1. Introduction
Bicuspid aortic valve (BAV) is a congenital valvular defect that affects approximately 0.5–2% of the general adult population [1]. The abnormal structure of the leaflets leads to the development of aortic valve dysfunction, both in the form of regurgitation and stenosis. Furthermore, an aortic aneurysm often accompanies this condition [2]. As a consequence, patients with a BAV frequently and at a young age require qualification for cardiac surgery. In the registry from Olmsted County in Minnesota, observing over 200 individuals with a BAV, the mean age at the time of cardiac surgery was 40 ± 20 years compared to 67 ± 16 years for patients with a tricuspid aortic valve [3,4]. Overall, up to 50 percent of BAV individuals undergo aortic valve replacement (AVR) [5]. Aortic stenosis (AS) is a frequent cause of surgery in this group. Calcification of the cusps often occurs by the age of 40 [4]. The BAV is associated with the occurrence of degenerative AS at a significantly younger age compared to the population with a tricuspid aortic valve [5,6].
On the other hand, the BAV population remains a heterogenous group, and the occurrence and course of valve defects in these patients remain unpredictable. While a BAV may lead to advanced calcification of the aortic valve, we do not observe this process in all BAV individuals. Therefore, among the BAV population, factors that may be predictors for the calcified AS have been investigated. Studies evaluating the association between the morphological type of BAV and the occurrence of valve stenosis have not yielded consistent results [6,7]. In a meta-analysis involving over 4000 patients, Zhenzhen Mai indicated that a type of BAV with right-coronary and non-coronary cusps fusion most frequent predisposes to AS [8]. However, earlier registries did not demonstrate similar results [9]. Uncertainties in the relationship between aortic valve cusps fusion morphology and the development of AS highlight the need to focus on modifiable risk factors for valve calcification.
The impact of lipid metabolism disorders on the progression of calcified AS has been demonstrated in tricuspid aortic valve populations [10,11]. High levels of lipids, especially low density lipoprotein cholesterol (LDL-C), stimulate a chronic inflammation of the endothelium resulting in progressive fibrosis and further reduction in the aortic valve area. It has been shown that apolipoprotein B (Apo B), the main and only essential structural protein component of low density lipoprotein (LDL), is a more precise marker for assessing cardiovascular risk than LDL-C levels. Plasma concentration of apo B is a reliable indicator of the number of atherogenic particles that contribute to the development of atherosclerosis. Serum Apo B concentrations are also associated with the AS development [12].
The role of high density lipoprotein cholesterol (HDL-C) levels in preventing atherosclerosis and endothelial dysfunction has been investigated [13]. Recent studies conducted in patients with tricuspid aortic valve suggest that HDL-C may also play a significant protective role in the pathogenesis of AS [14]. This connection underscores broader cardiovascular benefits of high density lipoprotein (HDL) beyond its traditional anti-atherosclerotic mechanisms. HDL has a multifaceted range of protective functions, including neutralizing free radicals and oxidized lipoproteins, facilitating reverse cholesterol transport, and demonstrating potent anti-inflammatory properties [15]. These mechanisms not only inhibit vascular damage but also halt the processes of degeneration and calcification in the aortic valve [16]. Traditionally, serum HDL-C levels have served as a readily accessible biomarker for cardiovascular risk assessment. However, elevated HDL-C levels do not always correlate with its protective function [17]. Moreover, high HDL-C levels may paradoxically exhibit a pro-inflammatory effect [18]. Increasingly, the evaluation of HDL antioxidant properties is recognized as a more precise indicator of cardiovascular risk.
A biomarker associated with HDL, paraoxonase-1 (PON-1), an enzyme exhibiting antioxidant properties and reducing the oxidation of LDL-C, have been studied among patients with AS. Several different activities of PON-1 were described with research mainly focusing on PON-1 paraoxonase (PON-1 ASE) and arylesterase activity (PON-1 ARE), and their role in the development of cardiovascular disease [19] Z. Wang has demonstrated, on over hundred patients who underwent AVR, that a lower PON-1 level in aortic valve tissue may be associated with the progression of calcification in AS [20].
Another marker linked to HDL is apolipoprotein A-I (Apo AI), the main protein component of HDL. Apo AI plays a key role in cholesterol’s transport, facilitates the efflux of cholesterol from macrophages in the arterial endothelium, supports antioxidant processes and regulation of inflammatory reactions, and has been shown an important indicator of the risk of AS occurrence [21,22].
The Apo B/Apo AI ratio represents the proportion between atherogenic and antiatherogenic lipoproteins in plasma. Thus, it constitutes an accurate marker of cardiovascular risk [23]. A correlation between this ratio and the occurrence of AS was also demonstrated. In a study involving the EPIC-Norfolk cohort, Kang H Zheng’s et al. demonstrated a correlation between the Apo B/Apo AI ratio and the incidence of AS [24].
Patients with a bicuspid and tricuspid aortic valve may differ in terms of their lipid parameters [25,26]. Moreover, BAV patients may be at higher risk of atherosclerosis and coronary artery disease occurrence [27]. Finally, BAV patients are not a homogenous group. The studies profiling the BAV population based on aortic valve function and lipid markers are lacking.
Therefore, we aimed to assess the relationship between the serum concentration of selected lipid markers and the occurrence of AS among BAV patients in different age groups.
2. Material and Methods
2.1. Group Characteritics
Adult patients with a BAV, diagnosed by echocardiography and admitted to the First Clinic of Cardiology of Medical University of Gdansk, were enrolled into the study. Exclusion criteria included active inflammatory process, autoimmune diseases, active oncological disease, hyperthyroidism, pregnancy, unstable clinical condition (clinical features of circulatory or respiratory failure), and familial hypercholesterolemia. Patients were divided into two age groups with an age burden of 45 years. Due to the assessment of the atherogenic markers impact on the occurrence of AS, this division into age groups was established based on the age burden defining young coronary artery disease [28,29]. Subsequently, each age group was divided into two subgroups depending on AS occurrence. Clinical data including age, anthropometric data (weight and height), chronic diseases (such as hypertension, diabetes mellitus, coronary artery disease), smoking habit, and statin therapy were collected during the medical interview. The study protocol was approved by the Local Bioethics Committee at the Medical University of Gdansk (protocol no. NKBBN/487-517/2019). Written informed consent was obtained from each patient prior to their inclusion in the study.
