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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

  • Author Footnotes
    1 F. Fogacci and A.F.G. Cicero are the first authors since they equally contributed to the paper.
    Federica Fogacci
    Correspondence
    Corresponding author at: Medical and Surgical Sciences Dept., Sant'Orsola-Malpighi University Hospital, Dyslipidemia and Atherosclerosis Research Group, U.O. Medicina Interna Borghi - Via Albertoni, 15, 40138, Bologna, Italy.
    Footnotes
    1 F. Fogacci and A.F.G. Cicero are the first authors since they equally contributed to the paper.
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
    Search for articles by this author
  • Author Footnotes
    1 F. Fogacci and A.F.G. Cicero are the first authors since they equally contributed to the paper.
    Arrigo Francesco Giuseppe Cicero
    Footnotes
    1 F. Fogacci and A.F.G. Cicero are the first authors since they equally contributed to the paper.
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
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  • Sergio D'Addato
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
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  • Laura D'Agostini
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
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  • Martina Rosticci
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
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  • Marina Giovannini
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
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  • Enrico Bertagnin
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
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  • Claudio Borghi
    Affiliations
    Atherosclerosis and Metabolic diseases Research Unit, Medical and Surgical Sciences Dept., University of Bologna, Italy
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  • on behalf of the Brisighella Heart Study Group
  • Author Footnotes
    1 F. Fogacci and A.F.G. Cicero are the first authors since they equally contributed to the paper.
Published:August 20, 2016DOI:https://doi.org/10.1016/j.ejim.2016.08.018

      Abstract

      Background

      High lipoprotein(a) [Lp(a)] levels have been re-evaluated as an independent risk factor for atherosclerotic vascular diseases.

      Methods

      We assessed whether serum Lp(a) levels can significantly influence long-term survival in subjects with an equal general cardiovascular (CV) risk profile.
      We prospectively evaluated a sample of 1215 adult subjects from the Brisighella Heart Study cohort (M: 608; F: 607; aged 40–69) who had no cardiovascular disease at enrolment. According to the CUORE project risk-charts (Italian-specific risk-charts), individuals were stratified into a low—(n = 865), an intermediate—(n = 275) and a high—(n = 75) cardiovascular risk groups. Kaplan–Meier 25-year survival analysis was carried out examining apart each class of risk and the log-rank statistic was used to estimate, when statistically possible, the survival time of the subjects stratified into quartiles of Lp(a).

      Results

      Subjects at high and intermediate CV risk aged 56–69 years (regardless of gender) and women aged 40–55 years with a low CV risk profile who had lower Lp(a) levels showed a significant benefit on CV mortality (P < 0.05 always) and, indicatively, on the estimated survival time (even P < 0.05). The ROC curves constructing for each CV risk group using Lp(a) as test-variable and death as state-variable identified serum Lp(a) as an independent long-term CV mortality prognosticator for subjects at high CV risk (AUC = 0.63, 95%CI [0.50–0.76], P = 0.049) and women with an intermediate CV risk profile (AUC = 0.7, 95%CI [0.52–0.79], P = 0.034).

      Conclusions

      In the light of our finding and at the best of the previous knowledge, dosing Lp(a) is confirmed as important in subjects at high or medium risk (even if in primary prevention for CV diseases), especially in women.

