Correlation of serum lipoprotein (a) levels with angiographic lesion severity in coronary artery disease

Vineet Kulkarni; Sukanya Shetty; K Subramanya; Anirban Chakraborty; Prakash Patil; Roopa Bhandary; Rashmi Kundapur

doi:10.4103/bbrj.bbrj_207_21

ORIGINAL ARTICLE

Year : 2021 | Volume : 5 | Issue : 4 | Page : 458-462

Correlation of serum lipoprotein (a) levels with angiographic lesion severity in coronary artery disease

Vineet Kulkarni¹, Sukanya Shetty¹, K Subramanya², Anirban Chakraborty³, Prakash Patil⁴, Roopa Bhandary¹, Rashmi Kundapur⁵
¹ Department of Biochemistry, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India
² Department of Cardiology, Justice KS Hegde Charitable Hospital, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India
³ Nitte University Center for Science Education and Research, Nitte (Deemed to be University), Paneer Campus, Mangalore, Karnataka, India
⁴ Central Research Laboratory, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India
⁵ Department of Community Medicine, KS Hegde Medical Academy, Nitte (Deemed to be University), Mangalore, Karnataka, India

Date of Submission	01-Sep-2021
Date of Acceptance	19-Oct-2021
Date of Web Publication	14-Dec-2021

Correspondence Address:
Sukanya Shetty
Department of Biochemistry, K S Hegde Medical Academy, Nitte (Deemed to be University), Deralakatte, Mangalore - 575 018, Karnataka
India

Source of Support: None, Conflict of Interest: None

DOI: 10.4103/bbrj.bbrj_207_21

Abstract

Background: The several epidemiological and meta-analysis studies suggested that the elevated lipoprotein (a) (Lp(a)) level is associated to cause the coronary artery disease (CAD). However, the role of this pro-atherogenic Lp (a) in regulating the severity of angiographic lesions in CAD is poorly understood. This study aimed to estimate the serum Lp (a) level and find its correlation with angiographic lesion severity in subjects with CAD. Methods: In this cross-sectional study, a total of 107 subjects angiographic lesion severity was determined by SYNergy between percutaneous coronary interventions with TAXUS and cardiac surgery (SYNTAX) scoring system and grouped into mild (<22) and severe (≤22) based on the SYNTAX score. The serum Lp (a) concentration in subjects' serum was measured by immunoturbidimetric assay. Results: The median Lp (a) level of all subjects was found to be 14.8 mg/dL, it was higher in severe angiographic lesion group (18.9 mg/dL, interquartile range [IQR]: 12.3–24.4) when compared to mild group (13.7 mg/dL, IQR: 6.6–18.6). The Spearman correlation analysis revealed that the relationship between serum Lp (a) level and angiographic lesion severity in mild and severe subjects is not statistically significant except with the mild group female subjects. Conclusions: Overall, this study does not support the association of angiographic lesion severity with serum Lp (a) levels in CAD. To infer precisely, similar studies with more subjects are needed to confirm this study's findings.

Keywords: Angiographic lesion severity, coronary artery disease, lipoprotein (a), SYNergy between percutaneous coronary interventions with TAXUS and cardiac surgery score

How to cite this article:
Kulkarni V, Shetty S, Subramanya K, Chakraborty A, Patil P, Bhandary R, Kundapur R. Correlation of serum lipoprotein (a) levels with angiographic lesion severity in coronary artery disease. Biomed Biotechnol Res J 2021;5:458-62

How to cite this URL:
Kulkarni V, Shetty S, Subramanya K, Chakraborty A, Patil P, Bhandary R, Kundapur R. Correlation of serum lipoprotein (a) levels with angiographic lesion severity in coronary artery disease. Biomed Biotechnol Res J [serial online] 2021 [cited 2023 Mar 23];5:458-62. Available from: https://www.bmbtrj.org/text.asp?2021/5/4/458/332458

