Correlation Between Elevated Lipoprotein(a) and Carotid Plaque in Asymptomatic Individuals

Article information

J Neurosonol Neuroimag. 2024;16(1):1-7

Publication date (electronic) : 2024 June 30

doi : https://doi.org/10.31728/jnn.2024-00154

Minsoo Sung, MD^*, Yo Han Jung, MD, PhD^*,†, Young Hoon Youn, MD, PhD^‡, Kyung-Yul Lee, MD, PhD^,*,†

^*Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

^†Severance Institute for Vascular and Metabolic Research, Yonsei University College of Medicine, Seoul, Korea

^‡Department of Internal Medicine, Gangnam Severance Hospital, Yonsei University College of Medicine, Seoul, Korea

Correspondence: Kyung-Yul Lee, MD, PhD Department of Neurology, Gangnam Severance Hospital, Yonsei University College of Medicine, 211 Eonju-ro, Gangnam-gu, Seoul 06273, Korea Tel: +82-2-2019-3325 Fax: +82-2-3462-5904 E-mail: kylee@yuhs.ac

Received 2024 April 22; Revised 2024 June 10; Accepted 2024 June 16.

Abstract

INTRODUCTION

Carotid plaque formation represents a significant global health challenge, while the associated carotid artery atherosclerotic disease is a life-threatening condition.1 Blood lipid levels are pivotal factors in carotid plaque development. Therefore, maintaining low low-density lipoprotein cholesterol (LDL-C) levels to reduce carotid plaque formation is crucial, and statins are used to achieve this goal. However, despite the successful lowering of LDL-C levels through statin therapy, residual risks have been increasingly recognized. The principal residual risk factor for carotid plaque formation is lipoprotein(a) [Lp(a)], a hepatically synthesized lipoprotein that shares a structural resemblance with LDL. Its formation involves the binding of apolipoprotein(a) to apolipoprotein B100, a constituent of LDL.2 Lp(a) is considered more atherogenic than LDL due to its heightened ability to permeate arterial walls, inciting inflammatory responses and thrombus formation.3 Genetic factors predominantly influence Lp(a) levels, while the impact from environmental factors is minimal.4 In patients with dyslipidemia who experience a reduction in LDL-C levels due to statin therapy, Lp(a) levels resist significant decrease and may even exhibit slight elevation.5-8

Several studies have shown a correlation between Lp(a) levels and vascular diseases, such as myocardial infarction, stroke, and peripheral arteriopathy.9-11 Various types of research, including epidemiological studies, meta-analyses, Mendelian randomization studies, and genome-wide association studies, have shown that elevated Lp(a) level is a risk factor for cerebrovascular and cardiovascular diseases.12-14 Although evidence suggests that elevated Lp(a) levels contribute to the progression of carotid plaque formation, this remains a topic of debate. Several studies have suggested that high Lp(a) levels are associated with presence of carotid plaques,15,16 while other studies have reported no relationship between them.17-20 Furthermore, one study on asymptomatic Japanese women reported that lower Lp(a) levels are associated with increased carotid intima-media thickness (IMT).21

This study aimed to determine the correlation between Lp(a) levels and carotid plaque formation in the general population.

SUBJECTS AND METHODS

RESULTS

A total of 4,896 participants were selected for the analysis. The mean age was 57.1±10.6 years and 65.7% were men. The prevalence rates of HTN, DM, dyslipidemia, and smoking were 30.9%, 10.7%, 28.2%, and 16.2%, respectively. The mean BMI was 24.8±3.6 kg/m². The mean levels of glucose, cholesterol, triglycerides, HDL-C, and LDL-C were 106.2±23.3 mg/dL, 200.8±43.4 mg/dL, 137.4±89.3 mg/dL, 55.3±13.4 mg/dL, and 122.5±36.3 mg/dL, respectively. The mean level of Lp(a) was 15.5±18.1 mg/dL, with 6.0% of participants having Lp(a) levels ≥50 mg/dL. Carotid artery plaques were detected in 41.8% of the participants (Table 1).

Table 1.

Demographic and clinical characteristics of the study population categorized by the presence or absence of carotid plaque

When comparing participants based on the presence or absence of carotid artery plaque, those with carotid plaques were, on average, older than those without plaques (62.2±9.2 years vs. 53.6±10.2 years, respectively, p<0.001). A higher proportion of men was observed among the participants with plaques than among those without plaques (70.2% vs. 62.5%; p<0.001). Participants with plaques had a higher prevalence of HTN (43.9% vs. 21.5%, p<0.001), DM (16.7% vs. 6.5%, p<0.05), and dyslipidemia (38.0% vs. 21.1%, p<0.001) than those without plaques. There was no significant difference in smoking history between the two groups (p=0.353). In the group with carotid artery plaques, glucose (110.7±26.0 vs. 103.0±20.6, p<0.001) and triglycerides (140.5±87.4 vs. 135.1±90.6, p=0.040) levels were significantly higher, while HDL-C (54.0±12.8 vs. 56.1±13.7, p<0.001) levels were significantly lower. Contrary to the expected outcomes, cholesterol (193.9±46.1 vs. 205.8±40.7, p<0.001) and LDL-C (117.5±38.7 vs. 126.2±34.0, p<0.001) levels were found to be significantly lower in the group with carotid artery plaques. Participants with carotid plaques had significantly higher mean Lp(a) levels compared to those without plaques (16.9±20.1 vs. 14.5±16.5, p<0.001). Furthermore, a greater proportion of individuals with Lp(a) levels ≥50 mg/dL were found in the group with carotid plaques than in those without plaques (7.4% vs. 5.1%, p<0.001) (Table 1).