      Keywords

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      References

        • McLean J.W.
        • Tomlinson J.E.
        • Kuang W.J.
        • Eaton D.L.
        • Chen E.Y.
        • Fless G.M.
        • et al.
        cDNA sequence of human apolipoprotein(a) is homologous to plasminogen.
        Nature. 1987; 330: 132-137
        • Boerwinkle E.
        • Leffert C.C.
        • Lin J.
        • Lackner C.
        • Chiesa G.
        • Hobbs H.H.
        Apolipoprotein(a) gene accounts for greater than 90% of the variation in plasma lipoprotein(a) concentrations.
        J Clin Invest. 1992; 90: 52-60
        • Kamstrup P.R.
        • Benn M.
        • Tybjaerg-Hansen A.
        • Nordestgaard B.G.
        Extreme lipoprotein(a) levels and risk of myocardial infarction in the general population: the Copenhagen City Heart Study.
        Circulation. Jan 15 2008; 117: 176-184
        • Erqou S.
        • Thompson A.
        • Di Angelantonio E.
        • Saleheen D.
        • Kaptoge S.
        • Marcovina S.
        • et al.
        Apolipoprotein(a) isoforms and the risk of vascular disease: systematic review of 40 studies involving 58,000 participants.
        J Am Coll Cardiol. May 11 2010; 55: 2160-2167https://doi.org/10.1016/j.jacc.2009.10.080
        • Nordestgaard B.G.
        • Chapman M.J.
        • Ray K.
        • Borén J.
        • Andreotti F.
        • Watts G.F.
        • et al.
        Lipoprotein(a) as a cardiovascular risk factor: current status.
        Eur Heart J. Dec 2010; 31: 2844-2853https://doi.org/10.1093/eurheartj/ehq386
        • Brown W.V.
        • Moriarty P.M.
        • Remaley A.T.
        • Tsimikas S.
        JCL roundtable: should we treat elevations in Lp(a)?.
        J Clin Lipidol. Mar-Apr 2016; 10: 215-224https://doi.org/10.1016/j.jacl.2016.02.012
        • Tselmin S.
        • Müller G.
        • Gelgaft E.
        • Fischer S.
        • Julius U.
        An elevated lipoprotein(a) plasma level as a cardiovascular risk factor.
        Atheroscler Suppl. May 2015; 18: 257-262https://doi.org/10.1016/j.atherosclerosissup.2015.02.038
        • Costello B.T.
        • Silverman E.R.
        • Doukky R.
        • Braun L.T.
        • Aggarwal N.T.
        • Deng Y.
        • et al.
        Lipoprotein(a) and increased cardiovascular risk in women.
        Clin Cardiol. 2016 Feb; 39: 96-102https://doi.org/10.1002/clc.22500
        • Catapano A.L.
        • Reiner Z.
        • De Backer G.
        • Graham I.
        • Taskinen M.R.
        • Wiklund O.
        • et al.
        ESC/EAS Guidelines for the management of dyslipidaemias. The Task Force for the management of dyslipidaemias of the European Society of Cardiology (ESC) and the European Atherosclerosis Society (EAS).
        Atherosclerosis. Jul 2011; 217: 3-46
        • Kronenberg F.
        Human genetics and the causal role of lipoprotein(a) for various diseases.
        Cardiovasc Drugs Ther. 2016; 30: 87-100https://doi.org/10.1007/s10557-016-6648-3
        • Kamstrup P.R.
        • Nordestgaard B.G.
        Lipoprotein(a) concentrations, isoform size, and risk of type 2 diabetes: a Mendelian randomisation study.
        Lancet Diabetes Endocrinol. 2013; 1: 220-227https://doi.org/10.1016/S2213-8587(13)70064-0
        • Cicero A.F.
        • Morbini M.
        • Urso R.
        • Rosticci M.
        • Parini A.
        • Grandi E.
        • et al.
        Association between self-reported snoring and arterial stiffness: data from the Brisighella Heart Study.
        Intern Emerg Med. 2016; 11: 77-83https://doi.org/10.1007/s11739-015-1310-9
        • Cicero A.F.G.
        • Dormi A.
        • D'Addato S.
        • Borghi C.
        • on behalf of the Brisighella Heart Study Staff
        From risk factor assessment to cardiovascular disease risk and mortality modification: the first 40 years of the Brisighella Heart Study.
        Clin Lipidol. 2011; 6: 269-276
        • Cicero A.F.
        • D'Addato S.
        • Santi F.
        • Ferroni A.
        • Borghi C.
        • Brisighella Heart Study
        Leisure-time physical activity and cardiovascular disease mortality: the Brisighella Heart Study.
        J Cardiovasc Med. 2012; 13: 559-564
        • Cicero A.F.
        • Rosticci M.
        • Tocci G.
        • Bacchelli S.
        • Urso R.
        • D'Addato S.
        • et al.
        Serum uric acid and other short-term predictors of electrocardiographic alterations in the Brisighella Heart Study cohort.
        Eur. J. Intern Med. 2015 May; 26: 255-258https://doi.org/10.1016/j.ejim.2015.02.007
        • Cicero A.F.
        • Derosa G.
        • Rosticci M.
        • D'Addato S.
        • Agnoletti D.
        • Borghi C.
        • et al.
        Long-term predictors of impaired fasting glucose and type 2 diabetes in subjects with family history of type 2 diabetes: a 12-years follow up of the Brisighella Heart Study historical cohort.
        Diabetes Res. Clin. Pract. 2014 Apr; 104: 183https://doi.org/10.1016/j.diabres.2014.02.005
        • Cicero A.F.
        • D'Addato S.
        • Veronesi M.
        • Rosticci M.
        • Santi F.
        • Dormi A.
        • et al.
        Brisighella Heart Study Group. Relationship between blood pressure, cholesterolemia and serum apolipoprotein B in a large population sample: the Brisighella Heart Study.