2.2. Echocardiographic Examination
Transthoracic examination was performed in each case and included following parameters: left ventricle ejection fraction (LVEF), aortic valve area (AVA), aortic valve peak transvalvular velocity (AV Vmax), mean transvalvular pressure gradient (PGmean); aortic regurgitation evaluation, aortic complex diameters. AS and aortic regurgitation were defined according to European Society of Cardiology Guidelines from 2021 [30]. Aortopathy was defined by an aortic root or ascending aorta diameter more than 40 mm. Patients with at least a mild stage of AS were included in the AS subgroups.
2.3. Biochemical Analysis
Peripheral blood samples were drawn from each patient between 7 and 8 a.m. following the overnight fast. The serum was separated by centrifugation at 1000× g for 15 min and was stored at −80 °C pending analysis. Total cholesterol (TC), HDL-C, and triglycerides (TG) were measured in serum using standard enzymatic colorimetric tests (Wiener Lab, Warsaw, Poland). LDL-C was calculated using the Friedewald formula (there were no cases of TG elevation above 400 mg/dL) [31,32]. The apolipoprotein (Apo AI and Apo B) serum concentrations were determined using the nephelometric method with antibodies obtained from Siemens Healthcare Diagnostics (Eschborn, Germany) on a Behring laser nephelometer. The PON-1 ASE and PON-1 ARE activities were analyzed in serum based on paraoxon and phenyl acetate hydrolysis, respectively, according to the procedure described earlier [33].
2.4. Statistic Analysis
All data were collected and computed in MS Excel and a standard statistical package. Variables with normal distribution were compared with the Student’s t-test; non-normally distributed data were compared with the U Mann–Whitney test. Dichotomous variables were compared with Chi-squared test with Yates’s correction for continuity. Correlation for data with non-normally distribution was calculated by the Spearman correlation. For selected biomarkers, the area under the curve (AUC) was calculated using receiver operating characteristic (ROC) analysis, and the optimal cut-off values corresponding to the minimal false positive and false negative parameters were determined. The continuous variables were expressed as medians with 25th and 75th percentiles. p-value less than 0.05 was considered valid for all tests.
3. Results
A total of 76 patients (21 female) were enrolled into the study. Clinical characteristics of the studied group are presented in Table 1 and Table 2. The average age of observed patients was 53.7 ± 13 years. A total of 54 patients (15 female) were in the age category of more than 45 years. A total of 22 patients (6 female) were aged 45 or younger. In the group aged >45, there were 35 patients (65%) with AS, and in the group aged ≤45, there were 9 patients (41%) with AS. The group aged >45 had significantly more frequent arterial hypertension (67% vs. 14% of patients; p < 0.001), coronary artery disease (35% vs. 5% of patients; p 0.014), and frequently required statins therapy (50% vs. 18% of patients; p 0.021) compared to patients aged ≤45 (Table 1).
In the group aged ≤45, there were no significant differences in terms of sex, age, body mass index, statin use, and the prevalence of hypertension, smoking, coronary artery disease, or diabetes mellitus depending on the presence of AS. On the contrary, in the cohort aged >45, patients with AS were characterized by their older age and more frequently requiring statins compared to patients without AS (Table 2).
3.1. Echocardiographic Characteristics of Groups
The prevalence of AS and aortopathy was similar in both age groups. Moderate to severe aortic regurgitation was more frequently observed in patients aged ≤45. Function of the left ventricle calculated by LVEF was in a similar range for both age groups (Table 3).
In the group aged >45, patients with AS and without AS differed in the frequency of aortic regurgitation occurrence. In the group aged ≤45, there was no significant difference in terms of LVEF, aortic regurgitation, and aortopathy prevalence depending on AS diagnosis (Table 4).
Among patients with AS, older patients aged >45 had lower AVA compared to those aged ≤45 [AVA 0.9 (0.8–1.2) cm2 vs. 1.3 (0.9–1.4) cm2; p 0.023]. We found no differences in AV Vmax and PGmean measurements (Table 5).
3.2. Biochemical Analysis
Patients aged ≤45 with AS in comparison to those without AS had significantly higher levels of Apo B [110.5 (102–132) vs. 95.6 (77–101) mg/dL; p 0.044] and Apo B/Apo AI ratio [(0.8 (0.7–1) vs. 0.6 (0.5–0.7); p 0.029]. We found no differences in the level of TC, HDL-C, LDL-C, and TG. Moreover, in the group aged ≤45, Apo B level and Apo B/Apo AI ratio showed a positive correlation with AV Vmax measurement (R Spearman was 0.6 for Apo B and AV Vmax, and 0.5 for Apo B/Apo AI and AV Vmax, p < 0.05 for both analyses) (Figure 1 and Figure 2). Furthermore, in the group aged ≤45, patients with AS had significantly lower activity of PON-1 ARE compared to those without AS [63.4 (52–80) vs. 85.3 (70–102) U/L; p 0.0124].
Among patients aged ≤45, the analysis for Apo B levels, Apo B/Apo AI ratio, and PON-1 ARE activity was extended to ROC analysis. AUC for Apo B was 0.761 [95% confidence interval (CI): 0.533 to 0.914; p 0.018], for Apo B/Apo AI ratio 0.782 (95% CI: 0.557 to 0.927; p 0.007), indicating a moderate to good ability to discriminate between patients with and without AS. PON-1 ARE activity demonstrated the highest AUC of 0.786 (95% CI: 0.561 to 0.930; p 0.004), indicating the best discriminatory power among the biomarkers tested (Figure 3).
Among patients aged >45, there were no differences in analyzed parameters depending on AS prevalence.
All results from the biochemical analysis were presented in Table 6.
4. Discussion
The findings of our study showed an association between AS and molecules associated with lipid metabolism, such as Apo B, Apo B/Apo AI ratio, and PON1-ARE in BAV patients at age ≤45. Moreover, the Apo B level and Apo B/Apo AI ratio correlated with the echocardiographic parameter of AS severity such as AV Vmax.
