Article ID: CJ-24-0242
Background: Because apolipoprotein-A2 (ApoA2), a key component of high-density lipoprotein cholesterol (HDL-C), lacks clear clinical significance, we investigated its impact on cardiovascular events in patients undergoing percutaneous coronary intervention (PCI).
Methods and Results: We examined 638 patients who underwent PCI with a new-generation drug-eluting stent for acute or chronic coronary syndrome and had their apolipoprotein levels measured between 2016 and 2021. The patients were divided into 2 groups based on the median serum ApoA2 values, and the incidence of major adverse cardiovascular events (MACE) was assessed. Of the 638 patients, 563 (88%) received statin treatment, with a median serum LDL-C level of 93 mg/dL. Furthermore, 137 patients (21.5%) experienced MACE, and Kaplan-Meier analysis revealed that the higher ApoA2 group had a significantly lower incidence of MACE than the lower ApoA2 group (30.9% vs. 41.6%). However, the other apolipoproteins, including ApoA1, ApoB, ApoC2, ApoC3, and ApoE, showed no significant differences in MACE. Multivariable Cox hazard analysis indicated that ApoA2 was an independent predictor of MACEs (hazard ratio, 0.666; 95% confidence interval, 0.465–0.954). Furthermore, ApoA2 levels exhibited the strongest inverse association with high-sensitivity C-reactive protein levels (rs=−0.479).
Conclusions: Among all the apolipoproteins, the serum ApoA2 level may be the strongest predictor of future cardiovascular events and prognosis in patients undergoing PCI.
Therapy to lower low-density lipoprotein cholesterol (LDL-C) levels, primarily statins, has significantly contributed to effective primary and secondary prevention of coronary artery disease (CAD). Current guidelines for lipid-lowering therapy for patients undergoing percutaneous coronary intervention (PCI) recommend a therapeutic LDL-C goal <100 mg/dL or <70 mg/dL in high-risk patients, such as those with acute coronary syndrome (ACS), diabetes mellitus or polyvascular disease.1,2 Recently, proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitors3,4 have become a powerful addition to statins and ezetimibe5 to achieve these therapeutic targets, as they are known to increase LDL receptors and lower serum LDL-C levels.6 However, some patients have recurrent cardiovascular events even when the LDL-C level is sufficiently lowered, which demonstrates the importance of elucidating residual risk and further strategies beyond LDL-C lowering therapy.
The apolipoproteins comprise lipoproteins, such as chylomicrons, chylomicron remnants, very-low-density lipoprotein cholesterol, intermediate-density lipoprotein cholesterol, LDL-C, high-density lipoprotein cholesterol (HDL-C), and lipoprotein-(a) [LP-(a)]. They act as structural components, ligands for cellular receptor binding, and enzyme activators or inhibitors.7 Apolipoproteins A1 (ApoA1), A2 (ApoA2), B (ApoB), C2 (ApoC2), C3 (ApoC3) and E (ApoE) are representative and although numerous studies have investigated the association between these lipoproteins and atherosclerosis, reports on ApoA2 are much fewer than for the other lipoproteins. ApoA1 and ApoA2 are structural and functional apolipoproteins of HDL-C, with ApoA2 being the second major apolipoprotein that constitutes HDL-C particles, following ApoA1.8 HDL-C can be divided into 2 main subfractions: those containing only ApoA1 (known as LpA-I), and those with both apoA1 and apoA2 (known as LpA-I/A-II).9,10 Although much basic and clinical research has focused on HDL-C subfractions, the differences in these fractions are not fully understood. In particular, the clinical effect of ApoA2 on future cardiovascular events in patients who have undergone PCI remains unclear. Therefore, in this study we evaluated the impact of ApoA2 on future cardiovascular risk in patients with secondary prevention for CAD in the LDL-C-lowering therapy era.
This single-center, observational, retrospective cohort study enrolled 1,006 consecutive patients who underwent their first PCI at Niigata University Medical and Dental Hospital between January 2016 and December 2021. The inclusion criteria were patients who underwent PCI with a newer-generation drug-eluting stent (DES) for ACS or chronic coronary syndrome (CCS). A new-generation DES included both durable polymer stents, such as Xience (Abbot Vascular, IL, USA) and Resolute (Medtronic, MN, USA), and biodegradable polymer stents, such as Synergy (Boston Scientific, CA, USA) and Ultimaster (Terumo, Tokyo, Japan).11 Patients were excluded if their apolipoprotein levels had not been measured (n=165) or they died in the hospital (n=4). The remaining 638 patients were included in the analysis and divided into 2 groups based on the median serum ApoA2 values: <24 mg/dL (n=318; lower group) and value ≥24 mg/dL (n=320; higher group) (Figure 1).
