Abstract
Objective
Elevated lipoprotein(a) level is an independent risk factor for atherosclerotic cardiovascular disease. However, the strength of this association in healthy individuals is unknown.
Methods
In this retrospective cohort study, we reviewed medical records obtained from a Health Examination Program. The records, covering the period 2002-2015, were from 2,634 men at low risk, as indicated by their Framingham Risk Score and Systematic Coronary Risk Evaluation (SCORE) score, and included lipoprotein(a) data. We categorized the participants on the basis of their lipoprotein(a) level and analyzed the association of this level with cardiovascular events.
Results
The study population had a mean age of 46 years. In total, 32 cardiovascular disease events – 6 strokes and 26 coronary artery events – were identified. An increase of 5 mg/dL in the lipoprotein(a) level (independent of low-density cholesterol) raised the cardiovascular disease risk by 8% over a period of 10 years (p = 0.014). Sensitivity analysis also yielded this result, even after excluding hypertension and diabetes.
Conclusions
Elevated lipoprotein(a) may be a risk factor for coronary artery disease, even in male populations defined as having a low risk according to the Framingham Risk Score and SCORE.
Keywords: Cardiovascular risk, Lipid, Lipoprotein(a), Myocardial infarction
INTRODUCTION
Cardiovascular disease (CVD) is the leading cause of death worldwide and Taiwan. Abnormal lipid profile is a major risk factor for both atherosclerosis and CVD.1,2 These profiles can be divided into four categories: elevated low-density lipoprotein cholesterol (LDL-C), elevated lipoprotein(a) (Lp[a]), elevated triglyceride (TG), and low high-density lipoprotein cholesterol (HDL-C) levels.
Lp(a) is an apolipoprotein B-100-containing lipoprotein which is unaffected by current statin therapies. Studies on familial hypercholesteremia have revealed that, compared with LDL-C, Lp(a) is a modest independent risk factor for CVD. However, among lipid profiles, Lp(a) is the least studied marker of lipid disorders.3-5 In 1990, Rosengren et al. reported a normal Lp(a) level to be approximately 17 mg/dL in a Caucasian population; they further indicated that levels over 30 mg/dL may be associated with a higher incidence of CVD events after 6 years of follow-up in a high-CVD-risk Swedish population.6 The European Atherosclerosis Society (EAS) later reported that, based on the results of a large meta-analysis, Lp(a) is high-risk factor for CVD at concentrations of higher than 50 mg/dL.7 The studies included in the group’s meta-analysis comprised a population of 93% Caucasian and 7% Black individuals, who had a mean age of 57 years, prehypertension (134 mmHg), and higher total cholesterol level (213 md/L) at baseline, which resembles a population with an intermediate CVD risk. In a randomized controlled trial meta-analysis, Willeit reported that high risk patients with abnormal Lp(a) levels had a linear CVD risk even when undergoing statin treatment.8 Racial differences have been reported with respect to Lp(a) levels, with Black individuals having the highest levels, followed by South Asian, Caucasian, Hispanic, and East Asian individuals.9,10 However, little information is available for Asian and clinically low-risk populations.
Nonalcoholic fatty liver disease is associated with a higher CVD risk. Several reports have suggested that Lp(a) level is inversely associated with the severity of fatty liver disease.11,12 However, little is known about the prevalence of abnormal Lp(a) levels and the association of Lp(a) with CVD risk in Asian populations. Therefore, we conducted this retrospective study with a focus on individuals with a low CVD risk and without hypertension or diabetes who attended a health checkup to evaluate the associations of Lp(a) level with CVD risk and the severity of fatty liver disease.
METHODS
Dataset
We retrospectively collected clinical data of individuals who underwent a health examination at the Chang Gung Memorial Hospital (CGMH) Healthcare Center between January 1, 2002 and December 31, 2015. We then used the CGMH admission electronic medical records database to follow these participants until December 31, 2015, to evaluate the association of Lp(a) level with cardiovascular outcomes and fatty liver disease (Figure 1). This study was approved by the Ethics Committee of the Institutional Review Board of CGMH (IRB No. 102e 4175B) and conducted in accordance with the ethical principles of the Declaration of Helsinki.
Figure 1.
Flowchart of healthcare center database cohort. baPWV, brachial-ankle pulse wave velocity.
