Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention

Nutrition, Metabolism & Cardiovascular Diseases (xxxx) xxx, xxx

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Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention Na Xu a,b, Xiao-fang Tang a,b, Yi Yao a,b, Si-da Jia a,b, Yue Liu a,b, Xue-yan Zhao a,b, Jue Chen a,b, Zhan Gao a,b, Yue-jin Yang a,b, Run-lin Gao a,b, Bo Xu a,b, Jin-qing Yuan a,b,* a State Key Laboratory of Cardiovascular Disease, Fuwai Hospital, National Center for Cardiovascular Diseases, The Chinese Academy of Medical Sciences, Beilishi Road No. 167, Xicheng District, Beijing 100037, People’s Republic of China b Peking Union Medical College, Beilishi Road No.167, Xicheng District, Beijing 100037, People’s Republic of China

Received 14 June 2019; received in revised form 2 August 2019; accepted 17 September 2019 Handling Editor: M Averna Available online - - -

KEYWORDS lipoprotein(a); Percutaneous coronary intervention; Major adverse cardiovascular and cerebrovascular events; SYNTAX

Abstract Background and aims: The association between lipoprotein(a) [Lp(a)] levels and the risk of cardiovascular disease is of great interest but still controversial. This study sought to investigate the impact of Lp(a) on coronary severity and long-term outcomes of patients who undergo percutaneous coronary intervention (PCI). Methods and Results: A total of 6714 consecutive patients who received PCI were enrolled to analyze the association between Lp(a) and coronary severity and major adverse cardiovascular and cerebrovascular events (MACCE). Patients were divided into tertiles according to Lp(a) levels on admission. Coronary severity was evaluated by SYNTAX scoring system. The MACCE included recurrent myocardial infarction, unplanned target vessel revascularization, stent thrombosis, ischemic stroke and all-cause mortality. Significantly, Lp(a) levels were positively associated with coronary severity (p < 0.001). Multivariate logistic regression analyses showed Lp(a) was an independent predictor of intermediate to high SYNTAX score. During an average of 874 days follow-up, 755 patients presented with MACCE (11.25%) were reported. The incidence rates of MACCE, all-cause mortality, cardiac death, target vessel revascularization, recurrent myocardial infarction, stent thrombosis, stroke and bleeding were not statistically different among the Lp(a) tertile groups. Furthermore, both KaplaneMeier and Cox regression analyses found no relationship between Lp(a) and cardiovascular outcomes (p > 0.05). Conclusion: Lp(a) is an independent predictor of the prevalence of more complex coronary artery lesions (SYNTAX score
23) in patients with PCI. In addition, our study has shown that Lp(a) has no relationship with long-term cardiovascular outcomes in Chinese patients with PCI. ª 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

* Corresponding author. Fuwai Hospital, Beilishi Road No.167, Xicheng District, Beijing 100037, People’s Republic of China. Fax: þ(86) 10 68333879. E-mail address: [email protected] (J.-q. Yuan). https://doi.org/10.1016/j.numecd.2019.09.020 0939-4753/ª 2019 The Italian Society of Diabetology, the Italian Society for the Study of Atherosclerosis, the Italian Society of Human Nutrition, and the Department of Clinical Medicine and Surgery, Federico II University. Published by Elsevier B.V. All rights reserved.

Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020

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Introduction Lipoprotein(a) [Lp(a)] consists of apolipoprotein(a) and apolipoprotein B-100 and has a similar structure both to low-density lipoprotein (LDL) and to plasminogen [1,2]. Also, plasma Lp(a) induces proatherogenic effects via LDL moiety and prothrombotic effects by the plasminogen-like apolipoprotein(a) [3]. Elevated Lp(a) levels are proven as a marker of increased cardiovascular risk in numerous epidemiological and genetic studies during the past decades [4e7]. Two recently studies from China suggest that Lp(a) levels are strongly associated with the presence and severity of stable coronary artery disease (CAD) in individuals with diabetes mellitus (DM) and patients with familial hypercholesterolemia [8,9]. Beyond the onset of a CAD event, the severity of CAD itself is also predictive of subsequent coronary events and longterm prognosis [10]. The angiographic scoring classification systems exist to provide an objective quantification of CAD, including the Gensini score and SYNTAX score (SYNergy between percutaneous coronary intervention with TAXUS and Cardiac Surgery) [11,12]. The SYNTAX score (SS) is a relatively new but well-validated scoring system, which has been shown to predict outcomes in patients undergoing percutaneous coronary intervention (PCI) [13]. The plasma levels of Lp(a) vary widely across populations and ethnicities [14]. However, several recent studies have suggested that Lp(a) is not independently associated with cardiovascular risk in patients with different clinical backgrounds [15,16]. Large-sample studies with respect to the association of Lp(a) level and coronary severity and the long-term outcomes of patients with PCI were still few in Chinese population [8,9]. We, therefore, investigated the impact of Lp(a) on coronary severity and long-term outcomes of patients underwent PCI. Methods Study design and population The study complied with the Declaration of Helsinki and was approved by the hospital’s ethical review board (FuWai Hospital & National Center for Cardiovascular Diseases, Beijing, China). Each participant provided written, informed consent before enrollment. This study was a cohort study and 10,724 consecutive patients who underwent PCI treatment at Fuwai Hospital, National Center for Cardiovascular Diseases, from January to December 2013, were included. For the purpose of the present study, 3751 patients who had a history of myocardial infarction (MI), or PCI/coronary artery bypass grafting (CABG) were excluded. We excluded patients for whom the on-admission Lp(a) data missing (n Z 174), the SS was not available (n Z 50) and missing follow up (n Z 35). A final total of 6714 patients were included in this study (Fig. 1). The detailed demographic, clinical, hematologic, and angiographic data were collected from all subjects at baseline. Coronary lesion severity was measured by SS. Then, the patients were followed up at

N. Xu et al.

regular intervals and evaluated for the development of major adverse cardiovascular and cerebrovascular events (MACCE). To achieve homogeneous distribution, patients were categorized into tertiles on the basis of Lp(a)[mg/dl]: low-Lp(a) group [ Lp(a)  10.59, 2238 patients], mid-Lp(a) group [ 10.59 < Lp(a) < 30.55, 2238 patients], and highLp(a) group [ Lp(a)
30.55, 2238 patients]. Biochemical analysis and measurement of plasma Lipoprotein(a) On admission, venous blood was obtained from all patients after fasting for at least 12 h. All the biochemical measurements were conducted in the clinical chemistry department of FuWai hospital. The concentrations of the serum total cholesterol (TC), triglyceride (TG), highdensity lipoprotein cholesterol (HDL-C), LDL-C, uric acid and creatinine concentrations were measured using an enzymatic assay by automatic Biochemistry analyzer (Hitachi 7150, Tokyo, Japan). Consistent with other similar studies [9,17], Lp(a) levels were assayed by an immunoturbidimetry method according to the manufacturer’s guide, a latex turbidimetric method [LASAY Lp(a) auto; SHIMA laboratories; Tokyo, Japan]. The concentrations of high sensitivity C-reactive protein (hs-CRP) were determined using immunoturbidimetry (Beckmann Assay 360,Bera, Calif., USA). HbA1c was measured using a Tosoh Automated Glycohemoglobin Analyzer HLC-723G8. Total leukocyte count and subtypes were measured using XE5000 automated hematology analyzer (Sysmex, Kobe, Japan). The glomerular filtration rate (GFR) was estimated by the simplified modification of diet in renal disease (MDRD) equation. Procedures and medications As described in our previous study [18], the PCI strategy and stent type were at the discretion of the treating physician. If a patient was not taking long-term aspirin and P2Y12 inhibitors, selective PCI patients received oral aspirin (300 mg) and clopidogrel (loading dose 300 mg) or ticagrelor (loading dose 180 mg) at least 24 h before the procedure. Acute coronary syndrome patients (ST-segment elevation myocardial infarction and non-ST-segment elevation acute coronary syndrome) scheduled for PCI received the same doses of aspirin and ticagrelor or clopidogrel (loading dose 300 mg or 600 mg) as soon as possible. During the procedure, unfractionated heparin (100 U/kg) was administered to all patients, and use of glycoprotein IIb/IIIa inhibitors was at the discretion of the medical team. After the procedure, aspirin was prescribed (100 mg daily indefinitely) and clopidogrel (75 mg daily) or ticagrelor (90 mg twice daily) was recommended for at least 1 year after PCI. Evaluation of coronary severity The coronary severity was calculated for each patient by the SYNTAX score system. SS was calculated in all patients

Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020

Chinese patients underwent percutaneous coronary intervention

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Figure 1 Flowchart illustrating study population. PCI, percutaneous coronary intervention; MI, myocardial infarction; CABG, coronary artery bypass grafting; Lp(a), lipoprotein(a); SS, SYNTAX scoring.

included in the study. SS was determined using the online calculator (http://www.syntaxscore.com). The SYNTAX score was the sum of points given to each individual coronary lesion with >50% narrowing in a vessel at least 1.5 mm in diameter. Additional points were allocated for lesion complexity including bifurcation/trifurcation lesions, total occlusion, calcification, presence of thrombus, and diffusely diseased segments [12]. All coronary angiograms were adjudicated independently by 2 experienced cardiologists centrally who were blinded to classification of patients as having elevated Lp(a), and disagreement was resolved by consensus. A low SS was defined as  22, an intermediate score as 23 to 32, and a high score as
33 [19]. Patients with SS
23 were considered to have moderate to severe coronary artery disease according to this definition. Thus, the patients were divided into 2 groups, those with low SS (22) and those with intermediate to high SS (
23).

thrombosis was defined according to the Academic Research Consortium, including “definite” and “probable” in the analysis [21]. Bleeding was quantified according to Bleeding Academic Research Consortium Definition criteria, including type 2, 3, and 5 in the analysis [22]. Major adverse cardiovascular and cerebrovascular events (MACCE) was defined as the occurrence of death, myocardial infarction, target vessel revascularization, stent thrombosis, and stroke during follow-up. All endpoints were adjudicated centrally by two independent cardiologists, and disagreement was resolved by consensus. Patients were evaluated during a clinic visit or by phone at 1, 6, 12 and 24 months postoperatively. Patients were advised to return for coronary angiography if clinically indicated by symptoms or documentation of myocardial ischemia.

Statistical analysis Clinical endpoints and follow-up Death that could not be attributed to a non-cardiac etiology was considered cardiac death. Myocardial infarction was defined using the third universal definition of myocardial infarction [20]. Revascularization was defined as repeated revascularization for ischemic symptoms and events by PCI or surgery of any vessel. Unplanned target vessel revascularization was defined as repeated percutaneous intervention or surgical bypass of any segment of the target vessel for ischemic symptoms and events. Stent

Continuous variables are expressed as mean  standard deviation (SD) or median with interquartile range (IQR), and one-way ANOVA was used to compare differences between continuous variables when normally distributed, KruskaleWallis tests for nonparametric variables. Categorical variables were presented as number (percentage) and analyzed by Chi-squared statistic test or Fisher’s exact test. Pearson’s correlations were used to analyze the correlation between Lp(a) and SS. To determine the independent predictors of intermediate to high SS, parameters (age, DM, left ventricular ejection fraction (LVEF),

Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020

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N. Xu et al.

glomerular filtration rate (GFR), hemoglobin, white blood cell count (WBCc), high-sensitivity C-reactive protein (hsCRP), HDL-C and Lp(a)) that were found to be significant in the univariate analysis were evaluated by stepwise forward logistic regression analysis. The event-free survival rates among tertiles Lp(a) subgroups were estimated by the KaplaneMeier method and compared by the logrank test. Univariate and multivariate Cox proportional regression analyses were performed to examine the risk of Lp(a) levels for MACCE. Data were analyzed using SPSS 20.0 (IBM Corp. Released 2011. IBM SPSS Statistics for Windows, ver. 20.0. Armonk, NY: IBM Corp.). A two-sided P < 0.05 was considered statistically significant.

Results Baseline characteristics The baseline demographical, clinical, and biochemical characteristics of the study population at baseline were shown in Table 1. Overall, the enrolled subjects were classified into three groups according to the tertiles of Lp(a) (10.59 in group 1; 10.59 < Lp(a) < 30.55 in group 2;
30.55 in group 3). There existed significant differences in SYNTAX score among the 3 groups (p < 0.001), and a significant gradient of the frequency of Intermediate to high SS across 3 groups with a markedly increased. The

Table 1 Demographical, clinical, and biochemical characteristics of patients by tertiles of the Lipoprotein(a). Variables

