Impact of Baseline LDL-C and Lp(a) Elevation on Coronary Revascularization in Patients with Acute Coronary Syndrome One-Year after First Percutaneous Coronary Intervention

Objective: The aim of this study was to investigate the effect of Lipoprotein-a [Lp(a)] on Coronary Revascularizaton (CR) on one year follow up in patients with Acute Coronary Syndrome (ACS) after the first Percutaneous Coronary Intervention (PCI). Method: A retrospective study was designed. A total of 475 patients that underwent their first PCI treatment due to ACS between January 2016 and December 2017 were recruited and followed for one year at the Zhongda Hospital, China. The clinical end point after first PCI was prevalence of Major Adverse Cardiovascular Events (MACE) including nonfatal Myocardial Infarction (MI), cardiovascular death, ischemic stroke and Coronary Revascularization (CR). According to the cut point of Lp(a), participants were divided into low Lp(a) subgroup (Lp(a) < 300 mg/L) and high Lp(a) subgroup (Lp(a) ≥ 300 mg/L). Furthermore, based on baseline Low Density Lipoprotein Cholesterol (LDL-C) level, participants were divided into low LDL-C (LDL-C < 1.8 mmol/L) and high LDL-C (LDL-C ≥ 1.8 mmol/L) subgroups. Results: The number of prevalence of CR was higher with elevated serum Lp(a) in both low LDL-C subgroup and high LDL-C subgroup, and was significantly different in both the low LDL-C subgroup and high LDL-C subgroup (p = 0.009 and p = 0.006, respectively). Multivariate Cox-hazard regression analysis for CR showed increase in serum LDL-C and Lp(a) increased prevalence of CR by 1.514 and 1.002 folds respectively. Furthermore, Kaplan-Meier cumulative survival curves showed that increased prevalence of CR within one year after first PCI in patients with high Lp(a) [log rank p = 0.000]. Conclusion: Baseline increase of serum LDL-C and Lp(a) significantly increases the prevalence of CR after first PCI within one year. It indicates How to cite this paper: Hameed, Q.A., Chen, L.J., Yang, M.M., Afzali, J. and Ma, G.S. (2020) Impact of Baseline LDL-C and Lp(a) Elevation on Coronary Revascularization in Patients with Acute Coronary Syndrome One-Year after First Percutaneous Coronary Intervention. World Journal of Cardiovascular Diseases, 10, 102-115. https://doi.org/10.4236/wjcd.2020.102012 Received: January 10, 2020 Accepted: February 18, 2020 Published: February 21, 2020 Copyright © 2020 by author(s) and Scientific Research Publishing Inc. This work is licensed under the Creative Commons Attribution International License (CC BY 4.0). http://creativecommons.org/licenses/by/4.0/ Open Access


Introduction
Hyperlipidemia, especially high serum level of low density lipoprotein-cholesterol (LDL-C) has been well documented as an important risk factor of atherosclerosis and its manifestation of atherosclerotic cardiovascular diseases (ASCVD) [1].
Although a significant progress have been made in recent years in the traditional risk factor control and treatment of Acute Coronary Syndrome (ACS). However, there are still a large number of patients with residual risk of cardiovascular events [2]. Hence, some epidemiological studies show that, although target LDL-C level has been achieved by statin therapy, residual cardiovascular risk such as coronary restenosis after Percutaneous Coronary Intervention (PCI) is still very high [3] [4]. It suggests that other risk factors besides LDL-C could also play a contributory role in the progression and recurrence of ACS after PCI, and identifying those potential risk factors would be beneficial for further improving cardiovascular outcome [3] [4].
Recently, some studies show that elevated plasma level of lipoprotein-a [Lp(a)] and LDL-C is associated with increased risk of Coronary Artery Disease (CAD) [5] [6]. Lp(a) is a lipoprotein particle with an LDL-like structure linked to apolipoprotein(a) [apo(a)] [6]. So, it has the effect similar to the LDL-C, and also carries atherothrombotic and proinflammatory properties [7] [8]. The combination of all these prothrombotic and atherosclerotic factors could trigger its atherosclerotic property. There is considerable heterogeneity with regards to the plasma level of Lp(a) among different ethnicities. Its cut-off value of significant risk for the Caucasians was recommended as 500 mg/L, whereas for the Chinese population, it is 300 mg/L considering far lower than the Caucasians [9] [10].
Currently, PCI is the preferred choice for ACS. The main strategy in the clinical practice after PCI is still focusing on atherogenic lipid profiles other than Lp(a), especially LDL-C, which is the main treatment target recommended by several guidelines [10] [11]. Although LDL-C has been recognized as one of the major risk factors for ACS, the residual risk for ACS despite intensive statin therapy indicates the important role for Lp(a) [12]. Therefore, preventing the incidence of coronary atherosclerosis after PCI is of paramount importance.
Notably, the pathophysiological process of coronary artery atherosclerosis is featured by endothelial dysfunction, smooth muscle cells proliferation and fibrin Q. A. Hameed et al. World Journal of Cardiovascular Diseases accumulation, and with respect to Lp(a)'s unique features such as atherosclerotic and proinflammatory properties, we speculated that Lp(a) elevation might be the potential risk factor responsible for the increased incidence of CAD due to coronary restenosis after PCI. A limited number of studies are available on the effect of LDL-C and Lp(a) on ACS patients after PCI treatment in Chinese patients. So, this study was conducted to determine the effect of Lp(a) elevation on ACS patients within one year after first therapeutic PCI, and also studied whether or not this effect of Lp(a) is dependent on LDL-C.

