Abstract
Aims: We aimed to evaluate the effect of serum lipoprotein(a) (Lp(a)) levels on carotid artery ulceration using digital subtraction angiography (DSA), which is the gold standard for assessing atherosclerotic plaque surface morphology.
Methods: Of the consecutive cerebrovascular patients prospectively collected serum Lp(a) levels from June 2021 to October 2024 admitted to our institution, patients with carotid artery stenosis were enrolled in this study. Blood samples were collected within three months of admission. Based on common carotid angiography and 3D rotational angiography to confirm the morphology of stenotic lesions, patients were dichotomized according to the presence or absence of carotid artery ulceration.
Results: Of the 439 cerebrovascular patients, 94 with carotid artery stenosis were analyzed (18 females, median 75 [interquartile range, 71–81] years) and carotid artery ulceration was confirmed in 38 (40.0 %) patients. Patients with carotid artery ulceration showed a higher proportion of dyslipidemia (94.7% versus 75.0%; p = 0.013), and higher L(a) levels (28 [11–56] vs 10 [5–25] mg/dL, p = 0.007) than those without. Multivariable logistic analysis adjusted for other atherosclerotic risk factors showed a significant association between higher Lp(a) levels and carotid artery ulceration (odds ratio per 10 mg/dL increase, 1.21; 95%CI, 1.02–1.43; p = 0.026). Receiver operating characteristic curve analysis showed that Lp(a) ≥ 26 mg/dL was the threshold to predict the presence of carotid artery ulceration (area under the curve = 0.67; sensitivity, 52.6%; specificity, 78.6%).
Conclusions: In patients with carotid artery stenosis who may be considered candidates for surgical treatment, elevated Lp(a) levels were associated with carotid artery ulceration.
Keywords: Lipoprotein(a), Ulcer, Carotid artery stenosis
Introduction
Lipoprotein(a) (Lp(a)) is an LDL (low-density lipoprotein)-like particle characterized by covalently bound Apo(a) to Apo B100 (Apolipoprotein B100) of LDL. Genetic and observational data have shown that elevated serum Lp (a) levels are independent risk factors of atherosclerotic diseases, contributing to increased atherogenesis, inflammation, and thrombosis 1) . For ischemic stroke which was one of the atherosclerotic diseases, elevated level of Lp(a) was associated with an increased risk of ischemic stroke, especially the stroke subtype of large artery atherosclerosis, including carotid artery stenosis 2) . Given the residual risk of atherosclerotic events, even when low-density lipoprotein cholesterol (LDL-C) levels are controlled within an optimal range, Lp(a) may be a potential target for blood lipid intervention to reduce atherosclerotic events, including ischemic stroke due to carotid artery stenosis 3) .
Vulnerable carotid plaques, including intraplaque hemorrhage, lipid-rich necrotic core, and plaque ulceration, can cause plaque rupture, which leads to thrombus formation and embolization into distally located intracranial arteries, and exert a higher risk of ischemic cerebrovascular events than stable plaques 4) . In addition, a report evaluating the association between carotid artery ulceration and ischemic stroke events showed that patients with carotid artery ulcers are four–seven times more likely to develop an ischemic stroke event or recurrence of ischemic stroke than those without 5) . Therefore, the stabilization of high-risk plaques using intensive LDL-C-lowering agents is an important treatment strategy for carotid artery stenosis with vulnerable plaques. However, there are still considerable residual risks that need to be understood. Some reports have recently shown an association between serum Lp(a) levels and the characteristics of vulnerable carotid plaques, such as intraplaque hemorrhage, lipid-rich necrotic core, and intraplaque neovascularization, which were assessed using ultrasonography and magnetic resonance imaging (MRI) 6 - 8) . However, the association between serum Lp(a) level and carotid artery ulceration, which is also a component of vulnerable plaque, was still not clear.
Aim
This study aimed to evaluate the effect of serum L (a) concentration on carotid artery ulceration using digital subtraction angiography (DSA), which offers superior accuracy to other imaging modalities, particularly in detecting subtle ulcerations.
