Association of lipoprotein(a) with all-cause and cause-specific mortality: A prospective cohort study

  • Author Footnotes
    1 Zhen-Wei Wang, Min Li and Jing-Jie Li contributed equally to this work.
    Zhen-Wei Wang
    1 Zhen-Wei Wang, Min Li and Jing-Jie Li contributed equally to this work.
    Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
    Search for articles by this author
  • Author Footnotes
    1 Zhen-Wei Wang, Min Li and Jing-Jie Li contributed equally to this work.
    Min Li
    1 Zhen-Wei Wang, Min Li and Jing-Jie Li contributed equally to this work.
    Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
    Search for articles by this author
  • Author Footnotes
    1 Zhen-Wei Wang, Min Li and Jing-Jie Li contributed equally to this work.
    Jing-Jie Li
    1 Zhen-Wei Wang, Min Li and Jing-Jie Li contributed equally to this work.
    Department of Hematology and Oncology, Affiliated Xuchang People's Hospital of Xinxiang Medical College, Xuchang, China
    Search for articles by this author
  • Nai-Feng Liu
    Corresponding author.
    Department of Cardiology, Zhongda Hospital, School of Medicine, Southeast University, Nanjing, China
    Search for articles by this author
  • Author Footnotes
    1 Zhen-Wei Wang, Min Li and Jing-Jie Li contributed equally to this work.
Published:September 18, 2022DOI:


      • Lp(a) was closely associated with all-cause and cause-specific mortality.
      • Lp(a) was linearly associated with all-cause and cause-specific mortality.
      • The association between Lp(a) and mortality remained robust in some populations.



      A growing number of studies have demonstrated a causal association between lipoprotein(a) [Lp(a)] and atherosclerotic cardiovascular diseases (ASCVDs), but its association with all-cause and cause-specific mortality remains unclear. Therefore, this study aimed to explore the association of Lp(a) with all-cause and cause-specific mortality.


      This prospective cohort study included 8,525 participants from the third National Health and Nutrition Examination Survey. Lp(a) was considered an exposure variable, all-cause and cause-specific mortality were used as outcome variables, and all participants were followed from the interview date until death or December 31, 2015. COX proportional hazards regression models, stratified analysis, sensitivity analysis, restricted cubic spline plots and Kaplan-Meier survival curves were used to analyze the association of Lp(a) with all-cause and cause-specific mortality.


      After adjusting for traditional cardiovascular risk factors, Lp(a) remained strongly associated with all-cause and CVDs-related mortality (P for trend = 0.007 and < 0.001). Subgroup analyses showed that higher Lp(a) remained associated with higher risk of all-cause mortality in those > 60 years of age, with a BMI < 30 kg/m2, and without diabetes, whereas the association between Lp(a) and CVDs-related mortality remained stable in participants ≤ 60 years of age, male, with a BMI < 30 kg/m2, with hypertension, without diabetes, or without CVDs (P < 0.05). In sensitivity analyses, we found that the association of Lp(a) with all-cause and CVDs-related mortality remained robust after excluding individuals who died within one year of follow-up (P for trend = 0.041 and 0.002).


      Lp(a) was associated with the risk of all-cause and CVDs-related mortality.


      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'


      Subscribe to European Journal of Internal Medicine
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect


        • BERG K
        A new serum type system in man—the LP system.
        Acta Pathol Microbiol Scand. 1963; 59: 369-382
        • Tsimikas S.
        A test in context: lipoprotein(a): diagnosis, prognosis, controversies, and emerging therapies.
        J Am Coll Cardiol. 2017; 69: 692-711
        • Berg K
        • Dahlén G
        • Frick MH.
        Lp(a) lipoprotein and pre-beta1-lipoprotein in patients with coronary heart disease.
        Clin Genet. 1974; 6: 230-235
        • Paré G
        • Çaku A
        • McQueen M
        • et al.
        Lipoprotein(a) levels and the risk of myocardial infarction among 7 ethnic groups.
        Circulation. 2019; 139: 1472-1482
        • Guan W
        • Cao J
        • Steffen BT
        • et al.
        Race is a key variable in assigning lipoprotein(|a) cutoff values for coronary heart disease risk assessment: the multi-ethnic study of atherosclerosis.
        Arterioscler Thromb Vasc Biol. 2015; 35: 996-1001
        • Wang Z
        • Zhai X
        • Xue M
        • Cheng W
        • Hu H.
        Prognostic value of lipoprotein (a) level in patients with coronary artery disease: a meta-analysis.
        Lipids Health Dis. 2019; 18 (Published 2019 Jul 8): 150
        • Tsimikas S
        • Fazio S
        • Ferdinand KC
        • et al.
        NHLBI working group recommendations to reduce lipoprotein(a)-mediated risk of cardiovascular disease and aortic stenosis.
        J Am Coll Cardiol. 2018; 71: 177-192
        • Kamstrup PR
        • Tybjærg-Hansen A
        • Nordestgaard BG.
        Extreme lipoprotein(a) levels and improved cardiovascular risk prediction.
        J Am Coll Cardiol. 2013; 61: 1146-1156
        • Collaboration Emerging Risk Factors
        • S Erqou
        • Kaptoge S
        • et al.
        Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
        JAMA. 2009; 302: 412-423
        • Consortium CARDIoGRAMplusC4D
        • Deloukas P
        • Kanoni S
        • et al.
        Large-scale association analysis identifies new risk loci for coronary artery disease.
        Nat Genet. 2013; 45: 25-33
        • Zhang M
        • Liu HH
        • Jin JL
        • Yan XN
        • Dong Q
        • Li JJ.
        Lipoprotein(a) and cardiovascular death in oldest-old (≥80 years) patients with acute myocardial infarction: a prospective cohort study.
        Atherosclerosis. 2020; 312: 54-59
      1. Plan and operation of the Third National Health and Nutrition Examination Survey, 1988-94. Series 1: programs and collection procedures.
        Vital Health Stat 1. 1994; : 1-407
        • Schmidt K
        • Noureen A
        • Kronenberg F
        • Utermann G.
        Structure, function, and genetics of lipoprotein (a).
        J Lipid Res. 2016; 57: 1339-1359
        • Kronenberg F.
        Human genetics and the causal role of lipoprotein(a) for various diseases.
        Cardiovasc Drugs Ther. 2016; 30: 87-100
        • Thomas T
        • Zhou H
        • Karmally W
        • et al.
        CETP (cholesteryl ester transfer protein) inhibition with anacetrapib decreases production of lipoprotein(a) in mildly hypercholesterolemic subjects.
        Arterioscler Thromb Vasc Biol. 2017; 37: 1770-1775
        • Scanu AM
        • Bamba R.
        Niacin and lipoprotein(a): facts, uncertainties, and clinical considerations.
        Am J Cardiol. 2008; 101 (44B–47B)
        • Nandakumar R
        • Matveyenko A
        • Thomas T
        • et al.
        Effects of mipomersen, an apolipoprotein B100 antisense, on lipoprotein (a) metabolism in healthy subjects.
        J Lipid Res. 2018; 59: 2397-2402
        • O'Donoghue ML
        • Fazio S
        • Giugliano RP
        • et al.
        Lipoprotein(a), PCSK9 inhibition, and cardiovascular risk.
        Circulation. 2019; 139: 1483-1492
        • Yeang C
        • Hung MY
        • Byun YS
        • et al.