The CGMH System includes three major teaching hospitals and four tertiary-care medical centers and is the largest healthcare provider in Taiwan. The CGMH System has more than 10,000 beds and admits more than 280,000 patients per year, servicing approximately one-tenth of the Taiwanese population annually. The CGMH Healthcare Center is a tertiary medical center- based service, serving anaverage of 10,000 patients undergoing health checkups each year. Every health checkup conducted at our healthcare center is performed using the standardized protocol described in the following section.13,14
Protocol
All participants included in this study were older than 18 years and afebrile before the checkup. All received a health checkup in accordance with the standardized protocol, which included a structured questionnaire covering lifestyle and personal and family histories of chronic diseases as well as anthropometric measurements including waist size, height, and weight. All participants received physical examinations and blood tests, including complete blood cell count, electrolyte, lipid profile, kidney, and liver function tests; thyroid function testing; hepatitis viral marker testing (hepatitis B and C); and tumor marker panel testing (AFP, CA199, PSA, CA125, and CA153). Lp(a) and brachial-ankle pulse wave velocity (baPWV) measurements were specified as additional options in the health checkup package. All participants also underwent chest and abdominal X-rays, pulmonary function tests, electrocardiography, and urine analysis. The baPWV was measured using automated apparatus (Colin VP-1000, Omron, Kyoto, Japan). The technicians at our single center were all similarly trained and accredited. We requested that participants avoid tobacco use and consumption of stimulant beverages, such as alcohol and coffee, for the night before the examination. A standard temperature was maintained in the examination room. Right and left baPWVs were calculated automatically as the distance between the right arm and both ankles divided by the corresponding transit time between the right arm and both ankles, and the mean of the right and left pulse wave velocities were calculated as the representative baPWV. Liver ultrasonography (Philips, Amsterdam, Netherlands) was performed to assess the extent of fatty liver disease, which was graded as normal (absent), mild, moderate, or severe on the basis of the reflection level of echogenicity (brightness) arising from the hepatic parenchyma with liver-kidney contrast and far attenuation signaled by echo penetration into the deep portion of the liver and obscured changes in the vessel and gallbladder walls.15,16
When the checkup was complete, the results of the physical examination, laboratory tests, and other examinations were explained to the participants by a senior physician. The participants were then referred to our specialty clinics, where further follow-up was scheduled if severe conditions such as CVD or cancer had been identified. If borderline or equivocal findings were obtained, follow-up evaluations at 3 months to more than 1 year were recommended. All participants were contacted through telephone on the day after the examination to discuss any further questions they might have. Participants with a Framingham Risk Score (FRS) of over 10% or Systematic Coronary Risk Evaluation (SCORE) score indicating higher than low-risk were excluded from our study follow-up.
For inpatient admission records, such as those for cases of CVD or cancer, all diseases were diagnosed using the International Classification of Diseases, Ninth Revision, Clinical Modification (ICD-9-CM) code, and diagnoses were confirmed by a hospital-based insurance group to ensure accuracy. An inaccurate claim by a hospital results in a fine by the National Health Insurance Administration. We searched for CVD-associated admission and discharge diagnosis records for all types of stroke (ICD-9-CM: 430-437) and for coronary artery disease (CAD; ICD-9-CM: 410-414).
Statistical analysis
The SAS statistical package (SAS for Windows, version 9.4; SAS Institute, Cary, NC, USA) was used to perform all statistical analyses. We used scatter plots and cluster bar plots to express the associations of Lp(a) level with age and severity of fatty liver disease. Kaplan-Meier curves and a Cox proportional hazards model were used to evaluate CVD risk. Finally, we analyzed the receiver operating characteristic (ROC) curve of Lp(a) values to determine the ideal cutoff value for predicting future CVD risk in the investigated clinically healthy male population.