Methods
Patients
All cerebrovascular patients (i.e., those with cerebral aneurysm, carotid artery or intracranial artery stenosis, dural arteriovenous fistula, and arteriovenous malformation) admitted to our institute for the purpose of implementing DSA were prospectively registered in the registry dataset from 2021 9 , 10) . In the registry, blood samples, including serum concentrations of Lp(a), were prospectively collected from consecutive patients who were admitted to our institute on a scheduled basis from June 2021 as part of routine blood tests performed during the usual course of clinical practice. Among the cerebrovascular patients enrolled in the registry between June 2021 and October 2024, those with carotid artery stenosis evaluated using DSA were enrolled in the analysis. The decision of whether to perform DSA in patients with carotid artery stenosis was made by the attending physician, based on findings from carotid ultrasonography, computed tomography angiography (CTA), magnetic resonance angiography (MRA), and the potential need for carotid artery stenting or carotid endarterectomy, which are typically considered in cases of symptomatic stenosis of ≥ 50% or asymptomatic stenosis of approximately 70–80% or greater 11 , 12) .
The registry was approved by the ethics committees of the participating institutions. The requirement for written informed consent was waived because the study was observational, did not impose no additional invasive procedures were performed on the participants, and the information was sufficiently anonymized. The data supporting the findings of this study are available from the corresponding author upon reasonable request. The corresponding author has full access to all data in the study and takes responsibility for their integrity and data analysis.
Clinical Assessments
The following clinical information was collected from medical records: age, sex, current smoking, medications (statin, ezetimibe, and antihypertensive drugs), and comorbidities. The comorbidities included: 1) hypertension, defined as diagnosis before index admission or as use of antihypertensive agents before admission; 2) diabetes mellitus, defined as diagnosis before index admission, as use of oral hypoglycemic agents or insulin, or as HbA1c ≥ 6.5% (National Glycohemoglobin Standardization Program); 3) dyslipidemia, defined as a LDL-C ≥ 140 mg/dL, high-density lipoprotein cholesterol (HDL-C) concentration ＜40 mg/dL, triglyceride concentration ≥ 150 mg/dL, or current use of lipid-lowering drugs; 4) coronary artery disease, including a history of myocardial infarction, angina, or coronary revascularization treatment; 5) stroke or transient ischemic attack (TIA), defined as all ischemic symptoms that developed regardless of their association to carotid artery stenosis. The definition of dyslipidemia did not include serum Lp(a) levels. Symptomatic ischemic lesions were defined as neurological symptoms that occurred due to stenosis of the carotid artery (ipsilateral to the stenotic lesion) before admission, including one or more TIA characterized by focal neurological dysfunction, transient monocular blindness, or one or more ischemic strokes. Blood samples were collected within 3 months prior to admission, including total cholesterol, LDL-cholesterol, HDL-cholesterol, triglycerides, Lp(a), estimated glomerular filtration rate (eGFR), and HbA1c. Systolic and diastolic blood pressure were measured on admission. LP (a) levels were measured using a latex agglutination immunoassay kit (Special Reference Laboratories).
Imaging Data Analysis
All DSA studies were performed using biplane angiography units (ARTIS icono D-Spin; Siemens Healthcare GmbH, Forchheim, Germany). Common carotid angiography and 3D rotational angiography were performed using a 4Fr or larger catheter to confirm the morphology of the stenotic lesions. The frame rate for common carotid angiography was set at four frames per second. All DSA procedures were performed by or in the presence of a board-certified neuro interventionalist (neurosurgeon or neurologist). The North American
The Symptomatic Carotid Endarterectomy Trial (NASCET) was used to calculate the degree of stenosis 13) . The degree of stenosis was set at 95% in cases of near occlusion, which was defined as very severe stenosis at the residual luminal site with delayed flow of angiographic contrast material and reduced arterial caliber secondary to arterial collapse. Carotid artery ulceration was defined as the extension of contrast material beyond the vascular lumen into the surrounding plaque in the presence of cavities 2 mm depth based on previous reports 14 - 16) . Board-certified neurosurgeon (Y.K.) and board-certified neuro interventionalist (K.F.), blinded to clinical information, independently assessed the presence of ulceration, and interobserver reliability for the presence of carotid artery ulceration was evaluated with the kappa coefficient 17) . In cases with a discrepancy for the presence of ulcer between the two readers, the opinion of another board-certified neuro interventionalist (H. S.), who was also blinded to clinical information, was sought to resolve the disagreements. For the analysis, the dataset was used after resolving disagreements regarding the presence or absence of ulcers. The presence of contralateral carotid stenosis was defined as a narrowing (50% or more based on the NASCET criteria) of the carotid artery on the opposite side of the neck from the one being assessed.
