saito Y, Kawabata K, Mende A, Kobayashi T and Kugiyama K: Echolucent carotid plaques predict in-stent restenosis after bare metal stenting in native coronary arteries. Atherosclerosis, 2008; 197: 177-182 [DOI] [PubMed] [Google Scholar]
- 35).Bhavanadhar P, Reddy YVS, Otikunta AN and Srinivas R: Evaluation of relationship between common carotid artery intima-media thickness and coronary in-stent restenosis: A case-control study. Interv Med Appl Sci, 2018; 10: 38-44 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 36).Nonin S, Iwata S, Sugioka K, Fujita S, Norioka N, Ito A, Nakagawa M and Yoshiyama M: Plaque surface irregularity and calcification length within carotid plaque predict secondary events in patients with coronary artery disease. Atherosclerosis, 2017; 256: 29-34 [DOI] [PubMed] [Google Scholar]
- 37).Nakahashi T, Tada H, Sakata K, Nomura A, Ohira M, Mori M, Takamura M, Hayashi K, Yamagishi M and Kawashiri MA: Additive Prognostic Value of Carotid Plaque Score to Enhance the Age, Creatinine, and Ejection Fraction Score in Patients with Acute Coronary Syndrome. J Atheroscler Thromb, 2018; 25: 709-719 [DOI] [PMC free article] [PubMed] [Google Scholar]
- 38).Lee S, Cho GY, Kim HS, Yoon YE, Lee SP, Kim HK, Kim YJ and Sohn DW: Common carotid intima-media thickness as a risk factor for outcomes in Asian patients with acute ST-elevation myocardial infarction. Can J Cardiol, 2014; 30: 1620-1626 [DOI] [PubMed] [Google Scholar]
- 39).Ibrahimi P, Jashari F, Bajraktari G, Wester P and Henein MY: Ultrasound assessment of carotid plaque echogenicity response to statin therapy: a systematic review and meta-analysis. Int J Mol Sci, 2015; 16: 10734-10747 [DOI] [PMC free article] [PubMed] [Google Scholar]