RESULTS
A total of 2,634 male participants with both baPWV and Lp(a) data were included for analysis in this study after excluding records with missing data. The baseline clinical characteristics of the study enrollees are listed in Table 1. The mean age, blood pressure, and baPWV were 46 years, 123/75 mmHg, and 1400 cm/s, respectively. The lipid profiles revealed mean total cholesterol, LDL-C, TG, HDL, and Lp(a) levels of 195, 119, 148, 48, and 14 mg/dL, respectively. All other laboratory results – including fasting plasma glucose, high-sensitivity C-reactive protein, and those of kidney and liver function tests – were within normal ranges. These data revealed that this cohort was at low risk according to traditional CVD prediction measures, such as the FRS and SCORE score. The severity of fatty liver disease in this population was mostly within the normal range (83%). The associations among Lp(a) level, age, and severity of fatty liver disease are displayed in Figure 2 and the Supplementary Figure 1, Supplemental Table 1, Supplemental Table 2, Supplementary Figure 2.
Table 1. Epidemiologic data of the overall and quartile lipoprotein(a) populations.
| Overall | Quartile 1 | Quartile 2 | Quartile 3 | Quartile 4 | p value | |
| Age (years) | 45.79 ± 10.60 | 45.29 ± 10.41 | 45.23 ± 10.10 | 46.16 ± 10.42 | 46.49 ± 11.38 | 0.073 |
| Lipoprotein(a) (mg/dL) | 13.56 ± 17.35 | 2.25 ± 0.82 | 5.29 ± 1.05 | 10.78 ± 2.41 | 36.07 ± 22.07 | < 0.001* |
| Total cholesterol (mg/dL) | 194.97 ± 33.17 | 188.09 ± 33.59 | 196.29 ± 32.01 | 196.03 ± 31.60 | 199.57 ± 34.37 | < 0.001* |
| HDL (mg/dL) | 47.68 ± 10.94 | 46.59 ± 11.35 | 48.04 ± 11.12 | 47.74 ± 10.52 | 48.36 ± 10.67 | 0.020* |
| LDL (mg/dL) | 118.51 ± 30.26 | 108.68 ± 29.31 | 119.46 ± 28.97 | 120.78 ± 28.41 | 125.25 ± 31.80 | < 0.001* |
| Triglycerides (mg/dL) | 147.58 ± 109.20 | 173.49 ± 153.23 | 145.74 ± 89.27 | 139.84 ± 90.82 | 130.88 ± 82.80 | < 0.001* |
| Fasting sugar (mg/dL) | 98.51 ± 22.82 | 101.59 ± 27.95 | 98.28 ± 21.71 | 97.93 ± 22.17 | 96.17 ± 17.95 | < 0.001* |
| Creatinine (mg/dL) | 0.97 ± 0.26 | 0.94 ± 0.16 | 0.97 ± 0.35 | 0.96 ± 0.19 | 0.98 ± 0.30 | 0.025* |
| High sensitivity CRP (mg/dL) | 2.15 ± 4.32 | 2.01 ± 3.51 | 1.95 ± 2.98 | 1.98 ± 3.22 | 2.64 ± 6.50 | 0.031* |
| AST (mg/dL) | 26.00 ± 15.01 | 27.59 ± 18.00 | 26.27 ± 16.40 | 25.18 ± 12.33 | 24.96 ± 12.32 | 0.005* |
| ALT (mg/dL) | 33.60 ± 30.34 | 36.81 ± 33.98 | 34.57 ± 36.47 | 32.30 ± 25.35 | 30.66 ± 23.14 | 0.001* |
| Body mass index (kg/m2) | 25.10 ± 3.48 | 25.51 ± 3.57 | 25.07 ± 3.42 | 25.02 ± 3.34 | 24.82 ± 3.56 | 0.003* |
| Systolic blood pressure (mmHg) | 122.76 ± 14.54 | 123.95 ± 14.50 | 122.21 ± 14.60 | 122.67 ± 13.82 | 122.19 ± 15.18 | 0.094 |
| Diastolic blood pressure (mmHg) | 74.70 ± 10.76 | 75.56 ± 11.02 | 74.69 ± 10.80 | 74.78 ± 10.24 | 73.77 ± 10.89 | 0.026* |
| baPWV L (cm/s) | 1403.12 ± 235.03 | 1413.52 ± 236.34 | 1391.16 ± 224.99 | 1407.40 ± 221.12 | 1400.22 ± 255.99 | 0.346 |
| baPWV R (cm/s) | 1405.38 ± 245.10 | 1413.43 ± 244.88 | 1396.62 ± 234.04 | 1411.95 ± 231.15 | 1399.38 ± 268.63 | 0.490 |
| Fatty liver disease score | 0.490 | |||||
| Fatty liver disease severity | 0.302 | |||||
| Normal | 2194 (83.3) | 538 (80.8) | 556 (84.9) | 541 (82.5) | 559 (85.1) | |
| Mild | 242 (9.2) | 64 (9.6) | 58 (8.9) | 69 (10.5) | 51 (7.8) | |
| Moderate | 174 (6.6) | 55 (8.3) | 35 (5.3) | 41 (6.2) | 43 (6.5) | |
| Severe | 24 (0.9) | 9 (1.4) | 6 (0.9) | 5 (0.8) | 4 (0.6) |
ALT, alanine aminotransferase; AST, aspartate aminotransferase; baPWV, brachial-ankle pulse wave velocity; CRP, C-reactive protein; HDL, high-density lipoprotein; LDL, low-density lipoprotein.