Our results suggest that lipid metabolism may play a significant role in the early development of calcific AS among patients with a BAV, which is a frequent BAV complication, affecting up to 45% of patients over the age of 50 [34]. It is also the most common cause of qualifying for aortic valve replacement in the BAV adult population [35]. Furthermore, patients with a BAV required surgery due to AS at a significantly younger age than patients with a tricuspid aortic valve [36]. In the study of a large Australian cohort by Michelle S Lim’s team, the mean age of BAV patients referred to AVR due to AS was 55 ± 17 years (22 years earlier than patients with tricuspid aortic valve) [37]. The exact origin of early calcification and accelerated development of AS in patients with BAV remains unclear. One possible hypothesis considers mechanical factors, such as endothelial damage of valve cusps caused by abnormal blood flow dynamics [38]. However, this anatomical aspect does not fully explain why only a subset of the BAV population experience progression to significant valve calcification, while some individuals remain without a valvular dysfunction throughout their life.
Consequently, attention has also been directed towards a risk factor for calcific AS that overlaps with those for atherosclerosis, including hyperlipidemia, hypertension, and diabetes mellitus [39]. Studies suggest that patients with a BAV constitute a heterogeneous group regarding their lipid profiles. For instance, Elena Sticch et al. showed that an elevated level of lipoprotein (a) in patients with BAV was associated with the degree of aortic valve calcification [40]. Additionally, it has been shown that LDL-C and Apo B levels may significantly affect the progression of BAV in case of aortopathy. [41] These findings underline the need for further investigation into the role of specific lipid markers in the early manifestation of BAV complications.
The second observation derived from our results highlights the need for a broader analysis of lipid markers. To date, the relationship between LDL-C levels and the risk of both atherosclerosis and AS has been well demonstrated [42,43]. The beneficial effect of high HDL-C on the occurrence of calcific AS or cardiac events is less clear [44,45]. Nevertheless, HDL-C and LDL-C levels are the most commonly used markers of cardiovascular risk assessment, though they do not always adequately reflect lipid balance [18,46].
Apo B is a protein found in all atherogenic lipoproteins. Studies have shown that Apo B levels may be a more precise marker of cardiovascular risk than LDL-C [47]. It should be noted that the measurement of Apo B is less dependent on triglyceride (TG) levels and fasting status, making it a more stable parameter than LDL-C [48]. The assessment of HDL properties, including its associated molecules, appears to better explain its role in both the development of atherosclerosis and AS. The main protein component of HDL is Apo AI [49]. The Apo B/Apo AI ratio enables the assessment of the balance between atherogenic and protective lipoproteins, making it an important marker for evaluating cardiovascular risk [50]. Ivert et al. proved an association between elevated Apo B/Apo AI ratio and increased appearance of AS among patients with tricuspid aortic valve [10]. Our findings demonstrate a similar observation among young individuals with BAV. Patients aged ≤45 with AS had increased concentrations of Apo B and Apo B/Apo AI ratio. We did not observe any differences in the levels of LDL-C and HDL-C. In our study, the cut-off value for Apo B obtained from the ROC analysis was 100.74 mg/dl, a value that corresponds to an increased cardiovascular risk [51]. The cut-off value for Apo B/Apo AI ratio was 0.56. For comparison, in the AMORIS and INTERHEART studies, the Apo B/Apo AI ratio below 0.7 for men and 0.6 for women was associated with low cardiovascular risk. Nevertheless, it should be noted that there are no clearly established cut-off values for Apo B levels and the Apo B/Apo AI ratio in the context of AS, and further research is needed in this area.
Another marker associated with HDL is PON-1, which demonstrates antioxidant properties. Although the relationship of its different activities and the occurrence of AS is less well understood, some studies have shown a correlation between low activity of PON-1 and the severity of AS [52]. In our study, patients with a BAV and AS at ≤45 years of age showed significantly lower activity of PON-1 ARE compared to those without AS, with the cut-off value below 83.5 U/L. The difference was observed despite the fact that the level of Apo AI did not differ between these groups. This relationship underscores the potential significance of the marker in various manifestations of BAV complications and emphasizes the need for further research to determine PON-1 activity values associated with the risk of AS development. By analyzing the antioxidant components of HDL and its associated biomarkers, we can gain a deeper understanding of HDL quality and functionality, which may provide a more accurate assessment of its cardiovascular protective capacity [17,53].
Interestingly, we did not observe similar relationships among patients above 45 years of age. However, it should be noted that in this group, the etiology of AS may be more multifactorial, considering the influence of age. Additionally, these patients more frequently had diagnosed hypertension and chronic coronary syndrome. It should be noted that in the group aged >45, patients with AS more often required statin treatment, which could have significantly affected the obtained results.
The main limitation of the current study is relatively small sample size, drawn from a single-center population, which may have reduced the statistical power of the analysis. Additionally, a longer follow-up period is required to assess the impact of Apo B levels, Apo B/Apo A1 ratio, and PON1 activity on the progression of AS in the BAV population. The study did not consider dietary habits or the dosage of lipid-lowering medications, which also may have affected the evaluated markers. However, the cohort aged ≤45 was homogeneous in terms of age, sex, and the chronic conditions included in the study; the older group exhibited greater heterogeneity. Patients aged >45 with AS were significantly older and more frequently used statins compared to those without AS. However, we would like to highlight that, to the best of our knowledge, this is the first prospective study in BAV patients which indicated that Apo B levels, Apo B/Apo A1 ratio, and PON-1 activity are associated with AS appearance. Our results require further prospective studies in larger cohorts.
5. Conclusions
In summary, the AS occurrence among the BAV population has complex etiology and is challenging to predict. Our results suggest a potential metabolic link between Apo B level and Apo B/Apo AI ratio and the occurrence of AS in patients with a BAV. Notably, this association was observed only in patients up to 45 years of age. Furthermore, our findings underscore the value of investigating molecules associated with HDL and its antioxidant function, such as PON1, as a useful marker for AS development, compared to traditionally measured HDL-C and LDL-C levels.