Flowchart of patient selection for the study. ApoA2, apolipoprotein-A2; PCI, percutaneous coronary intervention.
This study complied with the Declaration of Helsinki, and the Ethics Committee of Niigata University approved the study, from which all patients had the opportunity to opt out.
Data Collection and DefinitionsPatient characteristics were collected from hospital charts. Blood samples were collected during morning fasting before elective PCI for patients with CCS, and during morning fasting several days after emergency PCI for patients with ACS, and the following parameters were measured: LDL-C level by direct method; apolipoproteins and lipoprotein-(a) by turbidimetric immunoassay via external laboratory (BML, Tokyo, Japan); high-sensitivity C-reactive protein (hs-CRP) by nephelometry via BML; remnant-like particle-cholesterol by enzyme method via external laboratory (LSI Medience, Tokyo, Japan); fatty acid fraction by liquid chromatography-tandem mass spectrometry via LSI Medience.
Comorbidities were defined as follows: hypertension=blood pressure >140/90 mmHg or treatment with antihypertensive drugs;12 dyslipidemia=LDL-C >140 mg/dL or HDL-C <40 mg/dL or triglyceride >150 mg/dL or treatment with statin therapy;13 diabetes mellitus=both plasma glucose level and HbA1c of the diabetic type or treatment with glucose-lowering agents or insulin therapy;14 family history=any first-degree relative with cardiovascular disease; and obesity=body mass index >25 kg/m2.
The incidence of all-cause death and major adverse cardiovascular events (MACE), including cardiovascular death, nonfatal ACS, ischemic stroke, heart failure exacerbation, and any repeat revascularization, was assessed. Repeat revascularization was defined as PCI or coronary bypass surgery for target lesion revascularization or new lesion. Clinical follow-up data after the first intervention were collected from patients’ medical records or by contacting the patients or their families.
Statistical AnalysisData are expressed as mean±standard deviation or number (%) or median (interquartile ranges) if the data did not have a normal distribution. The patients’ baseline clinical characteristics were tested using the Mann-Whitney U test and Fisher’s exact test, as appropriate. Kaplan-Meier analysis for the cumulative incidence of MACE was used to compare groups based on the median ApoA2 levels, and differences between groups were assessed using the log-rank test. The risk of an incident was evaluated by hazard ratios (HRs) and their 95% confidence intervals (CI) using Cox proportional hazard models. In the multivariable Cox hazards model, covariates were selected based on a criterion of one-tenth of the number of incidents and those known as cardiovascular risk factors in the literature and from a medical perspective. All probabilities were expressed as two-sided values and considered statistically significant at P<0.05. All data were analyzed using JMP (version 17.0.0) for Macintosh (SAS Institute, Cary, NC, USA).
The patients’ baseline clinical characteristics and plasma lipid measurements are shown in Table 1. The median age was 71 years, and 78% were male. Overall, 88% received statin therapy, 26% were taking ezetimibe, and 1.4% received PCSK9 inhibitors. The median serum LDL-C value was 93 mg/dL, and 43 mg/dL for HDL-C value; 130 patients (20.4%) had LDL-C values <70 mg/dL. The prevalence of smoking was 67%, hypertension was 74%, dyslipidemia was 61%, diabetes mellitus was 41%, family history was 13%, obesity was 28%, and dialysis was 7%.