Introduction

According to the World Health Organization, cardiovascular disease is attributed to be one of the leading causes of death worldwide with a loss of 17.9 million lives every year.^[1] Coronary artery disease (CAD), a type of cardiovascular disease, occurs due to the formation of plaque in coronary arteries that leads to obstruction in oxygen flow to heart. CAD has been associated with more than 100 risk factors that are categorized into modifiable (can be reduced with effective treatment and lifestyle changes, such as smoking, obesity, physical inactivity, and diabetes mellitus) and non-modifiable (cannot be modified for reducing the risk, such as homocysteine and C-reactive protein levels) risk factors. It has been surprising to note that the modifiable risk factors account for about 50% of the development of CAD complications. In addition, the levels of C-reactive protein and homocysteine have been found to play a prominent role in the risk assessment of CAD. However, most studies have failed to find the association between the C-reactive protein and homocysteine levels with CAD, but deaths due to CAD are still rising year after year.^[2] Therefore, it is of utmost importance to identify novel, potential biomarkers for assessing the risk of angiographically proven CAD.

According to the 2019 European guidelines on cardiovascular disease prevention, the serum lipoprotein (a) (Lp[a]) level must be estimated at least once in individual's.^[3] Lp (a) is a low-density lipoprotein (LDL) like particle consisting of a glycoprotein apolipoprotein (a) that is covalently bound to apolipoprotein B-100 through a single disulfide bond.^[4] Actually, Lp (a) is composed of 35%–46% of cholesteryl ester, 17%–24% of phospholipids, 6%–9% of cholesterol, and 4%–8% of triglycerides (TGs).^[1] Further, it has been previously reported that Lp (a) level has a strong, independent association with lesion severity of CAD among various populations.^{[5],[6],[7],[8],[9]} The angiographic lesion severity is generally measured as SYNergy between percutaneous coronary interventions with TAXUS and cardiac surgery (SYNTAX) score, which is one of the angiographic scoring systems that measures angiographic lesion severity in patients with CAD. Moreover, it is a well-validated scoring method that can independently predict outcomes in patients with CAD. However, there are limited data available on the association of serum Lp (a) level with the severity of CAD as determined by SYNTAX score among the Indian population.^{[9],[10],[11]} In this regard, this cross-sectional study was conducted to determine the serum Lp (a) concentration in CAD subjects and find its correlation with the coronary angiographic lesion severity.

Materials and Methods

Study population

This single-center cross-sectional study consists of a total of 107 subjects of both sexes who were admitted to the Cardiology Department of Justice KS Hegde Charitable Hospital, Mangaluru from December 2019 to August 2020. The subjects who are diagnosed with angiographically proven CAD were recruited for the study after obtaining the written informed consent. CAD subjects with autoimmune disorder, cancer, nephritic syndrome, chronic kidney disease, and any severe infections that might cross-react with the variables under investigation were excluded from this study. The present study data were compiled with the Declaration of Helsinki, and the study was approved by the central ethics committee of Nitte (Deemed to be University). (Ref no: NU/CEC/2019/0252 dated 9th October 2019).

Demographic information and biochemical measurements

The demographic details including family and personal history information, biochemical parameters, such as TGs, high-density lipoprotein (HDL), LDL, total cholesterol (TC), and very LDL, cardiac markers such as troponin and creatinine kinase MD (CK-MB), and coronary angiographic (CAG) findings data were collected from the study subjects' case sheet. All the biochemical parameters data were expressed as mean ± standard deviation.

Blood collection and serum lipoprotein(a) estimation

To determine the Lp (a) concentration in the serum, venous blood (2 ml) was collected from the subjects in a plain vacutainer, centrifuged at 3000 rpm for 10 min to separate serum, and stored at −20°C till use. Lp (a) concentration was determined by immunoturbidimetric assay (Cobas e411, Roche diagnostics), which is based on antigen–antibody reaction wherein human Lp (a) agglutinates with latex particles coated with anti-Lp (a) antibodies leading to the precipitate formation. The resultant turbidity absorbance was measured at 659 nm. According to the manufacturer, the threshold value of Lp (a) that indicates the increased risk for CAD is 75 nmol (31.2 mg/dL). As the study subjects' Lp (a) values were not normally distributed, the data were expressed as median and interquartile range.