Demographics Age, years Male gender, n (%) BMI, kg/m2 Current smokers,n (%) Diabetes mellitus, n (%) Family history of CAD,n (%) Hypertension, n (%) Peripheral vascular disease,n (%) COPD,n (%) Therapy at admission Aspirin,n (%) Clopidogrel,n (%) b-Blockers, n (%) Statin, n (%) CCB,n (%) LVEF on admission,% GFR, ml/min/1.73m2 Laboratory parameters WBC, 103/uL Hemoglobin, g/L Total cholesterol, mmol/L LDL-C, mmol/L HDL-C, mmol/L Triglyceride, mmol/L Uric Acid, umol/L HbA1c, % hsCRP, mg/dL LP(a), mg/dL Angiographic characteristics LM,n (%) RCA,n (%) LAD,n (%) LCX,n (%) Multivessel disease,n (%) SYNTAX score Intermediate to high SS,n (%)

Lipoprotein(a)

P value*

Tertile 1 (n Z 2238)

Tertile 2 (n Z 2238)

Tertile 3 (n Z 2238)

57.6  10.3 1748 (78.1) 26.0  3.2 1273 (56.9) 700 (31.3) 517 (23.1) 1452 (64.9) 61 (2.7) 40 (1.8)

58.2  10.3 1678 (75.0) 26.0  3.3 1215 (54.3) 647 (28.9) 570 (25.5) 1429 (63.9) 59 (2.6) 56 (2.5)

58.5  10.0 1568 (70.1) 25.7  3.2 1153 (51.5) 604 (27.0) 571 (25.5) 1442 (64.4) 55 (2.5) 61 (2.7)

0.009 <0.001 0.006 0.002 0.007 0.234 0.482 0.849 0.095

2210 (98.7) 2207 (98.6) 2012 (89.9) 2160 (96.5) 1131 (50.5) 64.2  6.2 92.8  13.8

2215 (99.0) 2205 (98.5) 1983 (88.6) 2153 (96.2) 1138 (50.8) 64.0  6.3 91.9  14.7

2209 (98.7) 2205 (98.5) 2018 (90.2) 2158 (96.4) 1117 (49.9) 63.8  6.7 91.4  14.6

0.676 0.959 0.187 0.167 0.815 0.254 0.005

6.8  1.7 142.5  15.4 4.1  1.1 2.4  0.9 1.03  0.28 2.0  1.4 346.2  87.5 6.6  1.2 1.47 (0.75e3.13) 5.33 (3.18e7.79)

6.9  1.9 140.9  15.8 4.3  1.1 2.6  0.9 1.04  0.28 1.7  1.0 337.9  83.2 6.6  1.2 1.85 (0.87e4.26) 18.23 (13.86e23.56)

6.9  1.8 139.8  16.3 4.4  1.1 2.7  1.0 1.0 6  0.28 1.67  0.8 334.7  83.5 6.7  1.2 1.93 (0.93e4.69) 53.94 (40.02e78.60)

0.447 <0.001 <0.001 <0.001 <0.001 <0.001 <0.001 0.748 <0.001 <0.001

53 (2.4) 395 (17.6) 2053 (91.7) 387 (17.3) 1591 (71.1) 9.0 (6.0e15.5) 207 (9.2)

51 (2.3) 397 (17.7) 2038 (91.1) 415 (18.5) 1633 (73.0) 10.0 (6.0e17.0) 231 (10.3)

51 (2.3) 465 (20.8) 1998 (89.3) 412 (18.4) 1681 (75.1) 11.0 (7.0e17.5) 277 (12.4)

0.974 0.009 0.014 0.214 0.010 <0.001 0.003

Values are expressed as mean # SD or n (%), median (interquartile range), SD: Standard deviation. BMI, body mass index; CAD, coronary artery disease; COPD, chronic obstructive pulmonary disease; LVEF, left ventricular ejection fraction; GFR, glomerular filtration rate; WBC, white blood cell; LDL-C,low-density lipoprotein cholesterol; HDL-C,high-density lipoprotein cholesterol; HbA1c, glycosylated hemoglobin; hsCRP:high sensitivity C reactive protein; LP(a), Lipoprotein(a); CCB, calcium channel blocker; LM, left main coronary artery disease; RCA, Right coronary artery disease; LAD, left anterior descending coronary artery; LCX, Left circumflex coronary artery. SS, SYNTAX score.*p values from ANOVA or KruskaleWallis test as appropriate for continuous variables and with Chi-square test for categorical variables. p values < 0.05 indicate statistical significance.

Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020

Chinese patients underwent percutaneous coronary intervention

three groups had similar major cardiac risk factors of hypertension, family history of CAD, peripheral vascular disease, chronic obstructive pulmonary disease (COPD), therapy at admission and LVEF on admission, except that patients in the tertile 3 group were older, had higher prevalence of multivessel disease. Moreover, patients in the tertile 3 group were lower male gender, body mass index, current smokers, DM and GFR. In general, angiographic characteristics showed that patients in the tertile 3 group had more frequency of right coronary artery lesions but less left anterior descending coronary artery, other artery lessions was not significantly different between the groups. A comparison of the laboratory parameters divided by Lp(a) showed that compared to the tertile 1 and tertile 2 groups, the tertile 3 group were presented with higher level of hsCRP, TC, LDL-C, HDL-C, but lower level of hemoglobin, TG and uric acid.

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Lp(a) and coronary severity We also examined the correlation of Lp(a) with SYNTAX score in patients with PCI. As shown in Fig. 2, there was a significant but weak positive correlation between Lp(a) and SYNTAX score in patients with PCI (n Z 6,714, r Z 0.062, p < 0.001). Univariate and multivariate logistic regression analyses of the association between intermediate to high SYNTAX score and multiple variables are listed in Table 2. On univariate analysis, the Lp(a) showed a strong association with intermediate to high SYNTAX score (p Z 0.002). The other univariate predictors of intermediate to high SYNTAX score were age, male gender, body mass index, smoking, DM, hypertension, LVEF, GFR, WBCc, hemoglobin, LDL-C, HDL-C, uric acid, and hs-CRP. The univariate screen identified significant predictors that were assessed by multivariate analysis. In multivariate analysis, the independent predictors of intermediate to high SYNTAX score were Lp(a) (odds ratio [OR] 1.004, 95% confidence interval [CI] 1.001 to 1.006, p Z 0.009) together with the LVEF (OR 0.975, 95% CI 0.964 to 0.987, p < 0.001), diabetes (OR 1.275, 95% CI 1.078 to 1.509, p Z 0.005), WBC count (OR 1.069, 95% CI 1.024 to 1.115, p Z 0.002) and hemoglobin (OR 0.990, 95% CI 0.985 to 0.995, p < 0.001).

Cardiovascular outcomes during follow-up

Figure 2 Scatterplot between Lp(a) and SS. Lp(a) and SS had a weak but significant correlation (r Z 0.062, p < 0.001). Pearson’s correlations were used to analyze the correlation between Lp(a) and SS. Lp(a), Lipoprotein(a).; SS, SYNTAX score.

The mean follow-up period was 874 days. There were 755 patients presented with MACCE (11.25%) were reported. The long-term cardiovascular outcomes were stratified comparing Lp(a) tertile groups (Table 3). The incidence rates of MACCE, all-cause mortality, cardiac death, target vessel revascularization, recurrent myocardial infarction, stent thrombosis, stroke and bleeding were not statistically different among the groups.

Table 2 Independent predictors of intermediate-high syntax score in patients underwent percutaneous coronary intervention. Variables

Age Male gender BMI Current smokers Diabetes mellitus Hypertension LVEF on admission GFR WBC Hemoglobin LDL-C HDL-C Uric Acid hsCRP LP(a)

Univariate

Multivariate*

Odds Ratio (95% CI)

P value

Odds Ratio (95% CI)

P value

1.019 0.966 0.982 0.883 1.378 1.061 0.968 0.986 1.079 0.986 0.978 0.737 1.000 1.034 1.004

<0.001 0.706 0.134 0.117 <0.001 0.476 <0.001 <0.001 <0.001 <0.001 0.563 0.035 0.499 <0.001 0.002

1.009 (0.999e1.020)

0.076

1.275 (1.078e1.509)

0.005

0.975 0.994 1.069 0.990

<0.001 0.056 0.002 <0.001

(1.011e1.027) (0.808e1.155) (0.958e1.006) (0.756e1.032) (1.170e1.622) (0.901e1.249) (0.957e0.979) (0.981e0.991) (1.037e1.124) (0.981e0.991) (0.896e1.062) (0.554e0.979) (0.999e1.001) (1.015e1.053) (1.002e1.007)

(0.964e0.987) (0.987e1.000) (1.024e1.115) (0.985e0.995)

0.740 (0.546e1.003)