* p value < 0.05.
Figure 2.
Lipoprotein(a) distribution by age in a clinically healthy male population.
Supplementary Figure 1.
Association between lipoprotein(a) and severity of fatty liver disease.
Supplemental Table 1. Univariate and multivariable Cox analysis for association between lipoprotein(a) and cardiovascular events in a low risk healthy male population after excluding 159 subjects with diabetes.
| Outcome/model | HR (95% CI) of per 5 mg/dL increase | p value |
| Coronary or ischemic events | ||
| Model 1: Unadjusted | 1.106 (1.040, 1.175) | 0.001* |
| Model 2: Age, SBP, BMI | 1.101 (1.034, 1.172) | 0.003* |
| Model 3: Further adjusted for LDL | 1.087 (1.020, 1.159) | 0.011* |
| Coronary events | ||
| Model 1: Unadjusted | 1.123 (1.056, 1.195) | < 0.001* |
| Model 2: Age, SBP, BMI | 1.119 (1.050, 1.192) | 0.001* |
| Model 3: Further adjusted for LDL | 1.106 (1.036, 1.180) | 0.002* |
| Stroke events | ||
| Model 1: Unadjusted | 0.904 (0.610, 1.341) | 0.617 |
| Model 2: Age, SBP, BMI | 0.913 (0.620, 1.344) | 0.646 |
| Model 3: Further adjusted for LDL | 0.893 (0.596, 1.340) | 0.585 |
BMI, body mass index; CI, confidence interval; HR, hazard ratio; LDL, low-density lipoprotein; SBP, systolic blood pressure.
* p value < 0.05.
Supplemental Table 2. Univariate and multivariable Cox analysis for association between lipoprotein(a) and cardiovascular events in a low risk healthy male population after excluding 411 subjects with hypertension.
| Outcome/model | HR (95% CI) of per 5 mg/dL increase | p value |
| Coronary or ischemic events | ||
| Model 1: Unadjusted | 1.105 (1.024, 1.194) | 0.010* |
| Model 2: Age, SBP, BMI | 1.104 (1.022, 1.192) | 0.012* |
| Model 3: Further adjusted for LDL | 1.081 (0.997, 1.172) | 0.059 |
| Coronary events | ||
| Model 1: Unadjusted | 1.123 (1.038, 1.215) | 0.004* |
| Model 2: Age, SBP, BMI | 1.122 (1.037, 1.214) | 0.004* |
| Model 3: Further adjusted for LDL | 1.100 (1.013, 1.195) | 0.024* |
| Stroke events | ||
| Model 1: Unadjusted | 0.965 (0.682, 1.365) | 0.840 |
| Model 2: Age, SBP, BMI | 0.973 (0.690, 1.371) | 0.875 |
| Model 3: Further adjusted for LDL | 0.952 (0.663, 1.368) | 0.791 |
BMI, body mass index; CI, confidence interval; HR, hazard ratio; LDL, low-density lipoprotein; SBP, systolic blood pressure.
* p value < 0.05.
Supplementary Figure 2.
Cardiovascular outcome from top to down in female population: combined coronary and stroke events, coronary events, and stroke events.
The mean follow-up was 4.59 years [standard deviation (SD) = 2.26 years], and only 4 participants had no follow-up data. In total, 31 patients had 32 admissions for CVD events during the study period, including 6 stroke events [5 ischemic and 2 hemorrhagic strokes (one hospitalization had both ischemic and hemorrhagic strokes)], and 26 CAD events. Among the 26 events with hospitalization for CAD, 1 was acute anterior myocardial infarction [myocardial infarction (MI); ICD-9: 410], 3 were acute and subacute MI (ICD-9: 411), 10 were angina pectoris (ICD-9: 413), and 18 were other chronic ischemic MI (ICD-9: 414).