        Effect of therapeutic interventions on oxidized phospholipids on apolipoprotein B100 and lipoprotein(a).
        J Clin Lipidol. 2016; 10: 594-603
        • Yeang C
        • Witztum JL
        • Tsimikas S
        'LDL-C' = LDL-C + Lp(a)-C: implications of achieved ultra-low LDL-C levels in the proprotein convertase subtilisin/kexin type 9 era of potent LDL-C lowering.
        Curr Opin Lipidol. 2015; 26: 169-178
        • Contois JH
        • Nguyen RA
        • Albert AL.
        Lipoprotein(a) particle number assay without error from apolipoprotein(a) size isoforms.
        Clin Chim Acta. 2020; 505: 119-124
        • Sandholzer C
        • Hallman DM
        • Saha N
        • et al.
        Effects of the apolipoprotein(a) size polymorphism on the lipoprotein(a) concentration in 7 ethnic groups.
        Hum Genet. 1991; 86: 607-614
        • Clarke R
        • Peden JF
        • Hopewell JC
        • et al.
        Genetic variants associated with Lp(a) lipoprotein level and coronary disease.
        N Engl J Med. 2009; 361: 2518-2528
        • Cai DP
        • He YM
        • Yang XJ
        • Zhao X
        • Xu HF.
        Lipoprotein (a) is a risk factor for coronary artery disease in Chinese Han ethnic population modified by some traditional risk factors: a cross-sectional study of 3462 cases and 6125 controls.
        Clin Chim Acta. 2015; 451: 278-286
        • Brandt EJ
        • Mani A
        • Spatz ES
        • Desai NR
        • Nasir K.
        Lipoprotein(a) levels and association with myocardial infarction and stroke in a nationally representative cross-sectional US cohort.
        J Clin Lipidol. 2020; 14: 695-706.e4
        • Cui FM
        • Fang F
        • He YM
        • Cai DP
        • He J
        • Yang XJ.
        Establishing age and sex dependent upper reference limits for the plasma lipoprotein (a) in a Chinese health check-up population and according to its relative risk of primary myocardial infarction.
        Clin Chim Acta. 2018; 484: 232-236
        • Willeit P
        • Ridker PM
        • Nestel PJ
        • et al.
        Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials.
        Lancet. 2018; 392: 1311-1320
        • Kamstrup PR
        • Tybjaerg-Hansen A
        • Steffensen R
        • Nordestgaard BG.
        Genetically elevated lipoprotein(a) and increased risk of myocardial infarction.
        JAMA. 2009; 301: 2331-2339
        • Luke MM
        • Kane JP
        • Liu DM
        • et al.
        A polymorphism in the protease-like domain of apolipoprotein(a) is associated with severe coronary artery disease.
        Arterioscler Thromb Vasc Biol. 2007; 27: 2030-2036
        • Trégouët DA
        • König IR
        • Erdmann J
        • et al.
        Genome-wide haplotype association study identifies the SLC22A3-LPAL2-LPA gene cluster as a risk locus for coronary artery disease.
        Nat Genet. 2009; 41: 283-285
        • Saleheen D
        • Haycock PC
        • Zhao W
        • et al.
        Apolipoprotein(a) isoform size, lipoprotein(a) concentration, and coronary artery disease: a mendelian randomisation analysis.
        Lancet Diabetes Endocrinol. 2017; 5 ([published correction appears in Lancet Diabetes Endocrinol. 2017 Sep;5(9):e6]): 524-533
        • Fogacci F
        • Cicero AF
        • D'Addato S
        • et al.
        Serum lipoprotein(a) level as long-term predictor of cardiovascular mortality in a large sample of subjects in primary cardiovascular prevention: data from the Brisighella Heart Study.
        Eur J Intern Med. 2017; 37: 49-55
        • Langsted A
        • Kamstrup PR
        • Nordestgaard BG.
        High lipoprotein(a) and high risk of mortality.
        Eur Heart J. 2019; 40: 2760-2770
        • Arsenault BJ
        • Pelletier W
        • Kaiser Y
        • et al.
        Association of long-term exposure to elevated lipoprotein(a) levels with parental life span, chronic disease-free survival, and mortality risk: a Mendelian randomization analysis.
