Serum lipoprotein(a) and risk of periprocedural myocardial injury in patients undergoing percutaneous coronary intervention

Abstract Recent studies and guidelines have indicated that lipoprotein(a) [Lp(a)]was an independent risk factor of arteriosclerotic cardiovascular disease (ASCVD). This study aimed to determine the relationship between serum Lp(a) levels and the risk of periprocedural myocardial injury following percutaneous coronary intervention (PCI) in coronary heartdisease (CHD) patients. This study enrolled 528 nonacute myocardial infarction (AMI) coronary heart disease (CHD) patients who successfully underwent PCI. Fasting serum lipids including Lp(a) were tested before PCI. High‐sensitivity cardiac troponin I (hs‐cTnI) was tested before PCI and 24 h after PCI. Univariate and multivariate logistic regression analyses were used to determine the relationship between preprocedural Lp(a) levels and postprocedural cTnI elevation from 1 × upper limit of normal (ULN) to 70 × ULN. As a continuous variable, multivariate analyses adjusting for conventional covariates and other serum lipids revealed that increased Lp(a) levels were independently associated with the risk of elevated postprocedural cTnI values above 1 × ULN (odds ratio [OR] per log‐unit higher: 1.31, 95% confidence interval [CI]: 1.02–1.68, P = 0.033], 5 × ULN (OR: 1.25, 95%CI: 1.02–1.53, P = 0.032), 10 × ULN (OR: 1.48, 95%CI: 1.18–1.86, P = 0.001) and 15 × ULN (OR: 1.28, 95%CI: 1.01–1.61, P = 0.038). As a categorical variable, Lp(a) > 300 mg/L was an independent risk factor of postproceduralc TnI≥1 × ULN (OR 2.17, 95%CI 1.12–4.21, P = 0.022), ≥5 × ULN (OR 1.82, 95%CI 1.12–2.97, P = 0.017) and ≥10 × ULN (OR 2.17, 95%CI 1.33–3.54, P = 0.002). Therefore, it could be concluded that elevated preprocedural Lp(a) levels were associated with the risk of PCI‐related myocardial injury in non‐AMI CHD patients.


| INTRODUCTION
Lipoprotein(a) [Lp(a)] is a lipoprotein composed of low-density lipoprotein (LDL) and an additional protein apolipoprotein(a). 1 It is a member of human plasma lipoproteins which also include chylomicrons, very low-density lipoprotein (VLDL), intermediate-density lipoprotein (IDL), LDL and high-density lipoprotein (HDL). 2 LDL consisting of cholesterol and apoB-100 delivers cholesterol from liver to peripheral tissues. 3 For decades, low-density lipoprotein cholesterol (LDL-C) has already been proven to be the most important risk factor atherosclerosis cardiovascular disease (ASCVD). 2,[4][5][6][7] Different to LDL, an additional apolipoprotein(a) [apo(a)] makes the physiological and vascular effects of Lp(a) ambiguous. 1 However, uncertain mechanism as it was, studies have already reported the positive correlation between plasma Lp(a) levels and the risk of ASCVD. 8,9 Recent ESC/EAS guidelines for the management of dyslipidaemias recommended at least once measurement of Lp(a) in the lifetime to identify the persons who may have a lifetime risk of ASCVD. 2 Percutaneous coronary intervention (PCI) is the major therapeutic strategy of coronary heart disease (CHD). Myocardial infarction (MI) associated with PCI which was classified as type 4a MI in Fourth Universal Definition of Myocardial Infarction was one of the major complications of PCI. 10 Previous studies have already confirmed that type 4a MI would cause a poor prognosis after PCI. [11][12][13] Different to type 4a MI, elevation of cardiac troponin (cTn) after PCI which was defined as PCI-related myocardial injury was relatively common especially after the use of high-sensitivity cTn (hs-cTn). 14 Although the optimal cut-off value of postprocedural cTn which was of prognostic significance was still controversial, our previous study revealed that the higher the postprocedural cTnI, the worse the prognosis of patients. 15 The relationship between LDL-C, high-density lipoprotein cholesterol (HDL-C) or non-HDL-C and different levels of postprocedural cTn elevation have been studied before. [16][17][18] However, whether higher Lp(a) levels were associated with risk of PCI-related myocardial injury remained unknown.
Thus, this study sought to explore the association between preprocedural serum Lp(a) levels and PCI-related myocardial injury. Moreover, as mentioned above, the cut-off value of postprocedural cTnI with prognostic significance was controversial yet, therefore we investigated the association between Lp(a) and different elevations of postprocedural cTnI levels from 1 × ULN up to 70 × ULN.  Besides, 43 patients were excluded because of elevated preprocedural cTnI levels, 39 patients were excluded because their clinical data available were insufficient for the study, while four and two patients were excluded respectively because of severe bleeding complications and acute stent thrombosis after PCI. Eventually, 528 patients were included in the present study ( Figure 1). The current study was approved by the Institutional Review Board of the hospital.