Study Design
A retrospective study was conducted from January 2016 and December 2017 at the Department of Cardiology, Zhongda Hospital, China. All the patients were diagnosed with ACS through thorough angiographic assessment by 2 seasoned cardiologists.

Study Population
In our hospital from January 2016 and December 2017, total 1600 patients have undergone PCI treatments due to Coronary Artery Disease (CAD) and ACS. We have identified and enrolled 475 ACS patients who have undergone first PCI treatment. The study population consisted of patients presented with ACS consisting of Unstable Angina (UA), Non-ST segment Elevation ACS (NSTE-ACS) and ST segment Elevation ACS (STE-ACS) that necessitated therapeutic PCI after thorough angiographic assessment. Of the total enrolled patients, 51 patients were excluded due to in accordance with our exclusion criteria. A total of 424 patients were enrolled in our study ( Figure 1). All the patients were prescribed with recommended dose of statin and anti-platelet therapy following PCI and have been followed for one year for any cardiovascular events i.e. Major Adverse Cardiovascular Events (MACE) including, Coronary Revascularization (CR) due to coronary restenosis, hemorrhagic stroke, nonfatal Myocardial Infarction (MI) and cardiovascular death. Baseline demographic and laboratory information (see Table 1    level of less than 1.8 mmol/L; therefore, we used 1.8 mmol/L of LDL-C as cut-off point to categorize all patients into two subgroups. Plasma level of Lp(a) lower than 300 mg/L is considered within the normal range for the Chinese patients, therefore we considered plasma level of Lp(a) equal to or higher than 300 mg/L as abnormal [3].

Laboratory Measurement
For variable measurements in the hospital laboratory, blood samples were taken when the patients had been fasting for about 8 hours. Plasma Lp(a) level was analyzed with sandwich Enzyme Linked Immune-sorbent Assays (ELISA kit, Yaji Biosystems, Shanghai, China). All the procedures for variable measurements were performed according to the manual instruction and were evaluated by SYNCHRON LX20 UniCel DxC800 analyzer (Beckman Coulter Inc., USA).

Primary End Point
All the participants have been followed up for the cardiovascular events such as

Statistical Analysis
Continuous data was presented as mean ± SD or median (interquartile range) appropriately and compared by Student's t-test when data was normally distri-

Results
Baseline Characteristics of CAD patients with Lp-a < 300 mg/L subgroup and Lp-a ≥ 300mg/L subgroup One Year after first PCI: In the subgroup of low LDL-C (n = 211) subgroup, there were 147 patients with Lp(a) level lower than 300 mg/L, while another 64 were with Lp(a) level higher than 300 mg/L. As shown in Table 2, the number of prevalence of CR was higher as compared to the other adverse events of the total MACE in high Lp(a). In our study prevalence of total MACE and CR was significantly different between low and high Lp(a) groups (p = 0.002 and p = 0.009, respectively) in patients with low LDL-C. The prevalence of Stroke was higher in high Lp(a) subgroup and was significantly different (p = 0.031). It shows that elevated level of serum Lp(a) is a causative factor for adverse events i.e. CR and stroke even after achieving low LDL-C level.
Another 213 patients with LDL-C level equal to or higher than 1.8 mmol/L were divided into two subgroups according to the cut-off point of Lp(a). As shown in Table 2, same as in the subgroup with low LDL-C, in the subgroup of patients with high LDL-C level the number of prevalence of CR was higher as compared to the other adverse in total MACE. In this subgroup of patients with high LDL-C level the prevalence of CR and total MACE was significantly different (p = 0.006 and p = 0.001, respectively). Moreover, prevalence of other adverse events of MACE i.e. MI, stroke and Death were higher in high Lp(a) subgroup than the low Lp(a) subgroup though they weren't significant. So it shows that elevated level of both serum LDL-C and Lp(a) were associated with increased prevalence of MACE especially CR. Table 2. Cardiovascular outcomes comparison in the subgroup of patients with LDL-C Lower than 1.8 mmol/L and higher than 1.8 mmol/L after PCI.