Patient’s Baseline Clinical Characteristics
| Overall (n=638) |
Lower ApoA2 group (n=318) |
Higher ApoA2 group (n=320) |
P value (lower vs. higher) |
|
|---|---|---|---|---|
| Clinical characteristics | ||||
| Age, years | 71 [64, 78] | 73 [67, 80] | 70 [62, 76] | <0.001 |
| Male, n (%) | 499 (78%) | 243 (76%) | 256 (80%) | 0.292 |
| ACS, n (%) | 273 (43%) | 155 (49%) | 118 (37%) | 0.003 |
| Multivessel, n(%) | 301 (47%) | 172 (54%) | 129 (40%) | <0.001 |
| Cre, mg/dL | 0.89 [0.74, 1.12] | 0.94 [0.75, 1.3] | 0.84 [0.71, 1.03] | <0.001 |
| eGFR, mL/min/1.73 m2 | 62 [45, 78] | 57 [39, 76] | 67 [54, 79] | <0.001 |
| Hb, g/dL | 13.1 [11.7, 14.4] | 12.3 [11.1, 13.9] | 13.6 [12.6, 14.8] | <0.001 |
| HbA1c, % | 6.1 [5.8, 6.8] | 6.1 [5.7, 6.8] | 6.1 [5.8, 6.7] | 0.742 |
| LVEF, % | 58 [46.3, 66.5] | 55.1 [43.7, 65.4] | 60.4 [49.7, 67.4] | <0.001 |
| TG, mg/dL | 103 [76, 140] | 98 [73, 133] | 111 [81, 148] | 0.002 |
| LDL-C, mg/dL | 93 [73, 118] | 92 [73, 117] | 94 [74, 120] | 0.362 |
| HDL-C, mg/dL | 43 [35, 51] | 38 [32, 46] | 47 [40, 56] | <0.001 |
| RLP-C, mg/dL | 4.1 [2.7, 6.0] | 3.6 [2.4, 5.5] | 4.4 [3.0, 6.7] | <0.001 |
| LP-(a), mg/dL | 16.5 [8.8, 30.1] | 17.3 [9.4, 29.9] | 15.5 [7.6, 30.2] | 0.375 |
| EPA/AA ratio | 0.34 [0.23, 0.5] | 0.33 [0.22, 0.49] | 0.34 [0.23, 0.51] | 0.160 |
| Apolipoprotein | ||||
| ApoA1, mg/dL | 116 [101, 134] | 105 [91, 118] | 128 [116, 144] | <0.001 |
| ApoA2, mg/dL | 24 [20.5, 27.3] | 20.5 [18.4, 22.3] | 27.3 [25.7, 30.3] | <0.001 |
| ApoB, mg/dL | 80 [68, 96] | 79 [66, 96] | 82 [70, 97] | 0.062 |
| ApoC2, mg/dL | 3.7 [2.7, 4.8] | 3.2 [2.5, 4.3] | 4.1 [3.3, 5.4] | <0.001 |
| ApoC3, mg/dL | 8.3 [6.8, 10.7] | 7.6 [6.1, 9.8] | 9.2 [7.6, 11.9] | <0.001 |
| ApoE, mg/dL | 3.7 [3.1, 4.5] | 3.5 [2.9, 4.3] | 3.9 [3.4, 4.6] | <0.001 |
| LDL-C/ApoB ratio | 1.14 [1.02, 1.27] | 1.14 [1.02, 1.29] | 1.13 [1.03, 1.26] | 0.685 |
| HDL-C/ApoA1 ratio | 0.36 [0.33, 0.4] | 0.36 [0.33, 0.4] | 0.37 [0.33, 0.4] | 0.509 |
| ApoA1/ApoB ratio | 0.69 [0.55, 0.88] | 0.74 [0.61, 0.95] | 0.64 [0.51, 0.82] | <0.001 |
| Comorbidities | ||||
| Smoking, n (%) | 425 (67%) | 201 (63%) | 224 (70%) | 0.078 |
| Hypertension, n (%) | 475 (74%) | 242 (76%) | 233 (73%) | 0.364 |
| Dyslipidemia, n (%) | 390 (61%) | 164 (51%) | 226 (71%) | <0.001 |
| Diabetes mellitus, n (%) | 263 (41%) | 139 (44%) | 124 (39%) | 0.228 |
| Family history, n (%) | 84 (13%) | 36 (11%) | 48 (15%) | 0.198 |
| Obesity, n (%) | 181 (28%) | 86 (27%) | 95 (30%) | 0.483 |
| Dialysis, n (%) | 44 (7%) | 28 (9%) | 16 (5%) | 0.062 |
| Medications | ||||
| Statin, n (%) | 563 (88%) | 263 (83%) | 300 (94%) | <0.001 |
| Ezetimibe, n (%) | 164 (26%) | 73 (23%) | 91 (28%) | 0.124 |
| PCSK9 inhibitor, n (%) | 9 (1.4%) | 4 (1.2%) | 5 (1.5%) | >0.999 |
| ACE-i/ARB, n (%) | 453 (71%) | 234 (73%) | 219 (68%) | 0.163 |
| β-blocker, n (%) | 371 (58%) | 195 (61%) | 176 (55%) | 0.109 |
| CCB, n (%) | 253 (39%) | 123 (38%) | 130 (40%) | 0.628 |