Coronary angiographic scoring

The CAG scoring as determined by the SYNTAX scoring system was employed for the evaluation of lesion severity to diagnose the CAD. In brief, the SYNTAX score was determined for each subject using the online calculator tool, http://www.syntaxscore.com by the specialized cardiology interventionist. Actually, it is the sum of points given to each individual coronary lesion with 50% narrowing in coronary artery at least 1.5 mm diameter, and additional points were given for complexity in lesion formation including bifurcation/trifurcation lesions, total occlusion, calcification, presence of thrombus, and diffusely diseased segments.^[12] The SYNTAX score determined for each subject was obtained from their case sheet at the Department of Cardiology, Justice KS Hegde Charitable Hospital. Based on SYNTAX score, subjects were grouped into mild (≤22) and severe (>22) category.

Statistical analysis

The data were analyzed using SPSS (version 15.0) tool. Data on continuous and categorical variables were compared by independent sample t-test and Chi-square test, respectively. Lipid tetrad index (LTI) was calculated using the standard formula (TG × Lp (a) × TC/HDL).^[13] Spearman correlation method was performed to find the correlation between Lp (a) and lesion severity in CAD subjects. P < 0.05 was considered statistically significant.

Results

Demographic and biochemical characteristics

The demographic and biochemical characteristics of 107 study subjects (n = 72 male, 35 female) are summarized in [Table 1]. The mean age of all subjects was 59.68 ± 10.17 years, ranging from 30 to75 years. According to the coronary angiography scoring analysis, 80 (n = 56 male, 24 female) subjects had mild (≤22 syntax score) and 27 (n = 16 male, 11 female) had severe (>22 syntax score) CAD. The mean age and body mass index were not significantly different between the mild and severe group CAD subjects. Among the 107 study subjects, 44 (41.12%) had hypertension (n = 35 mild, 9 severe) and 37 (34.58%) had type II diabetes (n = 29 mild, 8 severe) comorbidities along with CAD. Meanwhile, TG level in mild subjects (162 ± 94.8 mg/dL) was found higher when compared to severe (153.7 ± 70.1 mg/dL) subjects. However, other biochemical parameters, such as TC, LDL, and non-HDL were found higher in severe subjects compared to mild subjects but are not statistically significant. The LTI was slightly higher in severe subjects (17250 ± 19733) compared to mild subjects (14505 ± 17824). Further, there was no significant difference observed in other biochemical parameters such as TC/HDL ratio, LDL/HDL ratio, LTI, and CK-MB among mild and severe groups.

Table 1: Demographic and biochemical characteristics of mild and severe subjects

Click here to view

Relationship between lipoprotein (a) level and angiographic lesion severity

The median Lp (a) level of all subjects was found to be 14.8 mg/dL (interquartile range [IQR], 8 to 23.5), which was lower than the level found in severe subjects (18.9 mg/dL (IQR, 12.3–24.4) compared to mild subjects (13.7 mg/dL [IQR, 6.6–18.6]). In addition, the subgroup analysis revealed that female subjects of severe group had higher Lp (a) level (19.7 mg/dL [IQR, 13–26.2]) compared to male subjects [13.7 mg/dL [12–19.5]). However, male subjects (13.7 mg/dL [IQR, 7.5–19.2]) of mild group had slightly higher Lp (a) level compared to female subjects (11.1 mg/dL [6–18.2]). The SYNTAX score in female subjects was higher compared to male subjects of both mild and severe groups, although there was no statistical significance observed [Table 2]. Furthermore, the Spearman correlation analysis for Lp (a) level and SYNTAX score was found that there was a significant correlation in female mild subjects (r = 0.408, P = 0.039) but not in male mild subjects. However, the severe group does not have a significant correlation between the Lp (a) and SYNTAX score in both male and female subjects [Figure 1].

