Introduction
Elevated lipoprotein(a) (Lp[a]), a low-density lipoprotein (LDL)-like lipoprotein containing apolipoprotein (a) homologous to plasminogen, with the molecular weight ranging from 300 to 800 kDa due to a variety of apolipoprotein (a) isoforms, is a well-established genetically determined risk factor for cardiovascular disease (CVD), including coronary artery disease (CAD), myocardial infarction (MI), stroke, and peripheral arterial disease (PAD) [1, 2]. The current guidelines recommend that Lp(a) measurement once in a lifetime should be included in a comprehensive CVD risk evaluation and suggest a global risk underestimation at high or very high Lp(a) concentrations [1, 2]. Little is known about Lp(a) levels in the Polish population except for a small sample (n = 200) from the EUROASPIRE V survey, in which the prevalence of Lp(a) >50 mg/dl was 22.5% in patients without diagnosed CVD but with known risk factors [3].
Given ongoing trials on novel agents substantially reducing Lp(a) by 80% [2], we decided to assess the prevalence of elevated Lp(a) concentration in a middle-aged Polish population and its association with other CVD risk factors.
Methods
We enrolled consecutive subjects participating in the “Malopolska coronary artery disease prophylactic program for people older than 40 years” from May 2022 to October 2022. The exclusion criteria were age <40 or >65 years, documented CAD or PAD, and a history of MI, stroke, or transient ischemic attack. The study was approved by the local Ethical Committee (OIL/KBL33/2022).
Data about baseline anthropometric and clinical characteristics, previous medical history, lifestyle, and family history of premature CVD were collected. The 10-year risk of the first CVD event was assessed with the Systematic Coronary Risk Evaluation 2 (SCORE2) algorithm. Dyslipidemia was defined as total cholesterol (TC) ≥190 mg/dl, or LDL cholesterol (LDL-C) ≥115 mg/dl, or triglycerides ≥150 mg/dl or statin use. Serum Lp(a) was determined using immunoturbidimetry (Roche Diagnostics, Mannheim, Germany). Elevated Lp(a) was defined as values >50 mg/dl [2]. Lp(a) >100 mg/dl was defined as a very high-risk group [2]. In that case, analysis of the LPA gene variant: c.5673A>G (p.Ile1891Met, used nomenclature: p.Ile4399Met, rs3798220), reported as associated with elevated plasma Lp(a) levels [4], was performed with a TaqMan SNP assay (Applied Biosystems, ThermoFisher Scientific, Foster City, CA, US) on the QuantStudio Dx Real-Time PCT Instrument (ThermoFisher Scientific).
Statistical analysis
Statistical analysis was performed with SPSS Statistics software (Version 28.0.1.0, IBM Corp., Armonk, NY, US). Continuous variables were expressed as medians (interquartile range) and categorical variables as numbers (percentage). Normal distribution was assessed using the Shapiro-Wilk test. Differences among the three groups were compared using the ANOVA test with the post-hoc Bonferroni correction when normally distributed or the Kruskal-Wallis test for multiple comparisons of non-normally distributed variables. Categorical variables were analyzed with the chi-square test or Fisher’s exact test with a post-hoc z-test for comparison of column proportions with the Bonferroni correction. Associations between nonparametric variables were assessed by the Spearman rank correlation coefficient. All independent variables associated (P <0.2) with Lp(a) in a univariate model and simultaneously not correlated with other independent variables were included in the multivariate linear regression analysis to determine independent predictors of Lp(a) levels. A two-sided P <٠.٠٥ was considered statistically significant.
Results and discussion
We studied 800 individuals aged 49 (44–53) years (68% women), including 17.8% with Lp(a) >50 mg/dl with a higher proportion of females in this subgroup (Table 1). The prevalence of Lp(a) >50 mg/dl was 18.4% in Germany, which is almost identical to our population while in Finland or Greece, it was 6.0% [5, 6]. Our result is slightly lower than in the study by Ratajczak et al. [3], which evaluated CVD risk factors in subjects aged 18–80 (median, 52 [43–60]) years, while we assessed younger subjects. However, we did not observe a significant correlation between Lp(a) and age in contrast to a previous study in the general population, in which Lp(a) increased slightly with age [2].