Data are presented as mean±SD or n (%) or median [25th; 75th]. P, Lower ApoA2 group vs. Higher ApoA2 group (Mann-Whitney U test and Fisher’s exact test). ACE-i, angiotensin-converting enzyme inhibitor; ACS, acute coronary syndrome; ApoA1, apolipoprotein-A1; ApoA2, apolipoprotein-A2; ApoB, apolipoprotein-B; ApoC2, apolipoprotein-C2; ApoC3, apolipoprotein-C3; ApoE, apolipoprotein-E; ARB, angiotensin II receptor blocker; CCB, calcium-channel blocker; Cre, creatinine; eGFR, estimated glomerular filtration rate; EPA/AA, eicosapentaenoic acid to arachidonic acid ratio; Hb, hemoglobin; HbA1c, hemoglobin A1c; HDL-C, high-density lipoprotein cholesterol; LDL-C, low-density lipoprotein cholesterol; LP-(a), lipoprotein (a); LVEF, left ventricular ejection fraction; Multivessel, multivessel disease; PCSK9, proprotein convertase subtilisin/kexin type 9; RLP-C, remnant-like lipoprotein cholesterol; TG, triglyceride.
The higher ApoA2 group was significantly younger, had a lower ratio of ACS and multivessel disease, lower creatinine levels, and higher left ventricular ejection fraction, hemoglobin level, proportion of dyslipidemia, and statin administration. Regarding lipid profiles, the higher ApoA2 group had significantly higher blood levels of HDL-C, triglyceride, remnant-like lipoprotein cholesterol, ApoA1, ApoC2, ApoC3, ApoE, and ApoA1:ApoB ratio than the lower ApoA2 group.
ApoA2 as a Predictive Factor for MACEThe median follow-up duration was 532 days (interquartile range, 334–1,005 days), and 137 patients (21.5%) experienced MACE, including 8 cardiovascular deaths (1.2%), nonfatal ACS in 21 patients (3.3%), ischemic stroke in 11 patients (1.7%), heart failure exacerbation in 21 patients (3.3%), and any repeat revascularization in 83 patients (13%) during the follow-up; 53 patients (8.3%) died of any cause, including cardiovascular death in 8 patients (1.2%), cancer in 14 patients (2.2%), infection in 8 patients (1.2%), and stroke in 4 patients (0.6%).
Kaplan-Meier analysis showed that the cumulative incidence rate of MACE was significantly lower in the higher ApoA2 group than in the lower ApoA2 group (30.9% vs. 41.6%, log-rank test, P=0.031) (Figure 2A). The main factors contributing to the difference in MACE were cardiovascular death, heart failure exacerbation, and ischemic stroke. Furthermore, the Kaplan-Meier curves for all-cause death in the higher ApoA2 group were significantly lower than those in the lower ApoA2 group (9.8% vs. 24.3%, log-rank test, P=0.002) (Figure 2B). Cardiovascular death contributed to the difference in all-cause death. However, the Kaplan-Meier curves for only ischemic cardiovascular events, including nonfatal ACS and any repeat revascularization, between the 2 groups according to serum ApoA2 levels were not significantly different (25.4% vs. 28.3%, log-rank test, P=0.660) (Figure 2C). The other apolipoproteins, including ApoA1, ApoB, ApoC2, ApoC3, and ApoE, showed no significant difference in MACE between the 2 groups classified according to the median value of each serum apolipoprotein (Supplementary Figure 1).
Kaplan-Meier curves for the cumulative incidence of (A) MACE, (B) all-cause of death, and (C) ischemic cardiovascular events between the higher and lower ApoA2 groups. ApoA2, apolipoprotein-A2; MACE, major adverse cardiovascular events.
The results of the Cox hazard analysis are shown in Table 2. Multivariable Cox hazard analysis indicated that ApoA2 level (HR, 0.666; 95% CI, 0.465–0.954; P=0.026) and multivessel disease (HR, 1.501; 95% CI, 1.058–2.129; P=0.022) were independent predictors of MACE.