Outcomes
This study aimed to measure the effect of serum L (a) concentration on the presence of ulcers in patients with carotid artery stenosis.
Statistical Analysis
Continuous variables are summarized as median and interquartile range (IQR). Categorical variables were summarized based on frequencies and percentages. Variables were analyzed using the Mann-Whitney U test for continuous data and Fisher’s exact test for categorical data. To elucidate the association between serum Lp (a) concentration and carotid artery ulceration, a multivariable logistic regression model was used, adjusted for age, Lp(a), and modifiable risk factors for carotid atherosclerosis including current smoking, diabetes mellitus, hypertension, and dyslipidemia as covariates (model 1). The other multivariate analyses were performed after replacing the covariates of dyslipidemia with LDL cholesterol (model 2) and further adding statin use to the covariates in model 2 (model 3). To investigate whether statin use modified the effect of Lp(a) on carotid artery ulceration in model 1, the interaction significance was assessed using the p-value for the interaction term. Odds ratios (OR) with 95% confidence intervals (CI) were used to describe the effect of each covariate on the presence of ulcers. Hosmer-Lemeshow χ2 statistics were used as goodness-of-fit indices for each multivariable logistic models. Furthermore, to estimate the threshold Lp(a) levels for predicting carotid artery ulceration, receiver operating characteristic (ROC) curve analyses were performed. The optimal threshold for the ROC curve analysis was determined by maximizing Youden’s index 18) . Significance was set at P＜0.05. All analyses were performed using Stata/IC statistical package (version 17.0; StataCorp, College Station, TX, USA).
Results
Patient Characteristics
Of the 439 cerebrovascular patients prospectively collected the serum concentration of Lp(a) from June 2021 to October 2024, a total of 94 patients with carotid artery stenosis evaluated with DSA were enrolled (18 females, median age 75 [IQR, 71-81] years). The kappa coefficient for the dichotomized presence or absence of carotid artery ulceration between the two DSA readers was 0.85, indicating almost perfect inter-observer agreement 17) . Resolution of discrepancies by a third DSA reader was required in seven cases. As a result of the imaging analysis, carotid artery ulceration was confirmed in 38 patients (40.0%). Representative cases showing the presence or absence of carotid artery ulceration were shown in Supplemental Fig.1 . The median serum concentration of L(a) was 17 (IQR, 6-40) mg/dL, and its distribution according to the presence or absence of carotid artery ulceration is shown in Fig.1 .
Supplemental Fig.1. Representative cases showing the presence or absence of carotid artery ulceration.
Digital subtraction angiography showed images of carotid artery ulceration (arrows) in cases A and B. Carotid artery ulceration was not confirmed in cases C and D.
Fig.1.
Distribution of serum concentration of Lp(a) according to the presence or absence of carotid artery ulceration
Abbreviations: Lp(a), lipoprotein(a).
The baseline characteristics of the enrolled patients according to the presence or absence of carotid artery ulceration are listed in Table 1 . Patients with carotid artery ulceration showed a significantly higher proportion of dyslipidemia (94.7% vs. 75.0%; p = 0.013) and higher L(a) levels (28 [11–56] vs. 10 [5–25] mg/dL, p = 0.007) than those without carotid artery ulceration. The degree of stenosis (75 [60–86] vs. 65 [46–80] %, p = 0.075) and proportion of symptomatic lesions (44.7% vs. 28.6%; p = 0.127) tended to be higher in patients with carotid artery ulceration.