The events mostly occurred over a period of 5 years, although we followed the cases for over 10 years. The results revealed that increased Lp(a) level was not associated with baPWV, severity of fatty liver disease, blood pressure, or age. Furthermore, we performed Kaplan-Meier survival analysis for CVD, and found that only combined and coronary events were significant (p = 0.04; Figure 3A-C).
Figure 3.
(A-C) Cardiovascular outcome of lipoprotein(a)-quartile population in a Kaplan-Meier survival model.
The results of univariate and multivariable Cox analyses of the association between Lp(a) level and CVD events are presented in Table 2. Every 5 mg/dL increase in Lp(a) level increased the CVD risk by 8% over a 10-year period (p = 0.014) independently of age, SBP, BMI, and LDL-C level. Sensitivity analysis also yielded generally consistent results with the primary analysis, even after excluding hypertension and diabetes (Supplemental Table 1-2). We then examined the ROC curve of Lp(a) values using a Youden index of 3 mg/dL. We found that an Lp(a) level of over 101 mg/dL may be suitable as a cutoff value to identify those at future high risk of CVD events in our cohort with a low risk according to FRS/SCORE scores (specificity = 92%, sensitivity = 0.6%; Table 3).
Table 2. Univariate and multivariable Cox analysis for association between lipoprotein(a) and cardiovascular events in a low risk healthy male population.
| Outcome/model | HR (95% CI) | p value |
| Coronary or ischemic events | Per 5 mg/dL | |
| Model 1: Unadjusted | 1.095 (1.029, 1.164) | 0.004* |
| Model 2: Age, SBP, BMI | 1.087 (1.020, 1.158) | 0.010* |
| Model 3: Further adjusted for LDL | 1.071 (1.003, 1.143) | 0.039* |
| Coronary events | Per 5 mg/dL | |
| Model 1: Unadjusted | 1.110 (1.043, 1.181) | 0.001* |
| Model 2: Age, SBP, BMI | 1.102 (1.033, 1.175) | 0.003* |
| Model 3: Further adjusted for LDL | 1.087 (1.017, 1.161) | 0.014* |
| Stroke events | Per 5 mg/dL | |
| Model 1: Unadjusted | 0.858 (0.558, 1.319) | 0.484 |
| Model 2: Age, SBP, BMI | 0.866 (0.573, 1.309) | 0.495 |
| Model 3: Further adjusted for LDL | 0.834 (0.533, 1.305) | 0.426 |
BMI, body mass index; CI, confidence interval; HR, hazard ratio; LDL, low-density lipoprotein; SBP, systolic blood pressure.
* p value < 0.05.
Table 3. Values of receiver operating characteristic curve (ROC curve).