Univariable and Multivariable Cox Hazard Analysis of MACE
| Univariable analysis | Multivariable analysis | |||||
|---|---|---|---|---|---|---|
| HR | 95% CI | P value | HR | 95% CI | P value | |
| Clinical characteristics | ||||||
| Age, 1-year increase | 1.002 | 0.986–1.019 | 0.781 | 0.996 | 0.979–1.014 | 0.675 |
| Male | 1.381 | 0.889–2.147 | 0.150 | 1.440 | 0.886–2.339 | 0.140 |
| ACS | 0.838 | 0.593–1.183 | 0.315 | |||
| Multivessel | 1.590 | 1.132–2.233 | 0.007 | 1.501 | 1.058–2.129 | 0.022 |
| HbA1c | 1.063 | 0.760–1.485 | 0.722 | |||
| LVEF | 0.709 | 0.506–0.994 | 0.465 | |||
| TG | 1.009 | 0.722–1.411 | 0.956 | |||
| LDL-C | 0.729 | 0.520–1.022 | 0.068 | 0.891 | 0.579–1.369 | 0.598 |
| HDL-C | 0.920 | 0.656–1.290 | 0.630 | |||
| RLP-C | 0.976 | 0.697–1.368 | 0.890 | |||
| LP-(a) | 0.867 | 0.620–1.213 | 0.405 | |||
| EPA/AA ratio | 0.915 | 0.652–1.282 | 0.605 | |||
| Apolipoprotein | ||||||
| ApoA1 | 0.852 | 0.610–1.192 | 0.351 | |||
| ApoA2 | 0.691 | 0.494–0.968 | 0.032 | 0.666 | 0.465–0.954 | 0.026 |
| ApoB | 0.715 | 0.510–1.002 | 0.051 | 0.706 | 0.453–1.101 | 0.125 |
| ApoC2 | 1.052 | 0.751–1.473 | 0.768 | 0.719 | 0.603–1.416 | 0.719 |
| ApoC3 | 1.263 | 0.898–1.776 | 0.180 | 1.386 | 0.909–2.114 | 0.128 |
| ApoE | 1.238 | 0.884–1.734 | 0.214 | 1.385 | 0.944–2.031 | 0.095 |
| Comorbidities | ||||||
| Smoking | 1.174 | 0.812–1.697 | 0.393 | 1.140 | 0.764–1.701 | 0.519 |
| Hypertension | 1.727 | 1.111–2.683 | 0.015 | 1.565 | 0.999–2.450 | 0.050 |
| Dyslipidemia | 1.101 | 0.775–1.564 | 0.591 | 1.223 | 0.844–1.773 | 0.285 |
| Diabetes mellitus | 1.296 | 0.926–1.813 | 0.130 | 1.124 | 0.795–1.589 | 0.507 |
| Obesity | 1.138 | 0.796–1.625 | 0.478 | |||
| Medications | ||||||
| Statin | 0.780 | 0.463–1.315 | 0.352 | |||
| Ezetimibe | 0.863 | 0.578–1.289 | 0.472 | |||
CI, confidence interval; HR, hazard ratio. Other abbreviations as in Table 1.
Correlation Between Apolipoproteins or Lipoprotein and hs-CRP Levels
Scatter plots of plasma HDL-C and ApoA1 or ApoA2 are shown in Supplementary Figure 2. Spearman analysis showed that ApoA2 had a weakly positive association with HDL-C levels, but ApoA1 had a strong association with HDL-C levels. Correlations between hs-CRP and age, HbA1c, lipoproteins, and apolipoproteins are shown in Table 3. ApoA2 levels exhibited the strongest inverse association with hs-CRP levels (rs=−0.479; P<0.001). HDL-C and ApoA1 demonstrated a weaker inverse correlation with hs-CRP than ApoA2 (HDL-C: rs=−0.231, P<0.001; ApoA1: rs=−0.425, P<0.001).
Spearman Analysis of Relationship Between Cardiovascular Risk Factors and hs-CRP
| hs-CRP | ||
|---|---|---|
| rs | P value | |
| Clinical characteristics | ||
| Age | −0.013 | 0.783 |
| HbA1c | −0.068 | 0.151 |
| TG | −0.027 | 0.561 |
| LDL-C | 0.161 | <0.001 |
| HDL-C | −0.231 | <0.001 |
| RLP-C | −0.148 | <0.001 |
| LP-(a) | 0.170 | <0.001 |
| EPA/AA ratio | −0.161 | <0.001 |
| Apolipoprotein | ||
| ApoA1 | −0.425 | <0.001 |
| ApoA2 | −0.479 | <0.001 |
| ApoB | 0.112 | 0.017 |
| ApoC2 | −0.048 | 0.309 |
| ApoC3 | −0.152 | 0.001 |
| ApoE | 0.011 | 0.817 |
hs-CRP, high-sensitivity C-reactive protein; rs, Spearman’s rank correlation coefficient. Other abbreviations as in Table 1.