Univariate (unadjusted) and multivariate logistic regression analysis were performed using SPSS version 26. Because of the significant correlations among cholesterol, triglycerides, and LDL-C, only the latter was included in the multivariate analysis. A stepwise method was employed to remove variables while selecting the model with the highest receiver operating characteristic (ROC) curve. The univariate logistic regression analysis revealed a significant association between Lp(a) levels ≥ 50 mg/dL and the presence of carotid plaques, with an unadjusted odds ratio (OR) of 1.508 (p<0.001, 95% confidence interval [CI]: 1.192–1.907). The multivariate logistic regression analysis was conducted, including the variables age, sex, HTN, DM, dyslipidemia, smoking, BMI, glucose, HDL-C, LDL-C, and Lp(a) ≥50 mg/dL. HDL-C and BMI were removed using a stepwise method. Consequently, the final model included the following variables: age, sex, HTN, DM, dyslipidemia, smoking, glucose, LDL-C, and Lp(a) ≥50 mg/dL. Lp(a) levels ≥50 mg/dL were significantly associated with the presence of carotid plaques, with an adjusted OR of 1.318 (p=0.038, 95% CI: 1.015–1.711). This indicates a persistent and significant association between Lp(a) levels ≥50 mg/dL and the presence of carotid plaques even after adjusting for age, sex, HTN, DM, dyslipidemia, smoking, glucose, LDL-C, and Lp(a) ≥50 mg/dL (Table 2, Fig. 1).

Table 2.

The results of unadjusted and adjusted logistic regression analyses

Fig. 1.

Odds ratios with 95% Wald confidence intervals for various risk factors. This figure illustrates the associations between several risk factors and the studied outcome. Odds ratios are depicted as points, with horizontal lines representing 95% Wald confidence intervals. LDL-C, low-density lipoprotein cholesterol.

DISCUSSION

This study aimed to elucidate the association between Lp(a) levels and carotid plaque formation. Despite the widespread use of statins to lower LDL-C levels, further decrease of cerebrovascular risk necessitates the exploration of additional risk factors such as Lp(a). Our study indicates that Lp(a) levels ≥50 mg/dL are significantly associated with the presence of carotid artery plaques, reinforcing the hypothesis that Lp(a) is an independent risk factor for carotid plaque formation.

Consistent with previous epidemiological studies and genetic analyses, our data support the hypothesis that Lp(a) levels are closely linked to atherogenesis. This is corroborated by our multivariate logistic regression analysis, which maintained the association of Lp(a) level with carotid plaques even after adjusting for other conventional risk factors such as age, sex, HTN, and dyslipidemia. These findings align with existing evidence on the fact that Lp(a) proinflammatory and prothrombotic properties exacerbate vascular disease pathogenesis.25,26

Nevertheless, in our study, traditional risk factors such as cholesterol and LDL-C levels were lower in participants with carotid plaques. Additionally, in the univariate logistic regression analysis, the unadjusted OR for LDL-C were <1. These findings may be related to the high prevalence of dyslipidemia among patients with carotid plaques. Consequently, these patients are more likely to receive dyslipidemia treatment, which could explain the lower cholesterol and LDL-C levels observed. However, data on dyslipidemia medication use were lacking, which is a limitation in our study.

These results underscore the need for a paradigm shift in cerebrovascular risk assessment and disease management. Currently, statin therapy is the cornerstone of dyslipidemia treatment; however, it has little effect on Lp(a) levels. Therefore, our study further emphasizes the need for targeted therapies such as proprotein convertase subtilisin-kexin 9 (PCSK9) inhibitors or antisense oligonucleotides to reduce Lp(a) levels.27-30

Our study has several strengths, including a large sample size and incorporation of a comprehensive set of cerebrovascular risk factors. However, there are several limitations. First, the cross-sectional nature of the study prevented the establishment of a causal relationship between Lp(a) levels and carotid plaques. Second, data on the use of lipid-lowering medications, particularly statins, were lacking. Given the high prevalence of dyslipidemia in the group with carotid plaques, it is likely that a substantial proportion of participants were receiving statin therapy, which could have influenced Lp(a) levels. Third, our data did not include information on plaque characteristics. Differences in plaque composition between the groups may have influenced the results. Fourth, most participants were from a single ethnic group undergoing health screening, which may have limited the generalizability of our findings.

In conclusion, our analysis provides further evidence on the significant role of Lp(a) in the pathogenesis of carotid plaques. However, prospective studies are required to evaluate the effectiveness of Lp(a)-lowering therapies on reducing carotid plaque formation and incidence of cerebrovascular events. Furthermore, our findings support the inclusion of Lp(a) level assessments in the routine evaluation of atherosclerotic cerebrovascular disease risk.

Article information Continued