| Lp(a) value | Sensitivity | Specificity |
| 3 (Best Youden index) | 81.1% (79.6-82.6) | 24% (22.4-25.6) |
| 30 | 12% (10.3-12.7) | 72% (70.3-73.7) |
| 50 | 5% (3.8-5.4) | 88% (86.8-89.2) |
| 70 | 2% (1.6-2.7) | 88% (86.8-89.2) |
| 101 (recommended cutoff level) | 0.6% (0.3-0.9) | 92% (91.0-93.0) |
DISCUSSION
This study is the first to report that a 5 mg/dL increase in Lp(a) level raises the future risk of CVD by 8% in low-risk healthy Taiwanese men. Circulating Lp(a) levels are genetically determined in more than 90% of individuals, and only slightly influenced by diet and environment.8 An association between CVD and abnormal Lp(a) level independent of LDL-C level is described in the CVD prevention strategies in European and American Heart Association guidelines.17,18 From the Emerging Risk Factors Collaboration, Danesh reported that the risk ratio for coronary heart disease (CHD) after adjusting for age and sex was 1.16 [95% confidence interval (CI): 1.11-1.22] per SD increase in Lp(a) level (a 3.5-fold higher concentration of Lp[a] than the normal 1.25 mg/dL), and that the risk ratio was 1.13 (95% CI: 1.09-1.18) in models adjusted for CVD risk factors and traditional lipids. Our data indicated the same effects but with a lower CHD risk in our Asian population compared with the Emerging Risk Factors Collaboration’s Western population.19
The INTERHEART study reported that among people worldwide, East Asian populations had the lowest Lp(a) levels, with a mean level of 7 mg/dL, and that an Lp(a) level of 50 mg/dL or higher was associated with higher CVD risk in an intermediate-risk population. Regarding primary prevention strategies, most guidelines suggest lifestyle modification only when LDL is under 116 mg/dL unless the patient is in a high or very high-risk group. However, Lp(a) level may also serve as a valuable guide for prevention. From the Fourier trial, O’Donoghue reported that Lp(a) level was an independent CVD risk factor in addition to LDL value, and that an Lp(a) level higher than 101 mg/dL (216 nmol/L) increased the MI risk by 28% over a 3-year follow-up period.20 However, all of these studies included patients with established CVD or an intermediate risk. Our study extends the prediction value of Lp(a) and its future pharmacologic intervention potential to a low-risk healthy population. In the ATTICA study, Kouvari reported that an Lp(a) level over 50 mg/dL was an independent CVD risk factor in healthy men but not women.21
Furthermore, although human genetic studies have indicated that Lp(a) level is related to the risk of CHD, randomized therapy trials have not provided evidence that lowering Lp(a) level reduces the CHD risk. Burgess reported that a large absolute reduction in Lp(a) level of approximately 100 mg/dL may be required to induce a clinically meaningful reduction in the risk of CHD.22 In our study, the Youden index was lower than that used in previous studies reporting that Lp(a) is correlated with future CVD risk independent of LDL level in a low-risk male population. However, in clinical practice, we suggest that an Lp(a) level > 101 mg/dL may be a useful as a CVD risk predictor (over 92% specificity), enabling doctors to identify the CVD risk in traditionally low-risk male patients. Further drug interventions in addition to lifestyle modifications should be considered. Finally, we also studied a female population in the health checkup cohort and found a nonsignificant correlation between Lp(a) level and CVD events/risk. However, the low number of events could have been the result of bias or ethnic differences and, therefore, further investigations are required (Supplementary Figure 2).
Limitations
This study has several limitations. First, this was a retrospective observational study based on data from a tertiary hospital database. Therefore, a substantial number of events were likely missing from our data due to some participants not attending follow-up visits at our hospital. The true incidence of events is also unclear due to the limited cohort size and may actually be higher. Further prospective studies with a longer follow-up period are required to verify our findings. Second, the overall number of events was limited, and the Kaplan-Meier and ROC curves did not ideally reflect our predictions. This is likely due to our use of a clinically healthy population. Another explanation may be moderate discrimination present in CVD risk prediction when using the FRS or SCORE in Asian populations; the overestimation of CVD risk has been found to be more likely in Asian cohorts than in those from other regions.23,24 Third, the lack of correlation of Lp(a) level with an atherosclerosis marker (baPWV) and in the female population may have been due to the low-risk population investigated. However, our findings indicate that Lp(a) is a key indicator of future CVD risk, even in a low-risk male population, and longer follow-up data may be required to confirm this in a female population. Finally, although a normal Lp(a) level is 30 mg/dL, a risk cutoff value for abnormal Lp(a) has not yet been established, with studies reporting cutoff values of 30, 50, and 70 mg/dL.22,25,26 Establishing an ideal cutoff value for a clinical biomarker is difficult, especially in low-risk populations. However, specificity of over 90% may be acceptable.27 Tsimikas et al. published a phase II Lp(a) drug trial that used an Lp(a) level cutoff of 60 mg/dL in a population with established CVD.28 In our study, an Lp(a) level of 101 mg/dL was considered an ideal cutoff marker for predicting future CVD events in a low-risk male population. In addition, these findings reinforce the potential of Lp(a) in CVD prevention strategies in Asian populations. Further studies are warranted to address the limitations of the present research.
CONCLUSIONS
Elevated Lp(a) level may be a CAD risk factor, even in a low-risk male population (as indicated by FRS/SCORE scores).
Acknowledgments
We thank Chris Kao for providing statistical assistance during the completion of this manuscript. This manuscript was edited by Wallace Academic Editing.