0.052

1.003 (0.982e1.024) 1.004 (1.001e1.006)

0.812 0.009

Values are presented with odds ratio (95% confidence interval).*Age, diabetes mellitus, LVEF on admission, GFR, WBC, Hemoglobin, HDL-C, hsCRP, Lp(a) are included into the Multivariate Cox proportional hazard regression analysis. BMI, body mass index; LVEF, left ventricular ejection fraction; GFR, glomerular filtration rate; LDL-C,low-density lipoprotein cholesterol; HDLC,high-density lipoprotein cholesterol; hsCRP:high sensitivity C reactive protein; LP(a),Lipoprotein(a). p values < 0.05 indicate statistical significance.

Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020

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N. Xu et al.

Table 3 2-Year follow up clinical outcomes. Variables

Lipoprotein(a)

P Value*

Tertile 1 (n Z 2238)

Tertile 2 (n Z 2238)

Tertile 3 (n Z 2238)

All-Cause Mortality,n (%) Cardiac Death,n (%) Myocardial Infarction,n (%) Stent Thrombosis,n (%) Target Vessel Revascularization,n (%) Stroke,n (%) MACCE,n (%) Bleeding,n (%)

26 (1.2%) 7 (0.3%) 27 (1.2%) 15 (0.7%) 182 (8.1%) 37 (1.7%) 257 (11.5%) 142 (6.3%)

15 (0.7%) 6 (0.3%) 48 (2.1%) 17 (0.8%) 188 (8.4%) 27 (1.2%) 252 (11.3%) 152 (6.8%)

15 (0.7%) 8 (0.4%) 34 (1.5%) 9 (0.4%) 183 (8.2%) 29 (1.3%) 246 (11.0%) 171 (7.6%)

0.113 0.866 0.041 0.279 0.941 0.504 0.873 0.222

Values are expressed as n (%). *p values from Chi-square test for categorical variables. MACCE, major adverse cardiovascular and cerebrovascular events.*p values from Chi-square test for categorical variables. p values < 0.05 indicate statistical significance.

Lp(a) and MACCE The KaplaneMeier analysis demonstrated that there was no significant difference in the event-free (MACCE) survival rate among Lp(a) tertile groups (p Z 0.692, Fig. 3). To further test whether Lp(a) was independently related to MACCE, univariate Cox proportional hazard regression analysis was performed in this analysis (Table 4). It was found that continuous Lp(a) levels had no relationship with MACCE (hazard ratio [HR]: 0.999, 95% confidence interval [CI]: 0.997e1.002, p Z 0.654). Specifically, age, DM, hypertension, WBCc, multivessel disease and higher SYNTAX score were risk factors of MACCE (all p < 0.05), while higher GFR (p Z 0.003) and higher LVEF (p Z 0.015) were protective factors of MACCE. In the multivariate Cox proportional hazard regression analysis, it was more fully demonstrated that Lp(a) were not a predictor of MACCE in patients with PCI. However, we found that hypertension (HR 1.177, 95% CI 1.003e1.380, p Z 0.046), WBCc (HR 1.068, 95% CI 1.027e1.111, p Z 0.001), multivessel disease (HR 1.633, 95% CI 1.328e2.008, p < 0.001) and SYNTAX

Figure 3 Kaplan-Maier curves for MACCE among Lp(a) tertiles. Lp(a), Lipoprotein(a); MACCE, major adverse cardiovascular and cerebrovascular event.

score (HR 1.020, 95% CI 1.011e1.029, p < 0.001) were all independent risk factors of MACCE.