| Measurement of laboratory data
After admission, fasting blood samples were obtained from each patient before the procedure. Serum lipids including total cholesterol (TC), triglyceride (TG), LDL-C, HDL-C, apoAI, apoB100 and Lp(a) were determined by Hitachi 7600 automatic biochemical analyzer. LDL-C and HDL-C were analyzed using the direct method. TC and TG were analyzed using enzyme colorimetry method. Lp(a) was determined by latex immunoturbidimetry method. ApoAI and apoB100 were determined by immunoturbidimetry method. Non-HDL-C levels were calculated from TC minus HDL-C levels. Hs-cTnI was analyzed by chemiluminescence method through Abbott ARCHITECT i2000SR chemiluminescence immunoanalyzer. Upper limit of normal (ULN) which was defined as the 99th percentile of normal population was used to replace upper reference limit (URL). ULN of hs-cTnI was 0.04 ng/ml of our test. Blood F I G U R E 1 Flowchart illustrating study population. CHD, coronary heart disease; PCI, percutaneous coronary intervention; AMI, acute myocardial infarction samples were obtained before PCI and 24 h after PCI to determine preprocedural and postprocedural cTnI levels.

| Coronary angiography and percutaneous coronary intervention
Each patient received sufficient dose of aspirin and clopidogrel before procedure (aspirin 0.1 g daily for at least 3 days or a loading dose of

| Statistical analysis
Continuous data were expressed as mean ± SD and categorical data were presented as frequencies with percentage. Student's t-test or one-way analysis of variance was performed to determine the differences in continuous data between groups and chi-square test was performed for categorical variables. Logistic regression analyses were performed to explore the relationship between Lp(a) and different times ULN of postprocedural cTnI elevations. Univariate logistic regression analyses were performed firstly. Lp(a) was respectively analyzed as a continuous variable or a categorical variable with a cut-off value as 300 mg/L according to Guidelines for the Prevention and Treatment of Dyslipidemia in Chinese Adults. 22    NT-proBNP was calculated using the following classification: "normal" was <300 pg/ml; "gray zone" was 300-450 pg/ml for<50 years, 300-900 pg/ml for 50-75 years and 300-1800 pg/ml for >75 years; "high" was >450 pg/ml for <50 years, >900 pg/ml for 50-75 years and > 1800 pg/ml for >75 years. have diabetes, higher BMI, lower NT-proBNP and creatine levels.
CHD drug therapies were not significantly different between two groups. As for serum lipids, patients with lower Lp(a) levels also had lower TC, LDL-C, HDL-C, non-HDL-C levels while TG levels were of no difference. CAG and PCI parameters were shown in Supplementary Table 1. There were no significant differences between two groups in terms of procedure parameters.  Table 2).