Conceptualization, M.K., A.M., M.F., A.K. (Agnieszka Kuchta) and A.K. (Aleksandra Krzesińska); methodology, M.K., A.M., M.F., A.K. (Aleksandra Krzesińska) and A.K. (Agnieszka Kuchta); software, M.K. and A.K. (Agnieszka Kuchta); validation, M.F., A.M. and A.K. (Agnieszka Kuchta); formal analysis, M.K. and A.K. (Aleksandra Krzesińska); investigation, M.K., A.M., A.K. (Aleksandra Krzesińska) and A.K. (Agnieszka Kuchta); resources, M.K., A.M., A.K. (Aleksandra Krzesińska) and A.K. (Agnieszka Kuchta); data curation M.K., A.M.; writing—original draft preparation, M.K.; writing—review and editing, A.M., A.K. (Agnieszka Kuchta), M.F., M.G. and M.J.; visualization, M.K.; supervision, A.M., M.F., A.K. (Agnieszka Kuchta), M.J. and M.G.; project administration, A.M., M.K., A.K. (Agnieszka Kuchta) and M.F. All authors have read and agreed to the published version of the manuscript.
The study was conducted in accordance with the Declaration of Helsinki, and approved by the Local Bioethics Committee at the Medical University of Gdansk (protocol no. NKBBN/487-517/2019).
Informed consent was obtained from all subjects involved in the study.
The original contributions presented in this study are included in the article/
The authors declare no conflict of interest.
Footnotes
Disclaimer/Publisher’s Note: The statements, opinions and data contained in all publications are solely those of the individual author(s) and contributor(s) and not of MDPI and/or the editor(s). MDPI and/or the editor(s) disclaim responsibility for any injury to people or property resulting from any ideas, methods, instructions or products referred to in the content.
Enlarge this image.Figure 1. Spearman’s rank correlation between AV max measurement and Apo B level. Abbreviations: AV Vmax—aortic valve peak transvalvular velocity, Apo B—apolipoprotein B.
Enlarge this image.Figure 2. Spearman’s rank correlation between AV max measurement and Apo B/Apo AI ratio. Abbreviations: AV Vmax—aortic valve peak transvalvular velocity, Apo B/Apo AI—apolipoprotein B/apolipoprotein A-I ratio.
Enlarge this image.Figure 3. ROC curves of Apo B levels (a), Apo B/Apo AI ratio (b), PON-1 ARE (c) activity and the presence of AS for patients aged ≤45. Abbreviations: AUC—Area Under the Curve; CI—Confidence Interval; Apo B—apolipoprotein B; Apo AI—apolipoprotein AI; PON-1 ARE—arylesterase activity.
Clinical characteristics of BAV patients age ≤ 45 and age > 45.
| Age ≤ 45 | Age > 45 | p Value | |
|---|---|---|---|
| No (female) | 22 (6) | 54(15) | 0.812 * |
| Age | 39.5 (33–42) | 60.5 (52–68) | <0.001 ** |
| BMI [kg/m2] | 26.6 (23–29) | 27.8 (25–31) | 0.145 ** |
| Smoking | 5 (23%) | 19 (35%) | 0.431 * |
| Hypertension | 3 (14%) | 36 (67%) | <0.001 * |
| Diabetes mellitus | 1 (5%) | 8 (15%) | 0.387 * |
| Coronary artery disease | 1 (5%) | 19 (35%) | 0.014 * |
| Statin therapy | 4 (18%) | 27 (50%) | 0.021 * |
Abbreviations: BMI—body mass index. * Chi-squared test with Yates’s correction, ** Mann–Whitney U test.
Comparison of clinical characteristics of patients in two age groups based on the AS presence.
| Age ≤ 45 | Age > 45 | |||||
|---|---|---|---|---|---|---|
| No AS | AS | p Value | No AS | AS | p Value | |
| No (female) | 13 (2) | 9 (4) | 0.309 * | 19 (3) | 35 (12) | 0.258 * |
| Age | 39 (31–41) | 40 (34–43) | 0.378 *** | 55 (49–61) | 65 (59–69) | 0.002 ** |
| BMI [kg/m2] | 27 (24–32) | 25 (23–27) | 0.190 *** | 27 (25–30) | 28 (26–31) | 0.340 *** |
| Smoking | 3 (23%) | 2 (22%) | 0.638 * | 7 (37%) | 12 (34%) | 0.912 * |
| Hypertension | 2 (15%) | 1 (11%) | 0.730 * | 13 (68%) | 23 (66%) | 0.920 * |
| Diabetes mellitus | 1(8%) | 0 | 0.845 * | 2 (10%) | 6 (17%) | 0.801 * |
| Coronary artery disease | 0 | 1(11%) | 0.845 * | 6 (32%) | 13 (37%) | 0.912 * |
| Statin therapy | 3 (2%) | 1(11%) | 0.878 * | 5 (26%) | 22 (63%) | 0.023 * |
Abbreviations: BMI—body mass index. * Chi-squared test with Yates’s correction, ** Mann–Whitney U test, *** Student’s t-test.
Echocardiographic assessment of BAV complications and LVEF according to age.
| Age ≤ 45 | Age > 45 | p Value | |
|---|---|---|---|
| LVEF [%] | 60 (35–65) | 60 (55–64) | 0.951 ** |
| AS | 9 (41%) | 35 (65%) | 0.097 * |
| AR | 13 (59%) | 14 (26%) | 0.013 * |
| Aortopathy | 13 (59%) | 37 (69%) | 0.604 * |
Abbreviations: LVEF—left ventricular ejection fraction, AS—aortic stenosis, AR—moderate to severe aortic regurgitation. * Chi-squared test with Yates’s correction, ** Mann–Whitney U test.
Echocardiographic assessment of BAV complications and LVEF in two age groups based on the AS presence.
| Age ≤ 45 | Age > 45 | |||||
|---|---|---|---|---|---|---|
| No AS | AS | p Value | No AS | AS | p Value | |
| LEVF [%] | 60 (40–64) | 60 (32–70) | 1.000 ** | 60 (55–64) | 60 (51–64) | 0.926 ** |
| AR | 7 (54%) | 6 (67%) | 0.873 * | 9 (47%) | 5 (14%) | 0.020 * |
| Aortopathy | 8 (61%) | 5 (56%) | 0.873 * | 17 (89%) | 27 (77%) | 0.455 * |
Abbreviations: LVEF—left ventricular ejection fraction, AS—aortic stenosis, AR—moderate to severe aortic regurgitation. * Chi-squared test with Yates’s correction, ** Mann–Whitney U test.