Discussion In the present study, we have shown that Lp(a) is an independent predictor of the prevalence of more complex coronary artery lesions (SYNTAX score
23) in patients with PCI. In addition, our study has shown that Lp(a) has no relationship with long-term cardiovascular outcomes in Chinese patients with PCI. These results are notable because there are no data about the relation between Lp(a) and cardiovascular events in terms of secondary prevention after PCI in Chinese patients. The relation of Lp(a) to the severity of CAD has less been investigated and also limited by small sample size or the different clinical backgrounds [8,23e25]. H.-W. Zhang et al. found that elevated Lp(a) levels were independently associated with the presence and severity of CAD in patients with T2DM and a cross-sectional study conducted by Sun di et al. on 1980 non-treated patients undergoing coronary angiography showed that Lp(a) is a useful marker for predicting the presence and severity of CAD [8,25]. From this point of view, our data demonstrated that elevated Lp(a) concentration was an independent predictor of the prevalence of more complex coronary artery lesions using a large Chinese cohort who underwent PCI. Also, we added tertiles analysis according to Lp(a) levels in order to perform a reliable relation of Lp(a) to the coronary severity in the present study. Thereby, our data with large sample size might provide additional and more important information with regard to the potential association of Lp(a) with the coronary severity in patients with PCI. Clinically, our study might indicate that Lp(a) is a useful marker for predicting severity of CAD and that more attention should be paid to Lp(a) management in patients with PCI. In fact, a large number of studies have already examined the associations between Lp(a) levels and the risk of cardiovascular diseases [14,22,26]. Especially, the recent two meta-analysis of prospective studies [22,26] and an

Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020

Chinese patients underwent percutaneous coronary intervention

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Table 4 Univariate and multivariate Cox proportional hazards regression analysis of the MACCE. Variables

Age Male gender BMI Current smokers Diabetes mellitus Hypertension Family history of CAD LVEF on admission GFR WBC Hemoglobin LDL-C HDL-C Uric Acid hsCRP Multivessel disease SYNTAX score LP(a)

Univariate

Multivariate*

hazards Ratio (95% CI)

P

hazards Ratio (95% CI)

P

1.010 1.081 1.000 1.020 1.284 1.245 1.043 0.987 0.993 1.085 0.998 1.021 0.927 1.001 1.016 1.998 1.030 0.999

0.004 0.358 0.978 0.781 0.001 0.005 0.612 0.015 0.003 <0.001 0.333 0.591 0.560 0.205 0.075 <0.001 <0.001 0.654

1.005 (0.996e1.015)

0.267

1.160 (0.995e1.353) 1.177 (1.003e1.380)

0.059 0.046

0.992 0.998 1.068 1.001

(0.981e1.003) (0.992e1.005) (1.027e1.111) (0.996e1.006)

0.152 0.627 0.001 0.656

0.998 1.633 1.020 0.999

(0.979e1.018) (1.328e2.008) (1.011e1.029) (0.996e1.001)

0.863 <0.001 <0.001 0.367

(1.003e1.018) (0.915e1.278) (0.978e1.022) (0.884e1.177) (1.104e1.492) (1.067e1.453) (0.886e1.229) (0.976e0.997) (0.988e0.998) (1.045e1.125) (0.993e1.002) (0.946e1.103) (0.718e1.197) (1.000e1.001) (0.998e1.034) (1.645e2.427) (1.022e1.038) (0.997e1.002)

Values are presented with odds ratio (95% confidence interval). *Age, diabetes mellitus, hypertension, LVEF on admission, GFR, WBC, Hemoglobin, hsCRP, multivessel disease, SYNTAX score, Lp(a) are included into the Multivariate Cox proportional hazard regression analysis. BMI, body mass index; CAD, coronary artery disease; LVEF, left ventricular ejection fraction; GFR, glomerular filtration rate; WBC, white blood cell; LDL-C,low-density lipoprotein cholesterol; HDL-C,high-density lipoprotein cholesterol; hsCRP:high sensitivity C reactive protein; LP(a),Lipoprotein(a). p values < 0.05 indicate statistical significance.

international, standardized case-control study (INTERHEART) showed that elevated Lp(a) concentrations were associated with an increased risk of cardiovascular events, but the results varied markedly among ethnic groups and different areas. Guillaume Paré et al. found that Chinese patients had the lowest concentration (median Z 7.8 mg/ dL) and largest isoform sizes (median Z 28) [14], and Christoph Waldeyer et al. performed a meta-analysis of 7 cohorts from 5 European countries with 56,804 individuals and a maximum follow-up time of 24 years within the Biomarker for Cardiovascular Risk Assessment in Europe (BiomarCaRE) project, the results show that regional differences within the European population have a different Lp(a) concentration and elevated Lp(a) was associated with an increased risk for cardiovascular events in particular among individuals with diabetes [22]. Also, Several studies have associated high serum levels of Lp(a) with increased of risk for cardiovascular diseases [27,28], whereas others have not [29,30]. Such as Michael G. Shlipak et al. studied the predict value of novel risk factors as Lp(a) with elderly persons with chronic kidney disease, and the results showed that Lp(a) was not associated with cardiovascular mortality among those elderly persons with chronic kidney disease [29]. Therefore, the inconsistent effects of Lp(a) on cardiovascular outcomes in different background patients may also imply that the role of Lp(a) in cardiometabolic diseases is complicated and should to be careful investigated. At the same time, large-sample study with respect to the association of Lp(a) level and cardiovascular outcomes of patients with PCI were still few. That is the reason why we performed the present