Table 1. Clinical characteristics of enrolled patients with carotid artery stenosis according to the presence of ulcer.
|
Overall (n = 94) |
Ulcer Present (n = 38) |
Ulcer Absent (n = 56) |
p value | |
|---|---|---|---|---|
| Age (years) | 75 (71-81) | 76 (73-80) | 74 (70-81) | 0.542 |
| Female | 18 (19.1) | 5 (13.2) | 13 (23.2) | 0.290 |
| Current smoking | 10 (10.6) | 6 (15.8) | 4 (7.1) | 0.306 |
| Comorbidities | ||||
| Hypertension | 78 (83.0) | 32 (84.2) | 46 (82.1) | 1.000 |
| Diabetes mellitus | 47 (50.0) | 19 (50.0) | 28 (50.0) | 1.000 |
| Dyslipidemia | 78 (83.0) | 36 (94.7) | 42 (75.0) | 0.013 |
| Coronary artery disease | 21 (22.3) | 9 (23.7) | 12 (21.4) | 0.806 |
| Stroke or TIA | 40 (42.6) | 19 (50.0) | 21 (37.5) | 0.127 |
| Medication | ||||
| Statin | 45 (47.9) | 21 (55.3) | 24 (42.9) | 0.294 |
| Ezetimibe | 2 (2.1) | 1 (2.6) | 1 (1.8) | 1.000 |
| Antihypertensive drugs | 56 (59.6) | 22 (57.9) | 34 (60.7) | 0.832 |
| Laboratory findings | ||||
| Total cholesterol (mg/dL) | 183 (151-203) | 161 (142-199) | 187 (154-204) | 0.165 |
| LDL-cholesterol (mg/dL) | 96 (73-118) | 92 (69-114) | 100 (75-122) | 0.353 |
| HDL-cholesterol (mg/dL) | 54 (45-67) | 53 (44-67) | 55 (47-69) | 0.269 |
| Triglyceride (mg/dL) | 81 (67-125) | 162 (79-183) | 116 (82-165) | 0.401 |
| Lipoprotein(a) (mg/dL) | 17 (6-40) | 28 (11-56) | 10 (5-25) | 0.007 |
| HbA1c (%) | 6.1 (5.7-6.8) | 5.2 (5.7-6.8) | 6.1 (5.7-6.8) | 0.911 |
| eGFR (mL/min/1.73 m2) | 59.9 (45.4-67.7) | 57.2 (45.4-57.2) | 62.2 (48.0-67.9) | 0.561 |
| Systolic BP (mmHg) | 134 (120-148) | 136 (122-147) | 133 (119-154) | 0.799 |
| Diastolic BP (mmHg) | 76 (67-83) | 76 (66-82) | 77 (68-83) | 0.624 |
| Degree of stenosis (%, NASCET) | 70 (50-83) | 75 (60-86) | 65 (46-80) | 0.075 |
| Symptomatic stenotic lesion | 33 (35.1) | 17 (44.7) | 16 (28.6) | 0.127 |
| Contralateral carotid stenosis | 19 (20.2) | 7 (18.4) | 12 (21.4) | 0.798 |
Data are presented as median (interquartile range) or numbers (%). BP, blood pressure; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; NASCET, The North American Symptomafic Carofid Endarterectomy Trial; TIA, transient ischemic attack.