Echocardiographic characteristics of patients with aortic stenosis according to age.
| Age ≤ 45 + AS | Age > 45 + AS | p Value | |
|---|---|---|---|
| AVA | 1.3 (0.9–1.4) | 0.9 (0.8–1.2) | 0.023 ** |
| AV Vmax | 3.5 (2.8–4.1) | 3.9 (3.4–4.4) | 0.161 * |
| AV PGmean | 32 (16–46) | 40 (25–46) | 0.457 * |
Abbreviations: AVA—aortic valve area, AV Vmax—aortic valve peak transvalvular velocity, AV PGmean—mean transvalvular pressure gradient. * Student’s t-test, ** Mann–Whitney U test.
Lipid parameters in BAV patients according to age and AS diagnosis.
| Age ≤45 | Age > 45 | |||||
|---|---|---|---|---|---|---|
| No AS | AS | p Value | No AS | AS | p Value | |
| Apo AI | 150 (126–168) | 144 (131–151) | 0.371 * | 167 (139–184) | 156 (146–173) | 0.306 * |
| Apo B | 95 (77–101) | 110 (102–132) | 0.044 ** | 100 (93–114) | 83 (77–106) | 0.144 * |
| Apo B/Apo AI | 0.6 (0.5–0.7) | 0.8 (0.7–1) | 0.029 ** | 0.6 (0.5–0.7) | 0.6 (0.5–0.7) | 0.096 * |
| TC | 153 (139–166) | 150 (126–164) | 0.640 ** | 144 (124–167) | 128 (113–147) | 0.065 ** |
| HDL-C | 51 (47–54) | 48 (45–52) | 0.344 * | 51 (47–61) | 50 (42–58) | 0.492 * |
| LDL-C | 101 (98–114) | 107 (94–111) | 0.358 ** | 99 (91–120) | 86 (80–106) | 0.056 ** |
| LDL-C/HDL-C | 2.1 (1.7–2.3) | 2.2 (1.9–2.3) | 0.860 * | 1.9 (1.7–2.2) | 1.8 (1.5–2.2) | 0.322 ** |
| non HDL-C/HDL-C | 2.1 (1.6–2.4) | 2.0 (1.9–2.4) | 0.874 * | 1.7 (1.4–2.2) | 1.6 (1.4–2) | 0.259 * |
| TG | 98 (47–113) | 63 (52–108) | 0.738 ** | 105 (69–138) | 87 (68–113) | 0.269 * |
| PON-1 ASE | 70 (55–151) | 127 (39–163) | 0.894 ** | 89 (53–154) | 59 (47–147) | 0.484 ** |
| PON-1 ARE | 85 (70–102) | 63 (52–80) | 0.012 * | 82 (71–99) | 79 (59–88) | 0.126 ** |
Abbreviations: Apo AI—apolipoprotein A-I; Apo B—apolipoprotein B; Apo B/Apo AI—apolipoprotein B/Apolipoprotein A-I ratio; TC—total cholesterol; HDL-C—high density lipoprotein cholesterol; LDL-C—low density lipoprotein cholesterol; non HDL-C—non-HDL cholesterol, TG—triglycerides; PON-1 ASE—paraoxonase activity; PON-1 ARE-arylesterase activity. * Student’s t-test, ** Mann–Whitney U test.
Supplementary Materials
The following supporting information can be downloaded at:
References
1. Braverman, A.; Guven, H.; Beardslee, M.; Makan, M.; Kates, A.; Moon, M. The Bicuspid Aortic Valve. Curr. Probl. Cardiol.; 2005; 30, pp. 470-522. [DOI: https://dx.doi.org/10.1016/j.cpcardiol.2005.06.002] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16129122]
2. Shah, S.Y.; Higgins, A.; Desai, M.Y. Bicuspid aortic valve: Basics and beyond. Cleve Clin. J. Med.; 2018; 85, pp. 779-784. [DOI: https://dx.doi.org/10.3949/ccjm.85a.17069] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30289756]
3. Michelena, H.I.; Desjardins, V.A.; Avierinos, J.F.; Russo, A.; Nkomo, V.T.; Sundt, T.M.; Pellikka, P.A.; Tajik, A.J.; Enriquez-Sarano, M. Natural history of asymptomatic patients with normally functioning or minimally dysfunctional bicuspid aortic valve in the community. Circulation; 2008; 117, pp. 2776-2784. [DOI: https://dx.doi.org/10.1161/CIRCULATIONAHA.107.740878]
4. Siu, S.C.; Silversides, C.K. Bicuspid Aortic Valve Disease. J. Am. Coll. Cardiol.; 2010; 55, pp. 2789-2800. [DOI: https://dx.doi.org/10.1016/j.jacc.2009.12.068] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/20579534]
5. Lindman, B.R.; Clavel, M.A.; Mathieu, P.; Iung, B.; Lancellotti, P.; Otto, C.M.; Pibarot, P. Calcific aortic stenosis. Nat. Rev. Dis. Prim.; 2016; 2, 16006. [DOI: https://dx.doi.org/10.1038/nrdp.2016.6]
6. Beppu, S.; Suzuki, S.; Matsuda, H.; Ohmori, F.; Nagata, S.; Miyatake, K. Rapidity of progression of aortic stenosis in patients with congenital bicuspid aortic valves. Am. J. Cardiol.; 1993; 71, pp. 322-327. [DOI: https://dx.doi.org/10.1016/0002-9149(93)90799-I] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8427176]