Figure 1: Correlation between serum Lp(a) and SYNTAX score among study subjects

Click here to view

Table 2: SYNTAX score and lipoprotein (a) level in study subjects

Click here to view

Discussion

Several studies report the positive correlation between serum Lp (a) and risk of developing CAD among various populations around the world.^[14],[15] However, there are insufficient data on the association of Lp (a) with the severity of CAD as determined by SYNTAX score. Therefore, this study aimed to find out the relationship between serum Lp (a) level and the angiographic lesion severity in107CAD subjects. We observed that the serum Lp (a) level was higher in severe when compared to mild CAD subjects. Overall, this study did not find any significant correlation between the angiographic lesion severity and serum Lp (a) levels in CAD except some differences in female mild subjects. However, a study in 1403 Chinese subjects showed the significant relationships between Lp (a), Lp (a)-associated SNPs, and CAD severity as determined by SYNTAX score.^[16] Furthermore, there was an association of SYNTAX score with the Lp (a) levels in stable CHD patients.^[17] On the contrary, there are other studies that have found conflicting results when determining the relationship between Lp (a) and angiographic lesion severity. A study conducted among male physicians has demonstrated that there is a lack of association between Lp (a) level and risk of myocardial infarction.^[18] Further, a study on women subjects also observed the negative correlation between Lp (a) level and the risk of cardiovascular disease.^[19] These types of irregularities in results about the Lp (a) and severity of CAD might be due to the wide variation in Lp (a) level among different ethnic population and the lack of universally accepted standard assays to determine Lp (a) level in the subjects' serum. The currently available methods, such as enzyme-linked immunosorbent assay and immunoturbidimetric assay, sometimes might overestimate or underestimate the Lp (a) level due to heterogeneity in the Lp (a) particle size.

In this study, we found that the serum Lp (a) level was higher among females compared to male subjects. These findings are in consistence with the study that showed elevated Lp (a) level in female among apparently healthy Indian subjects compared to males.^[8] The higher Lp (a) level observed in females could be due to the more number of aged subjects (60.5 ± 8.93 years) who were recruited for this study. It was reported that postmenopausal women had higher Lp (a) level compared to premenopausal women.^[16] Further, this study showed that the severe subjects had higher Lp (a) levels compared to mild angiographically proven CAD subjects. Similar results were observed in a cohort study on 147 subjects with premature coronary events which showed that Lp (a) levels were significantly elevated in subjects with higher SYNTAX scores.^[12] Although the present study did not find any significant correlation between Lp (a) level among study subjects, the probability of correlation in other populations who had different baseline Lp (a) distribution cannot be eliminated. Therefore, we suggest to confirm this study's findings by evaluating the correlation of Lp (a) with lesion severity in a large sample size in a prospective manner.

The limitations of this study include a single-center study, a cross-sectional study with limited sample size that may not give definite conclusions, and an observational study in which confounding factors such as comorbidities might impact the correlation of Lp (a) and lesion severity according to SYNTAX score.

Conclusions

In our study, we have shown that the serum Lp (a) level in severe subjects was higher compared to mild CAD subjects. In addition, female subjects had higher Lp (a) levels compared to male subjects but were significantly associated with the angiographic lesion severity in mild subjects. These results extend our understanding of Lp (a) as a potential risk factor for the severity of CAD, but it requires such more extensive investigations in the Indian population before concluding it as a significant causative factor.

Acknowledgment

The authors express their sincere acknowledgment to DST-FIST (Project No.SR/FST/LSI-637/2015) for providing grant for the development of infrastructure. The authors are thankful to all participants and staff of the Cardiology Department for providing demographical data and biochemical parameters, from the patient case sheet of this study, and also, we would like to acknowledge the support of clinical biochemistry staff, Justice K S Hegde Charitable Hospital.

Financial support and sponsorship

This work was supported by Nitte (Deemed to be University) (grant No-NUFR3/2017/06/02.

Conflicts of interest

There are no conflicts of interest.