This study evaluating the relationship between lipid-related factors and MACE in patients who underwent PCI and mostly received lipid-lowering therapy demonstrated that a lower ApoA2 level was the strongest predictor of future cardiovascular event risk compared with other apolipoproteins: ApoA1, ApoB, ApoC2, ApoC3, and ApoE. The finding that the ApoA2 level showed the strongest inverse correlation with the hs-CRP level indicated that ApoA2 has antiatherogenic and anti-inflammatory effects. Although numerous studies have shown a relationship between cardiovascular risk and lipoproteins, the number of studies focusing on ApoA2 has been fewer than for other lipoproteins, and the clinical significance of ApoA2 is not fully understood. Furthermore, as the blood levels of almost all lipoproteins are affected by LDL-C lowering therapy, studies that investigated healthy individuals have shown different results from those focusing on individuals who need therapy for atherosclerosis. To the best of our knowledge, this is the first report to demonstrate the clinical impact of ApoA2 on patients with secondary prevention after PCI, reflecting clinical practice in the LDL-C lowering therapy era.
The correlation between ApoA2 and CAD risk remains controversial. Several case–control studies have demonstrated an inverse relationship between plasma ApoA2 levels and myocardial infarction (MI).15,16 In a prospective study involving healthy subjects, Birjmohun et al reported that low serum ApoA2 levels were strongly associated with future CAD.17 In patients with diabetes mellitus, blood ApoA2 levels have been reported to be a predictor of CAD.18 Conversely, other studies have suggested no relationship between blood ApoA2 levels and CAD.19,20 Furthermore, genetic abnormalities that decrease blood ApoA2 levels have been shown not to be related to CAD.21,22 In addition, as many of these studies predate the statin era, the characteristics of the subjects differed from those in the present study. In our study, ApoA2 was the only lipoprotein significantly associated with MACE in the patient population, with 88% receiving statin therapy and having an average LDL-C level of 100 mg/dL. Our findings showed that blood ApoB levels, which have been established as a strong risk factor for CAD among apolipoproteins,6,23 were not associated with MACE. Rather, lower ApoB levels tended to be related to a higher incidence of MACE. ApoB is greatly reduced with LDL-C lowering therapy, which may have been affected by our practice for high-risk patients, such as those with ACS and multivessel disease who receive more aggressive medical therapy (e.g., adding ezetimibe or PCSK9 inhibitors).
It is noteworthy that the factors contributing to the difference in MACE were all-cause death, heart failure exacerbation, and ischemic stroke. However, no difference in the occurrence of MI or revascularization was observed. Klobučar et al also demonstrated that low ApoA2 levels were associated with poor prognosis at 1 year in patients with heart failure.24 In our results, the ratio of multivessel lesions was significantly higher in the lower ApoA2 group, which suggests that heart failure is associated with the severity of CAD. Furthermore, Duscheck et al reported that high ApoA2 levels were a favorable prognostic factor in patients after carotid endarterectomy.25 These findings suggest that lower ApoA2 levels reflect systemic vascular inflammation, leading to multivessel CAD or polyvascular disease, rather than focal plaque progression. The importance of addressing inflammation is attracting attention because even patients who achieve a very low LDL-C level can still demonstrate significant residual risk.26 Our result that ApoA2 and hs-CRP showed relatively the strongest inverse correlation may support the concept that ApoA2 reflects the severity and prognosis of systemic atherosclerosis in the context of chronic inflammation.