7. Yuan, M.; Yuan, S.-M. The anatomopathology of bicuspid aortic valve. Folia Morphol.; 2011; 70, pp. 217-227.
8. Mai, Z.; Guan, L.; Mu, Y. Association between bicuspid aortic valve phenotype and patterns of valvular dysfunction: A meta-analysis. Clin. Cardiol.; 2021; 44, 1683. [DOI: https://dx.doi.org/10.1002/clc.23736]
9. Tzemos, N.; Therrien, J.; Yip, J.; Thanassoulis, G.; Tremblay, S.; Jamorski, M.T.; Webb, G.D.; Siu, S.C. Outcomes in Adults With Bicuspid Aortic Valves. JAMA; 2008; 300, pp. 1317-1325. [DOI: https://dx.doi.org/10.1001/jama.300.11.1317] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18799444]
10. Ivert, T.; Hammar, N.; Talbäck, M.; Malmström, H.; Leander, K.; Walldius, G. Elevated Apolipoprotein B/A-1 Ratio is Associated With an Increased Risk of Aortic Stenosis: Experience From the AMORIS Cohort. Heart. Lung Circ.; 2021; 30, pp. 1050-1057. [DOI: https://dx.doi.org/10.1016/j.hlc.2020.12.005] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/33461915]
11. Yan, A.T.; Koh, M.; Chan, K.K.; Guo, H.; Alter, D.A.; Austin, P.C.; Tu, J.V.; Wijeysundera, H.C.; Ko, D.T. Association Between Cardiovascular Risk Factors and Aortic Stenosis: The CANHEART Aortic Stenosis Study. J. Am. Coll. Cardiol.; 2017; 69, pp. 1523-1532. [DOI: https://dx.doi.org/10.1016/j.jacc.2017.01.025] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/28335833]
12. Glavinovic, T.; Thanassoulis, G.; de Graaf, J.; Couture, P.; Hegele, R.A.; Sniderman, A.D. Physiological Bases for the Superiority of Apolipoprotein B Over Low-Density Lipoprotein Cholesterol and Non–High-Density Lipoprotein Cholesterol as a Marker of Cardiovascular Risk. J. Am. Heart Assoc. Cardiovasc. Cerebrovasc. Dis.; 2022; 11, 25858. [DOI: https://dx.doi.org/10.1161/JAHA.122.025858]
13. Nagao, M.; Nakajima, H.; Toh, R.; Hirata, K.I.; Ishida, T. Cardioprotective Effects of High-Density Lipoprotein Beyond its Anti-Atherogenic Action. J. Atheroscler. Thromb.; 2018; 25, 985. [DOI: https://dx.doi.org/10.5551/jat.RV17025] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30146614]
14. Hofmanis, J.; Hofmane, D.; Svirskis, S.; Mackevics, V.; Tretjakovs, P.; Lejnieks, A.; Signorelli, S.S. HDL-C Role in Acquired Aortic Valve Stenosis Patients and Its Relationship with Oxidative Stress. Medicina; 2019; 55, 416. [DOI: https://dx.doi.org/10.3390/medicina55080416]
15. Barter, P.J.; Nicholls, S.; Rye, K.A.; Anantharamaiah, G.M.; Navab, M.; Fogelman, A.M. Antiinflammatory properties of HDL. Circ. Res.; 2004; 95, pp. 764-772. [DOI: https://dx.doi.org/10.1161/01.RES.0000146094.59640.13] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15486323]
16. Lommi, J.I.; Kovanen, P.T.; Jauhiainen, M.; Lee-Rueckert, M.; Kupari, M.; Helske, S. High-density lipoproteins (HDL) are present in stenotic aortic valves and may interfere with the mechanisms of valvular calcification. Atherosclerosis; 2011; 219, pp. 538-544. [DOI: https://dx.doi.org/10.1016/j.atherosclerosis.2011.08.027] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/21917259]
17. Tsompanidi, E.M.; Brinkmeier, M.S.; Fotiadou, E.H.; Giakoumi, S.M.; Kypreos, K.E. HDL biogenesis and functions: Role of HDL quality and quantity in atherosclerosis. Atherosclerosis; 2010; 208, pp. 3-9. [DOI: https://dx.doi.org/10.1016/j.atherosclerosis.2009.05.034] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/19595353]
18. Liu, C.; Dhindsa, D.; Almuwaqqat, Z.; Ko, Y.A.; Mehta, A.; Alkhoder, A.A.; Alras, Z.; Desai, S.R.; Patel, K.J.; Hooda, A. et al. Association Between High-Density Lipoprotein Cholesterol Levels and Adverse Cardiovascular Outcomes in High-risk Populations. JAMA Cardiol.; 2022; 7, pp. 672-680. [DOI: https://dx.doi.org/10.1001/jamacardio.2022.0912]
19. Sökmen, E.; Çelik, M.; Sivri, S.; Güçlü, K. Relationship between Paraoxonase-1 and Arylesterase Enzyme Activities and SYNTAX I and II Scores in Patients with ST-Elevation Myocardial Infarction. J. Tehran Univ. Heart Cent.; 2019; 14, 156. [DOI: https://dx.doi.org/10.18502/jthc.v14i4.1989]
20. Song, J.; Zheng, Q.; Ma, X.; Zhang, Q.; Xu, Z.; Zou, C.; Wang, Z. Expression levels of paraoxonase-1 in aortic valve tissue are associated with the progression of calcific aortic valve stenosis. J. Thorac. Dis.; 2019; 11, pp. 2890-2898. [DOI: https://dx.doi.org/10.21037/jtd.2019.07.41] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31463118]
21. O’Brien, K.D.; Reichenbach, D.D.; Marcovina, S.M.; Kuusisto, J.; Alpers, C.E.; Otto, C.M. Apolipoproteins B, (a), and E accumulate in the morphologically early lesion of “degenerative” valvular aortic stenosis. Arterioscler. Thromb. Vasc. Biol.; 1996; 16, pp. 523-532. [DOI: https://dx.doi.org/10.1161/01.ATV.16.4.523] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/8624774]
22. Gebhard, C.; Maafi, F.; Stähli, B.E.; Dang, J.; Nachar, W.; de Oliveira Moraes, A.B.; Kernaleguen, A.E.; Lavoie, V.; Mecteau, M.; Mihalache-Avram, T. et al. Apolipoprotein A-I proteolysis in aortic valve stenosis: Role of cathepsin S. Basic Res. Cardiol.; 2018; 113, 30. [DOI: https://dx.doi.org/10.1007/s00395-018-0689-7] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/29915952]