AUTHOR CONTRIBUTIONS
YS Lin and PH Chu conceived and designed the study. YW Cheng and YS Lin collected the data and contributed the tools for analysis. YW Cheng, YS Lin, YC Huang, YW Kao, and VC Wu performed the analysis. YS Lin and YW Cheng wrote the manuscript. Critical readings were performed by CP Lin and VC Wu.
FUNDING
This work was supported by Chang Gung Memorial Hospital, Taipei, Taiwan (Grant Nos. CMRPG5D0101, CMRPG5H0221, and CMRPG5F0011). The funding source had no role in the design or conduct of the study; in the collection, analysis, or interpretation of the data; or in the preparation, review, or approval of the manuscript.
DATA AVAILABILITY STATEMENT
Data from this study are contained within this article.
DECLARATION OF CONFLICT OF INTEREST
All the authors declare no conflict of interest.
REFERENCES
- 1.Yusuf S, Hawken S, Ounpuu S, et al. Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study. Lancet. 2004;364:937–952. doi: 10.1016/S0140-6736(04)17018-9. [DOI] [PubMed] [Google Scholar]
- 2.Ko T, Yang CH, Mao CT, et al. Effects of national hospital accreditation in acute Coronary syndrome on in-hospital mortality and clinical outcomes. Acta Cardiol Sin. 2020;36:416–427. doi: 10.6515/ACS.202009_36(5).20200421A. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 3.Nordestgaard BG, Langsted A. Lipoprotein(a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res. 2016;57:1953–1975. doi: 10.1194/jlr.R071233. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 4.Kamstrup PR, Benn M, Tybjaerg-Hansen A, et al. Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study. Circulation. 2008;117:176–184. doi: 10.1161/CIRCULATIONAHA.107.715698. [DOI] [PubMed] [Google Scholar]
- 5.Cekici Y, Kilic S, Ovayolu A, et al. Prediction of lipoprotein-associated phospholipase A2 and inflammatory markers in subclinical atherosclerosis in premature ovarian failure patients. Acta Cardiol Sin. 2021;37:30–37. doi: 10.6515/ACS.202101_37(1).20200730A. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 6.Rosengren A, Wilhelmsen L, Eriksson E, et al. Lipoprotein(a) and coronary heart disease: a prospective case-control study in a general population sample of middle aged men. BMJ. 1990;301:1248–1251. doi: 10.1136/bmj.301.6763.1248. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 7.Nordestgaard BG, Chapman MJ, Ray K, et al. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010;31:2844–2853. doi: 10.1093/eurheartj/ehq386. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 8.Willeit P, Ridker PM, Nestel PJ, et al. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018;392:1311–1320. doi: 10.1016/S0140-6736(18)31652-0. [DOI] [PubMed] [Google Scholar]
- 9.Pare G, Caku A, McQueen M, et al. Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups. Circulation. 2019;139:1472–1482. doi: 10.1161/CIRCULATIONAHA.118.034311. [DOI] [PubMed] [Google Scholar]
- 10.Saeed A, Virani SS. Lipoprotein(a) and cardiovascular disease: current state and future directions for an enigmatic lipoprotein. Front Biosci (Landmark Ed) 2018;23:1099–1112. doi: 10.2741/4635. [DOI] [PubMed] [Google Scholar]
- 11.Nam JS, Jo S, Kang S, et al. Association between lipoprotein(a) and nonalcoholic fatty liver disease among Korean adults. Clin Chim Acta. 2016;461:14–18. doi: 10.1016/j.cca.2016.07.003. [DOI] [PubMed] [Google Scholar]
- 12.Yang MH, Son HJ, Sung JD, et al. The relationship between apolipoprotein E polymorphism, lipoprotein(a) and fatty liver disease. Hepatogastroenterology. 2005;52:1832–1835. [PubMed] [Google Scholar]
- 13.Lee HF, Wu CE, Lin YS, et al. Low bone mineral density may be associated with long-term risk of cancer in the middle-aged population: a retrospective observational study from a single center. J Formos Med Assoc. 2018;117:339–345. doi: 10.1016/j.jfma.2017.04.021. [DOI] [PubMed] [Google Scholar]