Predictors of Carotid Artery Ulceration
Univariate logistic regression analysis showed that dyslipidemia (odds ratio, 6.00; 95% CI, 1.28–28.18; p = 0.023) and higher Lp(a) levels (odds ratio per 10 mg/dL increase, 1.21; 95% CI, 1.03–1.41; p = 0.020) were associated with carotid artery ulceration ( Table 2 ) . Multivariable logistic regression analysis adjusted for age, current smoking, hypertension, diabetes mellitus, dyslipidemia showed that higher Lp(a) levels was associated with carotid artery ulceration (odds ratio per 10 mg/dL increase, 1.21; 95% CI, 1.02–1.43; p = 0.026; model 1 in Table 2 ), independent of comorbidities of dyslipidemia. The other multivariable logistic regression analyses also showed the significant association between higher Lp(a) levels and carotid artery ulceration, independent of LDL-cholesterol (odds ratio per 10 mg/dL increase, 1.25; 95% CI, 1.06–1.48; p = 0.010; model 2 in Table 2 ), and independent of statin use (odds ratio per 10 mg/dL increase, 1.24; 95% CI, 1.04–1.47; p = 0.015; model 3 in Table 2 ). After stratifying the patients by statin use, an association between higher Lp(a) levels and carotid artery ulceration was observed in patients without statin use (odds ratio per 10 mg/dL increase, 1.71; 95% CI, 1.10–2.65; p = 0.016) but not in those with statin use (odds ratio per 10 mg/dL increase, 1.07; 95% CI, 0.85–1.34; p = 0.582). The p-value for the interaction was 0.063, suggesting a potential difference in the effect of Lp(a) levels on carotid artery ulceration based on statin use, although the interaction was not statistically significant. Fig.2 depicts the ROC analysis of the threshold Lp(a) level to predict carotid artery ulceration. The area under the curve was 0.67. This analysis showed that Lp(a) ≥ 26 mg/dL was the threshold to predict the presence of carotid artery ulceration (sensitivity, 52.6%; specificity, 78.6%, respectively).
Table 2. Univariate and multivariate analyses evaluating the associations between each covariate and presence of ulcer.
| Univariate | Multivariate (model 1) | Multivariate (model 2) | Multivariate (model 3) | |||||
|---|---|---|---|---|---|---|---|---|
| OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | OR (95% CI) | p value | |
| Age (per 1 year increase) | 1.01 (0.96-1.07) | 0.657 | 1.01 (0.95-1.07) | 0.764 | 1.02 (0.96-1.08) | 0.511 | 1.02 (0.96-1.08) | 0.494 |
| Female | 0.50 (0.16-1.55) | 0.229 | ||||||
| Current smoking | 2.44 (0.64-9.31) | 0.192 | 3.16 (0.69-14.57) | 0.140 | 3.42 (0.79-14.85) | 0.100 | 3.46 (0.80-14.98) | 0.096 |
| Hypertension | 1.16 (0.38-3.51) | 0.794 | 1.12 (0.33-3.81) | 0.860 | 1.31 (0.40-4.27) | 0.656 | 1.35 (0.41-4.41) | 0.618 |
| Diabetes mellitus | 1.00 (0.44-2.28) | 1.000 | 0.90 (0.36-2.30) | 0.833 | 1.23 (0.50-3.01) | 0.657 | 1.22 (0.50-3.01) | 0.663 |
| Dyslipidemia | 6.00 (1.28-28.18) | 0.023 | 6.08 (1.18-31.45) | 0.031 | ||||
| Coronary artery disease | 1.14 (0.43-3.04) | 0.797 | ||||||
| Stroke or TIA | 1.67 (0.72-3.84) | 0.230 | ||||||
| Statin use | 1.65 (0.72-3.78) | 0.239 | 1.42 (0.54-3.72) | 0.474 | ||||
| Ezetimibe use | 1.49 (0.90-24.52) | 0.782 | ||||||
| Antihypertensive drugs | 0.89 (0.38-2.06) | 0.785 | ||||||
| Total cholesterol (per 10 mg/dL increase) | 0.94 (0.84-1.06) | 0.301 | ||||||
| LDL-cholesterol (per 10 mg/dL increase) | 0.96 (0.84-1.10) | 0.557 | 0.91 (0.79-1.05) | 0.203 | 0.93 (0.79-1.09) | 0.378 | ||
| HDL-cholesterol (per 10 mg/dL increase) | 0.87 (0.67-1.13) | 0.289 | ||||||
| Triglyceride (per 10 mg/dL increase) | 1.01 (0.96-1.05) | 0.802 | ||||||
| Lipoprotein(a) (per 10 mg/dL increase) | 1.21 (1.03-1.41) | 0.020 | 1.21 (1.02-1.43) | 0.026 | 1.25 (1.06-1.48) | 0.010 | 1.24 (1.04-1.47) | 0.015 |
| HbA1c (per 1% increase) | 1.00 (0.63-1.60) | 0.988 | ||||||
| eGFR (per 1mL/min/1.73 m2 increase) | 1.00 (0.97-1.02) | 0.758 | ||||||
| Systolic BP (per 10mmHg increase) | 1.03 (0.84-1.26) | 0.796 | ||||||
| Diastolic BP (per 10mmHg increase) | 0.98 (0.70-1.38) | 0.919 | ||||||
| Degree of stenosis (per 10% increase) | 1.16 (0.96-1.40) | 0.133 | ||||||
BP, blood pressure; CI, confidence interval; eGFR, estimated glomerular filtration rate; HDL, high-density lipoprotein; LDL, low-density lipoprotein; OR, odds ratio; TIA, transient ischemic attack.