23. Kaneva, A.M.; Potolitsyna, N.N.; Bojko, E.R.; Odland, J. The Apolipoprotein B/Apolipoprotein A-I Ratio as a Potential Marker of Plasma Atherogenicity. Dis. Markers; 2015; 2015, 591454. [DOI: https://dx.doi.org/10.1155/2015/591454] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25852220]
24. Zheng, K.H.; Arsenault, B.J.; Kaiser, Y.; Khaw, K.T.; Wareham, N.J.; Stroes, E.S.G.; Boekholdt, S.M. apoB/apoA-I Ratio and Lp(a) Associations With Aortic Valve Stenosis Incidence: Insights From the EPIC-Norfolk Prospective Population Study. J. Am. Heart Assoc. Cardiovasc. Cerebrovasc. Dis.; 2019; 8, e013020. [DOI: https://dx.doi.org/10.1161/JAHA.119.013020]
25. Duran Karaduman, B.; Ayhan, H.; Keleş, T.; Bozkurt, E. Association between monocyte to high-density lipoprotein cholesterol ratio and bicuspid aortic valve degeneration. Turk. J. Med. Sci.; 2020; 50, pp. 1307-1313. [DOI: https://dx.doi.org/10.3906/sag-2006-60]
26. Endo, M.; Nabuchi, A.; Okuyama, H.; Muto, Y.; Hiranuma, S.; Miyazaki, T.; Hosokawa, J.; Enjoji, Y.; Shimura, Y.; Hashimoto, O. Differing relationship between hypercholesterolemia and a bicuspid aortic valve according to the presence of aortic valve stenosis or aortic valve regurgitation. Gen. Thorac. Cardiovasc. Surg.; 2015; 63, pp. 502-506. [DOI: https://dx.doi.org/10.1007/s11748-015-0561-8]
27. Magni, P. Bicuspid aortic valve, atherosclerosis and changes of lipid metabolism: Are there pathological molecular links?. J. Mol. Cell. Cardiol.; 2019; 129, pp. 231-235. [DOI: https://dx.doi.org/10.1016/j.yjmcc.2019.03.004] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/30872037]
28. Aggarwal, A.; Srivastava, S.; Velmurugan, M. Newer perspectives of coronary artery disease in young. World J. Cardiol.; 2016; 8, 728. [DOI: https://dx.doi.org/10.4330/wjc.v8.i12.728]
29. Michos, E.D.; Choi, A.D. Coronary Artery Disease in Young Adults: A Hard Lesson But a Good Teacher. J. Am. Coll. Cardiol.; 2019; 74, pp. 1879-1882. [DOI: https://dx.doi.org/10.1016/j.jacc.2019.08.1023] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31601368]
30. Vahanian, A.; Beyersdorf, F.; Praz, F.; Milojevic, M.; Baldus, S.; Bauersachs, J.; Capodanno, D.; Conradi, L.; De Bonis, M.; De Paulis, R. et al. 2021 ESC/EACTS Guidelines for the management of valvular heart diseaseDeveloped by the Task Force for the management of valvular heart disease of the European Society of Cardiology (ESC) and the European Association for Cardio-Thoracic Surgery (EACTS). Eur. Heart J.; 2022; 43, pp. 561-632. [DOI: https://dx.doi.org/10.1093/eurheartj/ehab395]
31. Friedewald, W.T.; Levy, R.I.; Fredrickson, D.S. Estimation of the Concentration of Low-Density Lipoprotein Cholesterol in Plasma, Without Use of the Preparative Ultracentrifuge. Clin. Chem.; 1972; 18, pp. 499-502. [DOI: https://dx.doi.org/10.1093/clinchem/18.6.499]
32. Fukuyama, N.; Homma, K.; Wakana, N.; Kudo, K.; Suyama, A.; Ohazama, H.; Tsuji, C.; Ishiwata, K.; Eguchi, Y.; Nakazawa, H. et al. Validation of the Friedewald Equation for Evaluation of Plasma LDL-Cholesterol. J. Clin. Biochem. Nutr.; 2007; 43, pp. 1-5. [DOI: https://dx.doi.org/10.3164/jcbn.2008036] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/18648653]
33. Nakanishi, M.; Takanami, Y.; Maruyama, T.; Murata, M.; Motohashi, Y.; Nakano, S.; Uchida, K.; Maruyama, C.; Kyotani, S.; Tsushima, M. The ratio of serum paraoxonase/arylesterase activity using an improved assay for arylesterase activity to discriminate PON1(R192) from PON1(Q192). J. Atheroscler. Thromb.; 2003; 10, pp. 337-342. [DOI: https://dx.doi.org/10.5551/jat.10.337] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15037822]
34. Fenoglio, J.J.; McAllister, H.A.; DeCastro, C.M.; Davia, J.E.; Cheitlin, M.D. Congenital bicuspid aortic valve after age 20. Am. J. Cardiol.; 1977; 39, pp. 164-169. [DOI: https://dx.doi.org/10.1016/S0002-9149(77)80186-0]
35. Lewin, M.B.; Otto, C.M. The bicuspid aortic valve: Adverse outcomes from infancy to old age. Circulation; 2005; 111, pp. 832-834. [DOI: https://dx.doi.org/10.1161/01.CIR.0000157137.59691.0B] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/15723989]
36. Perrin, N.; Ibrahim, R.; Dürrleman, N.; Basmadjian, A.; Leroux, L.; Demers, P.; Modine, T.; Ali, W. Ben Bicuspid Aortic Valve Stenosis: From Pathophysiological Mechanism, Imaging Diagnosis, to Clinical Treatment Methods. Front. Cardiovasc. Med.; 2022; 8, 798949. [DOI: https://dx.doi.org/10.3389/fcvm.2021.798949]
37. Lim, M.S.; Strange, G.; Playford, D.; Stewart, S.; Celermajer, D.S. Characteristics of Bicuspid Aortic Valve Disease and Stenosis: The National Echo Database of Australia. J. Am. Heart Assoc. Cardiovasc. Cerebrovasc. Dis.; 2021; 10, e020785. [DOI: https://dx.doi.org/10.1161/JAHA.121.020785]
38. Otto, C.M. Calcification of bicuspid aortic valves. Heart; 2002; 88, pp. 321-322. [DOI: https://dx.doi.org/10.1136/heart.88.4.321] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/12231576]
39. Faggiano, P.; Antonini-Canterin, F.; Baldessin, F.; Lorusso, R.; D’Aloia, A.; Dei Cas, L. Epidemiology and cardiovascular risk factors of aortic stenosis. Cardiovasc. Ultrasound; 2006; 4, 27. [DOI: https://dx.doi.org/10.1186/1476-7120-4-27] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/16813661]