study using a large Chinese cohort. In our study, we found that Lp(a) has no relationship with long-term cardiovascular outcomes in Chinese patients with PCI. The conflicting results among studies might probably be due to multiple confounders, for example, the different population characteristics (age, sex, ethnicity, treatment), study design (cross-sectional or prospective, follow-up duration and sample size), disease status (duration of diabetes and its comorbidity), confounding variables (lipid disorders), or the assay methods of Lp(a). Whether Lp(a) is associated with the cardiovascular events or not depending on different situations such as the its concentration. Several previous studies have already indicated relations between serum Lp(a)
30 mg/dl and increased risk of cardiovascular disease in patients with CAD [31,32]. Especially, the recent INTERHEART study shows that high Lp(a) concentrations (>50 mg/dL) were associated with an increased risk of myocardial infarction (OR, 1.48; 95% CI, 1.32e1.67; p < 0.001) [3]. However, the media Lp(a) of our study was only 18.23 mg/dl, the value of the Lp(a) was relatively low, which may properly explain our results that Lp(a) was not associated cardiovascular outcomes in cohort of Chinese patients with PCI. In addition, almost all PCI patients received moderate-or high-intensity statin therapy for secondary prevention after enrollment, and the mean LDLC level of this study patients was 2.65 mmol/L, the relative low LDL-C lever may also affect the association of Lp(a) with the cardiovascular outcomes. To conclude, more studies are needed to investigate the relationship between Lp(a) and long-term cardiovascular outcomes with Chinese PCI patients.

Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020

8

N. Xu et al.

There are several limitations in the present study. Firstly, the study was a single center study, which might result in selective biases. Secondly, we measured Lp(a) only at baseline, and the follow-up levels of Lp(a) may also be clinically significant. Finally, although there was statistical significance between Lp(a) levels and the coronary severity in patients with PCI, the power was relatively weak and more studies are needed to confirm our findings. Conclusions Although the role of Lp(a) in cardiovascular risk has been previously evaluated, the present cohort study revealed that Lp(a) is an independent predictor of coronary severity in patients underwent PCI, however it has no relationship with long-term cardiovascular outcomes in Chinese patients with PCI. These findings might clinically indicate that Lp(a) is a useful marker for predicting the presence and severity of patients underwent PCI. Author contributions NX contributed to all aspects of this study, including study concept and design, data acquisition, analysis, and interpretation, drafting and revising the report. JQY contributed to providing revision of the report. YY, SDJ, YL, XYZ, JC contributed to data acquisition. ZG, XFT contributed to statistical analysis. JQY, RLG, YJY, and XB worked closely with NX and contributed to initial study conception and design, data interpretation, and critical revision of the report. All authors have approved the final article. Funding and acknowledgement The study was funded by National Key Research and Development Program of China during the 13th Five-Year Plan Period (Grant number: 2016YFC1301300) and subproject (Grant number: 2016YFC1301301); National Natural Science Foundation of China (Grant number: 81770365). We are grateful to the Department of Cardiology, Cardiovascular Institute of Fuwai Hospital for its help in recruiting patients. We thank all members who contributed to the study. Declaration of Competing Interest The Authors declare that there is no conflict of interest. References [1] Gaubatz JW, Heideman C, Gotto Jr AM, Morrisett JD, Dahlen GH. Human plasma lipoprotein (a)-Structural properties. J Biol Chem 1983;258(7):4582e9. [2] Mbewu AD, Durrington PN. Lipoprotein (a): structure, properties and possible involvement in thrombogenesis and atherogenesis. Atherosclerosis 1990;85(1):1e14. [3] Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res 2016;57(5): 745e57.

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Please cite this article as: Xu N et al., Lipoprotein(a) levels are associated with coronary severity but not with outcomes in Chinese patients underwent percutaneous coronary intervention, Nutrition, Metabolism & Cardiovascular Diseases, https://doi.org/10.1016/ j.numecd.2019.09.020