The multivariate (model 1) showed a Hosmer-Lemeshow χ2 statistic value of 5.19 (p = 0.737).
The multivariate (model 2) showed a Hosmer-Lemeshow χ2 statistic value of 9.53 (p = 0.299).
The multivariate (model 3) showed a Hosmer-Lemeshow χ2 statistic value of 8.19 (p = 0.415).
Fig.2. Receiver operating characteristic curves of Lp(a) level to predict carotid artery ulceration.
Abbreviations: Lp(a), lipoprotein(a).
Discussion
The present study showed that an elevated serum Lp(a) concentration was significantly associated with ulcer formation in patients with carotid artery stenosis who may be considered candidates for surgical treatment, independent of other atherosclerotic risk factors. Furthermore, Lp(a) ≥ 26 mg/dL may serve as a threshold for predicting the presence of carotid artery ulceration.
A previous report evaluated the association between Lp(a) levels and vulnerable plaques based on the assessment of plaque echogenicity and plaque irregularity using ultrasonography; however, the evaluation did not focus solely on the presence or absence of ulcer lesions 7) . Another report, which evaluated the association between carotid ulcers and Lp(a) using CTA, demonstrated an inconclusive association between them and implied a need for further investigation of the association 6) . Thus, the present study was focused on the carotid artery ulceration. DSA has a significant advantage in the assessment of carotid artery ulceration in aspects, such as high spatial and temporal resolution, compared with other imaging modalities such as ultrasonography, CTA, and MRI 14) . Therefore, the assessment of carotid artery ulceration in the present study was considered more accurate than that in previous studies. The prevalence of carotid artery ulceration evaluated using DSA was 40.0% in the present study, which was consistent with the 15.0-63.8% that were reported in previous reports 16 , 19) . However, because this study was conducted using imaging evaluation based on DSA findings, analyses based on other imaging findings that suggested vulnerable plaques other than ulcer formation were not conducted.
In the present study, the median serum concentration of L(a) was 17 mg/dL (IQR, 6-40) mg/dL. This distribution of serum L(a) level was considered keeping with those observed in previous studies, ranging from 13.9 (7.5-24.6) to 18 (9-36) mg/dL in the Japanese population 20 , 21) . In addition to showing the significant association between elevated Lp(a) levels and carotid artery ulceration, the ROC curve analysis showed that Lp(a) ≥ 26 mg/dL was the threshold to predict the presence of carotid artery ulceration. Previous reports have shown that Lp(a) ≥ 30 mg/dL increases the risk of carotid artery plaques and intraplaque neovascularization 8 , 22) . Furthermore, in the field of coronary artery disease and peripheral artery disease, Lp(a) ≥ 30 mg/dL was associated with disease progression or increased risk for major adverse cardiovascular events after revascularization therapy 21 , 23) . A Beijing Heart Society Expert Scientific Statement mentioned that Lp(a) ≥ 30 mg/dL is considered a cutoff value to be defined as a risk factor for atherosclerotic disease 3) . The threshold of Lp(a) ≥ 26 mg/dL shown in the present study was similar to the value Lp(a) ≥ 30 mg/dL, as previously reported. Thus, a cutoff point of 26 mg/dL shown in the present study was considered reasonable. However, the interpretation of the thresholds warrants caution in several aspects. First, there were cases with carotid artery ulceration even with Lp(a) levels ＜26 mg/dL. ( Fig.1 ) . This suggested that, while an elevated Lp(a) level is an important risk factor for carotid artery ulceration, other atherosclerotic risk factors may also influence ulcer formation, reflecting the complex pathogenesis of ulcer formation involving multiple risk factors. Second, given that this was a single-center study with a limited sample size, the threshold of Lp(a) ≥ 26 mg/dL identified in the present study should be interpreted with caution in the absence of external validation. Further investigation is warranted to determine the optimal cutoff value.