|
Lipoprotein (a), mg/dl |
P-value |
|||
|
<50 |
50–100 |
>100 |
||
|
n = 656 (82.0%) |
n = 101 (12.6%) |
n = 43 (5.4%) |
||
|
Age, years |
49 (44–52) |
47 (44–52) |
52 (43–56) |
0.20 |
|
Males |
222 (33.8) |
31 (30.7) |
5 (11.6)a |
0.001 |
|
BMI, kg/m2 |
26.4 (24.0–29.8) |
27.1 (24.2–31.3) |
27.3 (23.9–30.4) |
0.41 |
|
Current smoking |
210 (32.0) |
38 (37.6) |
14 (32.6) |
0.53 |
|
Hypertension |
167 (25.5) |
16 (15.8) |
13 (30.2) |
0.07 |
|
Diabetes mellitus |
34 (5.2) |
5 (5.0) |
2 (4.7) |
0.98 |
|
Dyslipidemia, |
179 (27.3) |
28 (27.7) |
20 (46.5)a |
0.025 |
|
Family history of premature CVD |
282 (43.0) |
39 (38.6) |
19 (44.2) |
0.69 |
|
SCORE2 |
2.40 (1.2–4.0) |
2.25 (1.1–4.2) |
2.35 (1.1–4.0) |
0.97 |
|
Fasting glucose, mmol/l |
5.2 (4.9–5.5) |
5.2 (4.9–5.5) |
5.2 (5.0–5.5) |
0.80 |
|
CRP, mg/l |
1.1 (0.6–2.3) |
1.2 (0.6–3.0) |
1.7 (0.7–3.5) |
0.08 |
|
Total cholesterol, mmol/l |
5.06 (4.52–5.67) |
5.22 (4.73–5.82) |
5.54 (5.19–6.02)a |
0.004 |
|
LDL-cholesterol, mmol/l |
3.23 (2.66–3.74) |
3.39 (2.81–3.99) |
3.56 (3.11–4.00)a |
0.015 |
|
HDL-cholesterol, mmol/l |
1.53 (1.28–1.82) |
1.53 (1.27–1.85) |
1.64 (1.36–1.99) |
0.14 |
|
Triglycerides, mmol/l |
1.12 (0.83–1.64) |
1.16 (0.89–1.51) |
1.08 (0.83–1.31) |
0.54 |
|
Fibrinogen, g/l |
2.84 (2.54–3.10) |
2.83 (2.52–3.07) |
3.10 (2.81–3.46)a, b |
<0.001 |
Individuals with Lp(a) >100 mg/dl (maximum 237 mg/dl) were more often female and had dyslipidemia compared with those with Lp(a) <50 mg/dl (n = 682, 82.0%). Moreover, TC, LDL-C, and fibrinogen levels were 7.16% (P = 0.008), 9.54% (P = 0.047), and 9.15% (P <0.001), respectively, higher in the Lp(a) >100 mg/dl group compared with < 50 mg/dl. We did not observe any intergroup differences in the prevalence of a family history of premature CVD and the 10-year CVD risk (Table 1).
In multivariable analysis, after adjustment for age, Lp(a) levels were independently associated with female sex, LDL-C, and fibrinogen (Supplementary material, Table S1). The associations of Lp(a) with these variables have been reported previously [2, 7]. Higher Lp(a) in women is largely explained by an increase in Lp(a) in the peri- and post-menopausal period, which corresponds to elevated CVD risk in that still undertreated population [2, 8]. We observed higher Lp(a) levels in women aged >52 years as compared to the remainder (10.1 [3.9–45.0] vs. 7.0 [2.9–33.2] mg/dl; P = 0.034). Although the expression, synthesis, and metabolism of Lp(a) and LDL-C are independent, a weak positive correlation of their levels (in the current study, r = 0.11, P = 0.002) has been reported previously [9]. Statin use cannot reduce Lp(a) concentrations, whereas PCSK9 inhibitors lower Lp(a) by 15%–30% [2, 10]. Statins were used by 15.3% (n = 122) participants without any effect on Lp(a), as expected.
A positive association between fibrinogen and Lp(a) in our study (r = 0.135; P <0.001) is consistent with previous studies performed in the general population [7]. This association is of importance since fibrinogen is the key modulator of fibrin clot properties, and elevated Lp(a) has been associated with reduced clot permeability and susceptibility to lysis [11, 12].
Nine patients of 43 subjects with Lp(a) >100 mg/dl were genotyped, and in 4 (44.4%), the heterozygous LPA variant (c.5673A>G) was detected. The rs3798220 variant has been reported in 6.5% of apparently healthy Poles and 18.1% of patients with Lp(a) >75 mg/dl worldwide [13]. To our knowledge, this is the first report on genetic assessment of LPA variants in Poles with elevated Lp(a). Further research is needed to examine the genetic background of elevated Lp(a) in the Polish population.
Our study has limitations. Firstly, the size of the study population was limited, though it was the largest study sample in the Polish population. Secondly, clinical characteristics of the study participants were typical of screening programs; therefore, the findings could not be likely extrapolated to younger or older individuals as well as to those with CVD or the whole Polish population.
In conclusion, this study shows a relatively high (17.8%) prevalence of hyperlipoproteinemia(a) in a large Polish middle-aged population without evident CVD. In the upcoming era of new drugs with a potent Lp(a) lowering effect (e.g. pelacarsen) [2, 4], screening for elevated Lp(a) in high CVD-risk countries, including Poland [14], should be encouraged. Now, in individuals with high Lp(a), free of CVD, the management of modifiable risk factors as well as screening for high Lp(a) in families of the “index” subject should be implemented.
Supplementary material
Supplementary material is available at https://journals.viamedica.pl/kardiologia_polska.
Article information
Conflict of interest: None declared.
Funding: The study was supported by the Malopolska Voivodeship (no. 5/PS.IV/22). This article was supported by the science fund of the John Paul II Hospital, Cracow, Poland (FN13/2023 to MK).
Open access: This article is available in open access under Creative Common Attribution-Non-Commercial-No Derivatives 4.0 International (CC BY-NC-ND 4.0) license, which allows downloading and sharing articles with others as long as they credit the authors and the publisher, but without permission to change them in any way or use them commercially. For commercial use, please contact the journal office at kardiologiapolska@ptkardio.pl.