        JAMA Netw Open. 2020; 3e200129
        • Duarte Lau F
        • Giugliano RP
        Lipoprotein(a) and its significance in cardiovascular disease: a review.
        JAMA Cardiol. 2022; 7: 760-769
        • Deb A
        • Caplice NM.
        Lipoprotein(a): new insights into mechanisms of atherogenesis and thrombosis.
        Clin Cardiol. 2004; 27: 258-264
        • Nielsen LB.
        Atherogenecity of lipoprotein(a) and oxidized low density lipoprotein: insight from in vivo studies of arterial wall influx, degradation and efflux.
        Atherosclerosis. 1999; 143: 229-243
        • Boffa MB
        • Koschinsky ML.
        Oxidized phospholipids as a unifying theory for lipoprotein(a) and cardiovascular disease.
        Nat Rev Cardiol. 2019; 16: 305-318
        • Boffa MB
        • Marcovina SM
        • Koschinsky ML.
        Lipoprotein(a) as a risk factor for atherosclerosis and thrombosis: mechanistic insights from animal models.
        Clin Biochem. 2004; 37: 333-343
        • Zheng KH
        • Tsimikas S
        • Pawade T
        • et al.
        Lipoprotein(a) and oxidized phospholipids promote valve calcification in patients with aortic stenosis.
        J Am Coll Cardiol. 2019; 73: 2150-2162
        • Otto CM
        • Lind BK
        • Kitzman DW
        • Gersh BJ
        • Siscovick DS.
        Association of aortic-valve sclerosis with cardiovascular mortality and morbidity in the elderly.
        N Engl J Med. 1999; 341: 142-147
        • Liu Q
        • Yu Y
        • Xi R
        • et al.
        Association between lipoprotein(a) and calcific aortic valve disease: a systematic review and meta-analysis.
        Front Cardiovasc Med. 2022; 9 (Published 2022 Apr 25)877140
        • Steffen BT
        • Duprez D
        • Bertoni AG
        • Guan W
        • Tsai MY.
        Lp(a) [Lipoprotein(a)]-related risk of heart failure is evident in whites but not in other racial/ethnic groups.
        Arterioscler Thromb Vasc Biol. 2018; 38: 2498-2504
        • Garg PK
        • Guan W
        • Karger AB
        • et al.
        Lp(a) (Lipoprotein [a]) and risk for incident atrial fibrillation: multi-ethnic study of atherosclerosis.
        Circ Arrhythm Electrophysiol. 2020; 13e008401
        • Ward NC
        • Nolde JM
        • Chan J
        • Carnagarin R
        • Watts GF
        • Schlaich MP.
        Lipoprotein (a) and hypertension.
        Curr Hypertens Rep. 2021; 23 (Published 2021 Dec 9): 44
        • Dentali F
        • Gessi V
        • Marcucci R
        • Gianni M
        • Grandi AM
        • Franchini M.
        Lipoprotein(a) as a risk factor for venous thromboembolism: a systematic review and meta-analysis of the literature.
        Semin Thromb Hemost. 2017; 43: 614-620
        • Lamina C
        • Ward NC.
        Lipoprotein (a) and diabetes mellitus.
        Atherosclerosis. 2022; 349: 63-71
        • Akinyemiju T
        • Moore JX
        • Judd SE
        • Pisu M
        • Goodman M
        • Howard VJ
        • et al.
        Pre-diagnostic biomarkers of metabolic dysregulation and cancer mortality.
        Oncotarget. 2018; 9: 16099-16109
        • Sawabe M
        • Tanaka N
        • Mieno MN
        • Ishikawa S
        • Kayaba K
        • Nakahara K
        • et al.
        Low lipoprotein(a) concentration is associated with cancer and all-cause deaths: a population-based cohort study (the JMS cohort study).
        PLoS One. 2012; 7: e31954
        • Chan JE
        • Mann AK
        • Kapp DS
        • Rehkopf DH.
        Income, inflammation and cancer mortality: a study of U.S. National Health and Nutrition Examination Survey mortality follow-up cohorts.
        BMC Public Health. 2020; 20: 1805
        • Deng T
        • Lyon CJ
        • Bergin S
        • Caligiuri MA
        • Hsueh WA.
        Obesity, inflammation, and cancer.
        Annu Rev Pathol. 2016; 11: 421-449