References

1.	Gencer B, Mach F. Potential of lipoprotein (a)-lowering strategies in treating coronary artery disease. Drugs 2020;80:229-39.
2.	Krintus M, Kozinski M, Kubica J, Sypniewska G. Critical appraisal of inflammatory markers in cardiovascular risk stratification. Crit Rev Clin Lab Sci 2014;51:263-79.
3.	Cegla J, Neely RD, France M, Ferns G, Byrne CD, Halcox J, et al. Heart UK consensus statement on lipoprotein (a): A call to action. Atherosclerosis 2019;291:62-70.
4.	Berg K. A new serum type system in man--the LP system. Acta Pathol Microbiol Scand 1963;59:369-82.
5.	Gazzaruso C, Bruno R, Pujia A, Amici E, Fratino P, Solerte SB, et al. Lipoprotein (a) apolipoprotein (a) polymorphism and coronary atherosclerosis severity in type 2 diabetic patients. Int J Cardiol 2006;108:354-8.
6.	Boroumand MA, Rekabi V, Davoodi G, Amirzadegan A, Saadat S, Abbasi SH, et al. Correlation between lipoprotein (a) serum concentration and severity of coronary artery stenosis in an Iranian population according to Gensini score. Clin Biochem 2008;41:117-120.
7.	Kral BG, Kalyani RR, Yanek LR, Vaidya D, Fishman EK, Becker DM, et al. Relation of plasma lipoprotein (a) to subclinical coronary plaque volumes, three-vessel and left main coronary disease, and severe coronary stenosis in apparently healthy African Americans with a family history of early onset coronary artery disease. Am J Cardiol 2016;118:656-61.
8.	Zhang HW, Zhao X, Guo YL, Gao Y, Zhu CG, Wu NQ, et al. Elevated lipoprotein (a) levels are associated with the presence and severity of coronary artery disease in patients with type 2 diabetes mellitus. Nutr Metab Cardiovasc Dis 2018;28:980-6.
9.	Ashfaq F, Goel PK, Sethi R, Khan MI, Ali W, Idris MZ. Lipoprotein (a) levels in relation to severity of coronary artery disease in north indian patients. Heart Views 2013;14:12-6. [PUBMED] [Full text]
10.	Mohan V, Deepa R, Haranath SP, Premalatha G, Rema M, Sastry NG, et al. Lipoprotein (a) is an independent risk factor for coronary artery disease in NIDDM patients in South India. Diabetes Care 1998;21:1819-23.
11.	Gambhir JK, Kaur H, Prabhu KM, Morrisett JD, Gambhir DS. Association between lipoprotein (a) levels, apo (a) isoforms and family history of premature CAD in young Asian Indians. Clin Biochem 2008;41:453-8.
12.	Chieng D, Pang J, Ellis KL, Hillis GS, Watts GF, Schultz CJ. Elevated lipoprotein (a) and low-density lipoprotein cholesterol as predictors of the severity and complexity of angiographic lesions in patients with premature coronary artery disease. J Clin Lipidol 2018;12:1019-26.
13.	Bansal SK, Agarwal S, Daga MK. Advanced atherogenic index for the assessment of consolidated lipid risk in premature coronary artery disease patients in India. J Lab Physicians 2016;8:77-84. [PUBMED] [Full text]
14.	Hoogeveen RC, Gambhir JK, Gambhir DS, Kimball KT, Ghazzaly K, Gaubatz JW, et al. Evaluation of Lp[a] and other independent risk factors for CHD in Asian Indians and their USA counterparts. J Lipid Res 2001;42:631-8.
15.	Hopewell JC, Seedorf U, Farrall M, Parish S, Kyriakou T, Goel A, et al. Impact of lipoprotein (a) levels and apolipoprotein (a) isoform size on risk of coronary heart disease. J Intern Med 2014;276:260-8.
16.	Liu SL, Wu NQ, Guo YL, Zhu CG, Gao Y, Sun J, et al. Lipoprotein (a) and coronary artery disease in Chinese postmenopausal female patients: A large cross-sectional cohort study. Postgrad Med J 2019;95:534-40.
17.	Xu N, Tang X, Yao Y, Jia S, Liu Y, Zhao X, et al. Lipoprotein (a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention. Nutr Metab Cardiovasc Dis 2020;30:265-73.
18.	Ridker PM, Hennekens CH, Stampfer MJ. A prospective study of lipoprotein (a) and the risk of myocardial infarction. JAMA 1993;270:2195-9.
19.	Cook NR, Mora S, Ridker PM. Lipoprotein (a) and cardiovascular risk prediction among women. J Am Coll Cardiol 2018;72:287-96.