The major function of ApoA2 is related to HDL-C remodeling and cholesterol efflux. Low HDL cholesterolemia is an important risk factor for CAD. Although the interventions to affect HDL-C have been expected to prevent further cardiovascular events, medicines for increasing blood HDL-C levels, such as nicotinic acid fibrates and cholesteryl ester transfer protein (CETP) inhibitors, have not shown better clinical outcomes when LDL-C is adequately controlled with standard statin therapy.27–29 However, recent findings have demonstrated that HDL-C is important not only in terms of quantity but also in terms of quality. HDL-C has subfractions containing only ApoA1 (LpA-I) or both ApoA1 and ApoA2 (LpA-I/A-II). Consistent with this fact, our results revealed that ApoA1 showed a strong correlation with total HDL-C concentration, including both LpA-I and LpA-I/A-II. In contrast, the correlation between ApoA2 and HDL-C levels was weak. Because ApoA2 is only present in LpA-I/LpA-II HDL-C, it is thought that the concentration of ApoA2 provides a robust measure of the number of LpA-I/LpA-II particles.17 Although the functional difference among these subfractions is not fully understood, it has been reported that LpA-I/LpA-II demonstrated higher cholesterol efflux capacity than LpA-I.30–32 The lower cholesterol efflux capacity of HDL-C was reported as an independent cardiovascular event risk.33 Because ApoA2 interacts with ABCA1, an important transporter for cholesterol efflux from macrophages, it may be reasonable that LpA-I/LpA-II HDL-C has a higher cholesterol efflux capacity than LpA-I.34 Thus, the mechanism underlying the antiatherosclerotic effect of ApoA2 may be related to the fact that ApoA2 reflects the presence of high-quality and functional HDL-C. Our findings support the importance of focusing on high-quality HDL-C through ApoA2 beyond the total HDL-C concentration.
Interestingly, our results demonstrated that ApoA2 inversely correlated with hs-CRP and showed a higher correlation coefficient than ApoA1. Several reports have shown the anti-inflammatory effects of HDL-C through its interaction with immune cells.35 HDL-C suppresses the expression of adhesion molecules on monocytes and inhibits their recruitment into the vessel wall.36,37 HDL-C also promotes the differentiation of monocytes into M2 macrophages and contributes to the expression of anti-inflammatory cytokines.36,38,39 Moreover, it has been reported that inhibition of activating transcription factor (ATF3) expression, one of the key molecules in downstream signaling of toll-like receptor, suppresses inflammatory signals in macrophages.40 However, whether there is a difference in anti-inflammatory effect between ApoA1 and ApoA2 or between LpA-I and LpA-I/LpA-II is unknown. Our findings indicated that LpA-I/LpA-II, which contains ApoA2 HDL-C, has stronger anti-inflammatory effects than LpA-I. In the absence of definitive interventions targeting HDL-C, we are still exploring how to treat HDL-C in clinical practice. Although further investigations are required, understanding the function of ApoA2 could lead to the development of new lipid therapies focusing on HDL-C.
Study LimitationFirst, this study had a small sample size and was a single-center, observational, retrospective study. Second, the results were a combination of data from patients with ACS and those with CCS. hs-CRP was higher in patients with ACS than in those with CCS. Third, the type and intensity of lipid-lowering therapy varied among patients according to their backgrounds. At our institution, we aggressively introduce combination therapy, maximum intensity statin therapy, and ezetimibe in patients at a greater risk of multivessel disease and ACS. Furthermore, patients with lower LDL-C levels were significantly older and had a higher prevalence of diabetes mellitus and hemodialysis complications than those with higher LDL-C levels. Although we believe that our data reflect real patient characteristics with secondary prevention for CAD, patient characteristics may also contribute to the results. Finally, the appropriate reference value of ApoA2 to evaluate the risk of CAD remains unknown. Many apolipoprotein studies have used the median value as a cutoff in their analysis, and the median value varies according to the study population. Our analysis was conducted with a cutoff value of 24 mg/dL, which may be lower than that in previous studies for ApoA2. Our study population may have included more high-risk patients with CAD.
Serum ApoA2 levels in patients who underwent PCI and received LDL-C lowering therapy demonstrated the strongest association with MACE compared with other lipoproteins. Furthermore, ApoA2 showed a stronger inverse correlation with hs-CRP than ApoA1 and HDL-C. Thus, ApoA2 could strongly predict cardiovascular event risk, reflecting the severity and prognosis of systemic atherosclerosis. These findings indicate that ApoA2 in the context of high-quality HDL-C could be a promising candidate for further investigation.
We thank Enago (www.enago.jp) for the English language review.
All authors have no conflicts of interest to disclose.
This study complies with the Declaration of Helsinki and the Ethics Committee of Niigata University approved this study, and all patients had the opportunity to opt out of the study (IRB No. 2023-0168).
Please find supplementary file(s);
https://doi.org/10.1253/circj.CJ-24-0242