In addition to elevated Lp(a) levels, dyslipidemia, defined as LDL-C, HDL-C, triglycerides, or the current use of lipid-lowering drugs, was also associated with carotid artery ulceration in the present study. However, elevated LDL-C level was not associated with carotid artery ulceration. The reason why no significant association was found between LDL-C alone and carotid ulceration may be that patients with elevated LDL-C or symptomatic carotid stenosis are often already being treated with lipid-lowering drugs when blood samples are collected, and that the LDL-C value itself may only reflect the status after therapeutic intervention with lipid-lowering drugs. Thus, LDL-C alone is not a sufficient marker to suggest the presence of an ulcer; however, Lp(a) can be a predictive marker because the serum concentration of Lp(a) is predominantly (＞90%) determined by genetic variability and only to a lesser extent by non-genetic influences and external factors 24) . Non-genetic factors including hormone-related conditions (hypothyroidism, growth hormones treatment, and pregnancy) and chronic kidney disease have been reported to increase serum Lp(a) concentration. Statin has also been reported to possibly cause a slight increase in serum Lp(a) concentration, although this effect remains controversial 24) . In the present study, statin use itself was not associated with carotid artery ulceration. However, in our stratified analysis, the association between higher Lp(a) levels and carotid artery ulceration appeared to be modified by statin use. Although the interaction did not reach the threshold for statistical significance (p = 0.063), the trend suggested a potential differential effect of higher Lp(a) levels on carotid artery ulceration according to statin use.
The pathophysiological mechanisms underlying the effects of elevated serum Lp(a) levels on carotid artery ulceration were considered. Inflammatory accumulation, proteolytic enzyme release by macrophages, and local hemodynamic factors play roles in the pathogenesis of ulceration, and intraplaque inflammation promotes ulceration 25) . Lp(a) and its carrying oxidized phospholipids have been reported to induce an inflammatory response in the arterial wall by activating the proinflammatory signaling in endothelial cells, smooth muscle cells, and macrophages 26 , 27) . Angiographical appearance of ulceration observed on carotid lumen imaging has been reported to be associated with rupture of the fibrous cap and reduced fibrous tissue on histological examination 16) . The inflammatory response of the arterial wall induced by Lp(a) and its carrying oxidized phospholipid might lead to rupture of the fibrous cap and ulcer formation in the arterial wall.
The present study had several limitations. First, this study was conducted at a single center, consisting of only 94 patients with carotid stenosis. Second, a selection bias for the indication for DSA may exist. Although no explicit criteria for performing DSA were established in the present study, DSA tended to be performed in patients with symptomatic carotid artery stenosis of ≥ 50% or asymptomatic carotid artery stenosis of approximately 70–80% or greater, who may be considered candidates for carotid artery stenting or carotid endarterectomy. Patients with mild stenosis might not have undergone DSA. Therefore, the results of this study may not be generalizable to patients who are not suitable candidates for surgical treatment. Third, this was an observational study in a Japanese population. Due to differences in Lp(a) levels among different racial and ethnic populations, the generalizability of our findings may be limited 25) .
Conclusion
The present study showed that higher Lp (a) levels were associated with ulcer formation in patients with carotid artery stenosis who may be considered candidates for surgical treatment. Future studies are needed to examine the relationship between Lp(a) levels and carotid artery ulceration in patients who are not considered candidates for surgical treatment.
Acknowledgements:
None.
Notice of Grant Support.
None.
Conflicts of Interest
The authors declare no conflicts of interest.
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