Cox Regression Hazards Model for Factors Associated with Coronary Revascularizartion (CR) with CAD after first PCI within One Year:
We performed Cox regression Hazard analysis to analyze the predictors for CR. After performing univariate Cox analysis, significant predictors for CR were Lp(a), total Cholestrol, Triglyceride, Apo-A1, hsCRP, Creatinine and LDL-C, Table 3

Discussion
Our study showed that the number of prevalence of stent-restenosis and CR was higher as compared to the other adverse events of the total MACE in high Lp(a) in patients with low LDL-C subgroup. The increase in serum LDL-C and Lp(a) were associated with increase in prevalence of total MACE and CR. The prevalence of CR after the first PCI was significantly higher in the group with high Lp(a) subgroup than low Lp(a) subgroup. Our study also showed that LDL-C and Lp(a) increases prevalence of CR by 1.514 and 1.002 folds respectively. This association was significant even after adjustment for other independent variables. After the treatment with PCI all the patients were well followed up and were prescribed with recommended medications such as antiplatelet and statin therapies.
At present, PCI is largely applied in patients with significant coronary artery stenosis, and this reperfusion approach has overwhelmingly enhanced cardiovascular outcomes during last two decades. However, the accumulation of evidence from retrospective and perspective studies show that, despite the patients treated with PCI and strictly adhering to recommended guidelines, a significant introduced, and a more aggressive LDL-C reduction treatment is considered as one of the most attractive and potential strategy.
Recently LIPID [13] study has shown the relationship between serum Lp(a) and further CVD events in patients with CAD on statin therapy. Formerly, observation of patients with CAD treated with intensive statin therapy in PROVE IT-TIMI [14], IDEAL [4] and TNT [15] [19]. Lp(a) could be a risk factor for plaque destabilization and thrombosis and not the severity of coronary heart disease, and associated with myocardial lesions in patients with unstable angina [17]. High concentrations of serum Lp(a) could predict ischaemic heart disease (IHD) and myocardial infarction (MI) in the general public, and the predictive capability was not exaggerated by normal food intake, but was minimally elevated to a level high CRP [18]. A study by Juan Chen et al. demonstrated that Lp(a) is an independent predictor for the severity of coronary heart disease (CHD) in type 2 diabetes patients (T2DM) [19]. It has been shown that Lp(a) has shown that the severity of coronary atherosclerosis is predicted independently of conventional CV risk factors.

3) Lp(a) directly increases the activity of plasminogen activator inhibitors in
human endothelial cells and promotes atherorombosis [23]. Lp(a) was involved in the activation of endothelial uptake, oxidative alteration and cell formation.
Additionally, Lp(a) is also associated with 1) thrombus formation due to vascular lesion, 2) elastic recoil, 3) migration of smooth muscle cells in Intima and 4) vascular remodelling. A study by Minz et al. [24] used intravascular ultrasound to study CAD patients for coronary restenosis through Percutaneous angiography without stent treatment and reported that 73% of the mechanism underlying a decrease in lumen diameter is because of remodelling and 27% is due to an increase in plaque and intima. On the other hand, another study by Hoffmann et al. [25] demonstrated that in-stent restenosis results from neo-intimal tissue proliferation, which has been accredited due to Lp(a) in vitro [8]. In the present study, Lp(a) was significantly associated with CR which is in parallel with the previous studies. Recently a meta-analysis on statin therapy following PCI show beneficial role of high intensity loading dose of statin therapy was more beneficial to patients with ACS in Chinese patients and was suitable for clinical application [26]. In addition, a study by Zhi Liu et al. [27] demonstrated that high-intensity atorvastatin therapy over the duration of 1 year after PCI was superior in ACS patients in decreasing MACE. Moreover, novel drugs, including PCSK9 inhibitors, as well as antisense oligonucleotide for Apo-A, have exhibited efficacy in decreasing Lp(a) substantially [28] [29].
Several limitations of this retrospective study should be given consideration.
It's a single-center retrospective study, enrolling data of 2 years of patients and other confounding factors might have influenced the outcomes independently of adjustments in the statistical analysis. Thus an observational study with larger population is required for further proper analysis. In addition we had no proper knowledge about the patients' compliance with the prescribed medications.

Conclusion
In conclusion, this study revealed that in patients with first PCI, Lp(a) elevation is positively associated with coronary restenosis and CAD within one year which requires revascularization and the prevalence of CR is significantly higher in elevated level of serum LDL-C and Lp(a). It indicates that after PCI treatment, in patient with serum LDL-C and Lp(a) elevation, treatment with high-dose statin therapy or PCSK9 inhibitors may alleviate the adverse effects imposed by Lp(a) elevation.