| DISCUSSION
Our study demonstrated the positive correlation of preprocedural Lp(a) levels and postprocedural cTnI levels in non-AMI CHD patients undergoing elective PCI, indicating that Lp(a) was an independent risk factor of PCI-related myocardial injury.
For these years, the status of Lp(a) in risk of ASCVD have been receiving increasing attention. As we know, cigarette smoking, diabetes, hypertension and elevated LDL-C level were the major risk factors promoting ASCVD. 23   Highly related as it was between lipids and CHD, previous studies have also focused on the relationship between serum lipids and type 4a MI or PCI-related myocardial injury. Elevated LDL-C or non-HDL-C levels have been found to be positively correlated to postprocedural cTnI levels. 16 Another study considered non-HDL-C was more valuable in predicting PCI-related myocardial injury than LDL-C in type 2 diabetes patients. 18 Moreover, higher HDL-C levels were reported to be associated with less risk of PCI-related myocardial injury in patients with LCL-C < 70 mg/dL. 17 Our previous study 15 exploring the risk factors of type 4a MI found LDL-C was an independent risk factor and 1-SD increment of LDL-C (1.05 mmol/L in the study) increased the risk of type 4a MI by 44%. In the study we have already noticed that Lp(a) levels seemed to be higher in patients with type 4a MI but the difference was not statistically significant. Therefore, we expanded the sample size and finished our present study. In this study, we analyzed 528 non-AMI CHD patients and finally we found elevating Lp(a) was associated with risk for postprocedural cTnI levels above 1 × ULN up to 15 × ULN after adjustment of covariates including other serum lipids, indicating that Lp(a) was associated to PCI-related myocardial injury independently of other serum lipids.
Definition and prognostic significance of PCI-related myocardial infarction or injury have been developing for these years. 10,[38][39][40] The preferred biomarker has been identified as cTn rather than CK-MB 10,38 considering to the better sensitivity and specificity. Among the assays, high-sensitivity cTn was more recommended. 41 According to the most recent universal definition of MI, 10 in patients with normal preprocedural cTn level, PCI-related MI was defined as elevation of postprocedural cTn levels more than 5 × ULN with evidence of new myocardial ischemia. As mentioned above, PCI-related MI would cause a poor prognosis after PCI. [11][12][13] Unlike PCI-related MI, elevation of cTn values after PCI which was arbitrarily defined as PCI-related myocardial injury was of controversially significance. 11,39,[42][43][44][45][46] In our previous study, 15  were similar after adjusted covariates including TG, LDL-C, non-HDL-C and HDL-C. Therefore, it can be deduced that Lp(a) was correlated to the minor myocardial injury after PCI. Larger mass of myocardial injury, however, was much more strongly correlated to the heart function, complexity of coronary artery lesion and acute damage of PCI procedure as previous article reported. 15  were linked to the risks of both coronary thrombosis and venous thrombosis. 8 Because apo(a) moiety and plasminogen was of structural similarities, the reasons why Lp(a) caused thrombosis were speculated to be inhibiting fibrinolysis by interfering with the conversion of plasminogen to plasmin. 8,9,48 Therefore, besides the atherogenic risk of LDL particles, the proinflammatory and thrombotic effects of Lp(a) might cause the myocardial injury after PCI. However, further definitive mechanisms how Lp(a) promotes atherosclerotic lesions require more appropriate animal models and basic researches to figure out.
As mentioned above, plasma Lp(a) levels were mainly genetically determined, 33 which were insensitive to lifestyle such as diet and exercise. 8 Effects of statins on Lp(a) metabolism remained uncertain and controversial. 2 Therefore, Lp(a) levels were much more stable than LDL-C. Since there were plenty of evidences demonstrating the association between Lp(a) and ASCVD, it could be expected as a good predictor in the risk of cardiovascular events. Lowering Lp(a) therapies has been developing for these years. Appropriate dose of nicotinic acid which was unique in lowering Lp(a) levels have been showed no beneficial effects. 19 PCSK9 inhibitors could reduce Lp(a) levels by 25-30% while LDL-C by 50-60% according to the clinical trials. 9 The treatment of PCSK9 inhibitors could significantly decrease the ASCVD events but whether it was due to lowering of Lp(a) or simply due to lowering LDL-C to levels remained controversial. [49][50][51] Our study rev- Therefore, we can draw a conclusion that Lp(a) was associated to the risk of minor myocardial injury after PCI and could be a good predictor of PCI-related myocardial injury.