- 14.Tsai SS, Lin YS, Chen ST, et al. Metabolic syndrome positively correlates with the risks of atherosclerosis and diabetes in a Chinese population. Eur J Intern Med. 2018;54:40–45. doi: 10.1016/j.ejim.2018.04.009. [DOI] [PubMed] [Google Scholar]
- 15.Saverymuttu SH, Joseph AE, Maxwell JD. Ultrasound scanning in the detection of hepatic fibrosis and steatosis. Br Med J (Clin Res Ed) 1986;292:13–15. doi: 10.1136/bmj.292.6512.13. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 16.Chen LW, Chien CH, Kuo SF, et al. Low vitamin D level was associated with metabolic syndrome and high leptin level in subjects with nonalcoholic fatty liver disease: a community-based study. BMC Gastroenterol. 2019;19:126. doi: 10.1186/s12876-019-1040-y. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 17.Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the management of blood cholesterol: a report of the American College of Cardiology/American Heart Association Task Force on clinical practice guidelines. J Am Coll Cardiol. 2019;73:e285–e350. doi: 10.1016/j.jacc.2018.11.003. [DOI] [PubMed] [Google Scholar]
- 18.Mach F, Baigent C, Catapano AL, et al. 2019 ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2019 doi: 10.1093/eurheartj/ehz455. [DOI] [PubMed] [Google Scholar]
- 19.Emerging Risk Factors C. Erqou S, Kaptoge S, et al. Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality. JAMA. 2009;302:412–423. doi: 10.1001/jama.2009.1063. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 20.O'Donoghue ML, Fazio S, Giugliano RP, et al. Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk. Circulation. 2019;139:1483–1492. doi: 10.1161/CIRCULATIONAHA.118.037184. [DOI] [PubMed] [Google Scholar]
- 21.Kouvari M, Panagiotakos DB, Chrysohoou C, et al. Lipoprotein(a) and 10-year cardiovascular disease incidence in apparently healthy individuals: a sex-based sensitivity analysis from ATTICA Cohort Study. Angiology. 2019;70:819–829. doi: 10.1177/0003319719854872. [DOI] [PubMed] [Google Scholar]
- 22.Burgess S, Ference BA, Staley JR, et al. Association of LPA variants with risk of coronary disease and the implications for lipoprotein(a)-lowering therapies: a Mendelian randomization analysis. JAMA Cardiol. 2018;3:619–627. doi: 10.1001/jamacardio.2018.1470. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 23.Chia YC, Gray SY, Ching SM, et al. Validation of the Framingham general cardiovascular risk score in a multiethnic Asian population: a retrospective cohort study. BMJ Open. 2015;5:e007324. doi: 10.1136/bmjopen-2014-007324. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 24.Chia YC, Lim HM, Ching SM. Validation of the pooled cohort risk score in an Asian population - a retrospective cohort study. BMC Cardiovasc Disord. 2014;14:163. doi: 10.1186/1471-2261-14-163. [DOI] [PMC free article] [PubMed] [Google Scholar]
- 25.Klose G, Beil FU, Dieplinger H, et al. New AHA and ACC guidelines on the treatment of blood cholesterol to reduce atherosclerotic cardiovascular risk. Wien Klin Wochenschr. 2014;126:169–175. doi: 10.1007/s00508-014-0513-9. [DOI] [PubMed] [Google Scholar]
- 26.Tsimikas S. A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies. J Am Coll Cardiol. 2017;69:692–711. doi: 10.1016/j.jacc.2016.11.042. [DOI] [PubMed] [Google Scholar]
- 27.Nakata K, Komukai K, Yoshii Y, et al. The optimal cut-off value of plasma BNP to differentiate heart failure in the emergency department in Japanese patients with dyspnea. Intern Med. 2015;54:2975–2980. doi: 10.2169/internalmedicine.54.4786. [DOI] [PubMed] [Google Scholar]
- 28.Tsimikas S, Karwatowska-Prokopczuk E, Gouni-Berthold I, et al. Lipoprotein(a) reduction in persons with cardiovascular disease. N Engl J Med. 2020;382:244–255. doi: 10.1056/NEJMoa1905239. [DOI] [PubMed] [Google Scholar]
Associated Data
This section collects any data citations, data availability statements, or supplementary materials included in this article.
Data Availability Statement
Data from this study are contained within this article.