40. Sticchi, E.; Giusti, B.; Cordisco, A.; Gori, A.M.; Sereni, A.; Sofi, F.; Mori, F.; Colonna, S.; Fugazzaro, M.P.; Pepe, G. et al. Role of lipoprotein (a) and LPA KIV2 repeat polymorphism in bicuspid aortic valve stenosis and calcification: A proof of concept study. Intern. Emerg. Med.; 2019; 14, pp. 45-50. [DOI: https://dx.doi.org/10.1007/s11739-018-1925-8]
41. Alegret, J.M.; Masana, L.; Martinez-micaelo, N.; Heras, M.; Beltrán-debón, R. LDL cholesterol and apolipoprotein B are associated with ascending aorta dilatation in bicuspid aortic valve patients. QJM Int. J. Med.; 2015; 108, pp. 795-801. [DOI: https://dx.doi.org/10.1093/qjmed/hcv032] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25660598]
42. Baigent, C.; Blackwell, L.; Emberson, J.; Holland, L.E.; Reith, C.; Bhala, N.; Peto, R.; Barnes, E.H.; Keech, A.; Simes, J. et al. Efficacy and safety of more intensive lowering of LDL cholesterol: A meta-analysis of data from 170,000 participants in 26 randomised trials. Lancet; 2010; 376, pp. 1670-1681. [DOI: https://dx.doi.org/10.1016/S0140-6736(10)61350-5]
43. Smith, J.G.; Luk, K.; Schulz, C.A.; Engert, J.C.; Do, R.; Hindy, G.; Rukh, G.; Dufresne, L.; Almgren, P.; Owens, D.S. et al. Association of Low-Density Lipoprotein Cholesterol–Related Genetic Variants With Aortic Valve Calcium and Incident Aortic Stenosis. JAMA; 2014; 312, 1764. [DOI: https://dx.doi.org/10.1001/jama.2014.13959] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/25344734]
44. Holmes, M.V.; Asselbergs, F.W.; Palmer, T.M.; Drenos, F.; Lanktree, M.B.; Nelson, C.P.; Dale, C.E.; Padmanabhan, S.; Finan, C.; Swerdlow, D.I. et al. Mendelian randomization of blood lipids for coronary heart disease. Eur. Heart J.; 2015; 36, pp. 539-550. [DOI: https://dx.doi.org/10.1093/eurheartj/eht571] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/24474739]
45. Nazarzadeh, M.; Pinho-Gomes, A.C.; Bidel, Z.; Dehghan, A.; Canoy, D.; Hassaine, A.; Ayala Solares, J.R.; Salimi-Khorshidi, G.; Smith, G.D.; Otto, C.M. et al. Plasma lipids and risk of aortic valve stenosis: A Mendelian randomization study. Eur. Heart J.; 2020; 41, pp. 3913-3920. [DOI: https://dx.doi.org/10.1093/eurheartj/ehaa070] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/32076698]
46. Stanciulescu, L.A.; Scafa-Udriste, A.; Dorobantu, M. Exploring the Association between Low-Density Lipoprotein Subfractions and Major Adverse Cardiovascular Outcomes—A Comprehensive Review. Int. J. Mol. Sci.; 2023; 24, 6669. [DOI: https://dx.doi.org/10.3390/ijms24076669]
47. Galimberti, F.; Casula, M.; Olmastroni, E. Apolipoprotein B compared with low-density lipoprotein cholesterol in the atherosclerotic cardiovascular diseases risk assessment. Pharmacol. Res.; 2023; 195, 106873. [DOI: https://dx.doi.org/10.1016/j.phrs.2023.106873] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/37517561]
48. Behbodikhah, J.; Ahmed, S.; Elyasi, A.; Kasselman, L.J.; De Leon, J.; Glass, A.D.; Reiss, A.B. Apolipoprotein B and Cardiovascular Disease: Biomarker and Potential Therapeutic Target. Metabolites; 2021; 11, 690. [DOI: https://dx.doi.org/10.3390/metabo11100690]
49. Walldius, G.; Jungner, I. Apolipoprotein A-I versus HDL cholesterol in the prediction of risk for myocardial infarction and stroke. Curr. Opin. Cardiol.; 2007; 22, pp. 359-367. [DOI: https://dx.doi.org/10.1097/HCO.0b013e3281bd8849] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/17556890]
50. Deng, F.; Li, D.; Lei, L.; Yang, Q.; Li, Q.; Wang, H.; Deng, J.; Zheng, Q.; Jiang, W. Association between apolipoprotein B/A1 ratio and coronary plaque vulnerability in patients with atherosclerotic cardiovascular disease: An intravascular optical coherence tomography study. Cardiovasc. Diabetol.; 2021; 20, 188. [DOI: https://dx.doi.org/10.1186/s12933-021-01381-9] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/34526013]
51. Mach, F.; Baigent, C.; Catapano, A.L.; Koskina, K.C.; Casula, M.; Badimon, L.; Chapman, M.J.; De Backer, G.G.; Delgado, V.; Ference, B.A. et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: Lipid modification to reduce cardiovascular risk. Atherosclerosis; 2019; 290, pp. 140-205. [DOI: https://dx.doi.org/10.1016/j.atherosclerosis.2019.08.014] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/31591002]
52. Küçük, H.O.; Küçük, U.; Demirtaş, C.; Özdemir, M. Role of serum high density lipoprotein levels and functions in calcific aortic valve stenosis progression. Int. J. Clin. Exp. Med.; 2015; 8, 22543.
53. Endo, Y.; Fujita, M.; Ikewaki, K. HDL Functions—Current Status and Future Perspectives. Biomolecules; 2023; 13, 105. [DOI: https://dx.doi.org/10.3390/biom13010105] [PubMed: https://www.ncbi.nlm.nih.gov/pubmed/36671490]
© 2025 by the authors. Licensee MDPI, Basel, Switzerland. This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC BY) license (https://creativecommons.org/licenses/by/4.0/). Notwithstanding the ProQuest Terms and Conditions, you may use this content in accordance with the terms of the License.
Details
; Mickiewicz, Agnieszka 1
; Krzesińska, Aleksandra 2
; Kuchta, Agnieszka 2
; Jankowski, Maciej 2 ; Gruchała, Marcin 1 ; Fijałkowski, Marcin 1
1 1st Department of Cardiology, Medical University of Gdańsk, 80-211 Gdańsk, Poland;
2 Department of Clinical Chemistry, Medical University of Gdańsk, 80-211 Gdańsk, Poland;