Background
Atherosclerotic cardiovascular disease (ASCVD) is the leading cause of death and low-density lipoprotein cholesterol (LDL-C) is the well-established risk factor of ASCVD. The epidemiological and Mendelian randomization studies [
1,
2] had shown that serum LDL-C level was correlated to ASCVD risk and had significant impact on the clinical outcomes. LDL-C lowering therapies had been proved to reduce ASCVD risk regardless of the patients’ background [
3‐
6]. But the data of 13,167 patients from JUPITER [
7], LIPID [
8] and AIM-HIGH [
9] showed 61% more risk of major adverse cardiovascular event (MACE) in patients with higher lipoprotein (a) (Lp(a)) level than those with similar LDL-C level, but lower Lp(a). That indicated Lp(a) may be another ASCVD risk factor needed to be taken seriously. The relation between Lp(a) and ASCVD has been confirmed by at least 3 meta-analyses [
10‐
12] and recently published result from ODYSSEY Outcomes [
13]. The analysis of the Copenhagen City Heart Study and Copenhagen General Population Study showed a higher cardiovascular disease (CVD) risk when Lp(a) > 30 mg/dL [
14]. But there was a contradiction point in LDL-C and Lp(a) control, as statin, the most widely used LDL-C-lowering agent in the world, leading to 15–37% ASCVD risk reduction, could increase Lp(a) by 8.5–19.6% [
4,
15]. The clinical benefit of LDL-C lowering with statin could be diminished with the Lp(a) increasing effect. Besides, the optimal clinical control points of LDL-C and Lp(a) is still pending. In this study, we tried to find the relationship between LDL-C, Lp(a) and coronary atherosclerotic lesion in a group of patients with exact evidence of coronary atherosclerosis, and compared correlation strengths within different LDL-C concentrations to find out the balance point of LDL-C and Lp(a) in ASCVD prevention.
Discussion
In this study, we found the distinct CAHD risk factors in patients with different LDL-C levels. Moreover, in the correlation analysis, we found the linear correlation between Lp(a), LDL-C and Gensini and the correlation was influenced by LDL-C concentration. A meta-analysis of 49 clinical trials, over 312,000 patients, showed a great 23% MACE risk reduction achievement with 1 mmol/L LDL-C reduction in statin therapy [
18]. But under statin therapy background, additional LDL-C lowering with evolocumab, a proprotein convertase subtilisin/kexin type 9 (PCSK9) inhibitor, achieved additional 60% LDL-C reduction but only 1.5% MACE risk reduction [
5]. Those results indicated that the clinical benefit of LDL-C lowering therapy descended with LDL-C decrease which is consistent with our finding in this study that the correlation between LDL-C and Gensini dropped with the LDL-C level decrease.
Even the Guideline recommended LDL-C concentration was strict for patients at very-high CVD risk, < 55 mg/dl, in both primary and secondary prevention [
16]. The data in the secondary prevention of vascular disease showed that the recurrent 10-year risk of vascular events is still over 30% in 9% patients with vascular disease, who’s risk factors were all at guideline-recommended targets [
19]. Lp(a) may contribute to the residual risk. In a recently published epidemiological study, Hu etc. fund the Lp(a) co-contributed with LDL-C to the incidence of acute myocardial infarction in Chinese people [
20]. In this study, we found the same trend, especially in patients with LDL-C < 100 mg/dL. In the subgroup analysis of Low-LDL-C Group in this study, near 43% patients were taking statin, the pathogenicity of Lp(a) may partly due to the effect of statins on Lp(a) increasing.
Lp(a) is mainly composed with an apolipoprotein a (apo(a)), an LDL like particle and phospholipid (PL). Under the stimulation of inflammation, LDL and PL enter the vascular endothelium and convert to oxidized LDL (Ox-LDL) and oxidized phospholipids (Ox-PL), which are critical in the process of atherosclerosis. Lp(a) can induce and accelerate atherothrombosis beyond its LDL components and is more effective than LDL in atherosclerosis inducing. However, 70–80% patients with the risk of CVD have low Lp(a) level and LDL-C present in significant excess to Lp(a), the LDL-driven CVD risk is mainly due to LDL-C. But the traditional clinical panel couldn’t distinguish Lp(a) from LDL-C, 30–45% of the reported LDL-C is contributed by Lp(a). In more extreme cases, the majority of LDL-C was carried by Lp(a) when LDL-C less than 25 mg/dL[
21]. In our study, Lp(a) showed no significant relation to CAHD in High-LDL-C Group but a strong relation to CAHD in patients with LDL-C < 100 mg/dL. That was partly because the weakened pathogenicity of LDL-C in the Low-LDL-C Group and the particle-enhanced turbidimetric immunoassay measurement of Lp(a), we adopted in this study.
The apo(a) component of Lp(a) contains three kringles, KII, KIV and KV. Among the 10 subtypes of KIV, KIV 1–10, there are large variations in the copies of KIV 2 domain, leading to over 40 different sizes of Lp(a). It was reported that over 80% individuals caring 2 different-size apo (a) isoforms [
22]. The common clinical report of Lp(a) was in total mass (mg/dL), but it has significant limitation of bias in measurement, considering the variable of Lp(a) components among patients. Thus, the National Heart, Lung, and Blood Institute (NHLBI) Working group recommended that Lp(a) should be reported in particle concentration [
23]. The measurement of Lp(a) in this study was based on a latex coated antibody of lipoprotein, Tina-quant Lipoprotein (a) Gen.2, which is free from the influence of Lpa(a) polymorphism, and the accuracy is higher among six common commercial measurements [
24].
A prospective study suggested that the relationship between Lp(a) and CVD was a J-curve with a low slop when Lp(a) level was very low and sharply raised when Lp(a) level increased [
25]. Dr. Tsimikas thought the correlation of CVD risk and circulating Lp(a) mass is in a linear ship, when Lp(a) level increased over 25 mg/dl [
26]. As the result showed in this study, the molar concentration of Lp(a) correlated with coronary atherosclerotic lesions in a linear shape, but it was influenced by LDL-C level. We also noticed that both the correlations of Lp(a)-Gensini, and LDL-C-Gensini were weakest in LDL-C = 2.51–2.75 mmol/L, which is near to the recommended LDL-C level for patients with low CVD risk [
16]. The reason for that phenomenon may be the advantage number of non-statins intervened Non-CAHD patients in this subgroup.
In this study, we set the 50% coronary stenosis, measured in naked eye, as the as grouping basis. There would be errors in the grouping of patients with borderline lesions, without the intravascular imaging examination. 37% of the total patients in this study were under statin therapy and the duration of medication varied, the effect of statin on Lp(a) cannot be determined. In the correlation analysis of Lp(a)- Gensini and LDL-C-Gensini in different LDL-C intervals, the numbers of patients varied greatly among subgroups, leaded to unavoidable measurement bias. Besides, our study just proved the strong correlation between Lp(a) and CAHD in low LDL-C patients, but hardly confirm the clinical benefits of Lp(a) lowering intervention in those patients.
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