        J Hypertens. 2012; 30: 492-496
        • Earley A.
        • Miskulin D.
        • Ej L.
        • Levey A.S.
        • Uhlig K.
        Estimating equations for glomerular filtration rate in the era of creatinine standardization: a systematic review.
        Ann Intern Med. 2012; 156: 785-795
        • Cicero A.F.
        • Reggi A.
        • Tartagni E.
        • Grandi E.
        • D'Addato S.
        • Borghi C.
        • et al.
        Dietary determinants of oxidized-low-density lipoprotein antibodies in a sample of pharmacologically untreated non-smoker subjects: data from the Brisighella heart study.
        Adv Clin Exp Med. Jan-Feb 2013; 22: 69-76
        • Giampaoli S.
        CUORE: a sustainable cardiovascular disease prevention strategy.
        Eur J Cardiovasc Prev Rehabil. Apr 2007; 14: 161-162
        • Giampaoli S.
        • Palmieri M.
        • Donfrancesco C.
        • Panico S.
        • Vanuzzo D.
        • Pilotto L.
        • et al.
        Cardiovascular risk assessment in Italy: the CUORE project risk score and risk chart.
        Ital J Public Health. 2007; 4: 102-109
        • Donfrancesco C.
        • Palmieri L.
        • Cooney M.T.
        • Vanuzzo D.
        • Panico S.
        • Cesana G.
        • et al.
        Italian cardiovascular mortality charts of the CUORE project: are they comparable with the SCORE charts?.
        Eur J Cardiovasc Prev Rehabil. Aug 2010; 17: 403-409https://doi.org/10.1097/HJR.0b013e328334ea70
        • Donfrancesco C.
        • Palmieri L.
        • Vanuzzo D.
        • Panico S.
        • Ferrario M.M.
        • Cesana G.
        • et al.
        The CUORE project: preliminary analysis for the updating of the cardiovascular risk charts and individual scores.
        G Ital Cardiol (Rome). May 2010; 11: 20S-24S
        • Rydén L.
        • Grant P.J.
        • Anker S.D.
        • Berne C.
        • Cosentino F.
        • Danchin N.
        • et al.
        ESC Guidelines on diabetes, pre-diabetes, and cardiovascular diseases developed in collaboration with the EASD: the Task Force on diabetes, pre-diabetes, and cardiovascular diseases of the European Society of Cardiology (ESC) and developed in collaboration with the European Association for the Study of Diabetes (EASD).
        Eur Heart J. Oct 2013; 34: 3035-3087https://doi.org/10.1093/eurheartj/eht108
        • Bewick V.
        • Cheek L.
        • Ball J.
        Statistics review 12: survival analysis.
        Crit Care. 2004; 8: 389-394
        • Erqou S.
        • Kaptoge S.
        • Perry P.L.
        • Di Angelantonio E.
        • Thompson A.
        • et al.
        • Emerging Risk Factors Collaboration
        Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
        JAMA. Jul 22 2009; 302: 412-423https://doi.org/10.1001/jama.2009.1063
        • Smolders B.
        • Lemmens R.
        • Thijs V.
        Lipoprotein (a) and stroke: a meta-analysis of observational studies.
        Stroke. Jun 2007; 38: 1959-1966
        • Kamstrup P.R.
        • Nordestgaard B.G.
        Elevated lipoprotein(a) levels, LPA risk genotypes, and increased risk of heart failure in the general population.
        JACC Heart Fail. Jan 2016; 4: 78-87https://doi.org/10.1016/j.jchf.2015.08.006
        • Moriarty P.M.
        • Hemphill L.
        Lipoprotein apheresis.
        Endocrinol Metab Clin North Am. Mar 2016; 45: 39-54https://doi.org/10.1016/j.ecl.2015.09.003
        • Kajinami K.
        Lipoprotein(a): revisiting a next therapeutic target.
        Circ J. Jan 25 2016; 80: 329-331https://doi.org/10.1253/circj.CJ-15-1381
        • HPS2-THRIVE Collaborative Group
        HPS2-THRIVE randomized placebo-controlled trial in 25 673 high-risk patients of ER niacin/laropiprant: trial design, pre-specified muscle and liver outcomes, and reasons for stopping study treatment.
        Eur Heart J. May 2013; 34: 1279-1291https://doi.org/10.1093/eurheartj/eht055
        • Anderson T.J.
        • Boden W.E.
        • Desvigne-Nickens P.
        • Fleg J.L.
        • Kashyap M.L.
        • McBride R.
        • et al.
        Safety profile of extended-release niacin in the AIM-HIGH trial.
        N Engl J Med. Jul 17 2014; 371: 288-290https://doi.org/10.1056/NEJMc1311039
        • Raal F.J.
        • Giugliano R.P.
        • Sabatine M.S.
        • Koren M.J.
        • Blom D.
        • Seidah N.G.
        • et al.
        PCSK9 inhibition-mediated reduction in Lp(a) with evolocumab: an analysis of 10 clinical trials and the role of the LDL receptor.
        J Lipid Res. Apr 21 2016; ([pii: jlr.P065334])
        • Stein E.A.
        • Raal F.
        Future directions to establish lipoprotein(a) as a treatment for atherosclerotic cardiovascular disease.
        Cardiovasc Drugs Ther. Feb 2016; 30: 101-108https://doi.org/10.1007/s10557-016-6654-5
        • Banerjee Y.
        • Santos R.D.
        • Al-Rasadi K.
        • Rizzo M.
        Targeting PCSK9 for therapeutic gains: have we addressed all the concerns?.
        Atherosclerosis. Mar 9 2016; 248: 62-75https://doi.org/10.1016/j.atherosclerosis.2016.02.018
        • Haring B.
        • von Ballmoos M.C.
        • Appel L.J.
        Sacks FM4. Healthy dietary interventions and lipoprotein (a) plasma levels: results from the Omni heart trial.
        PLoS One. Dec 15 2014; 9: e114859https://doi.org/10.1371/journal.pone.0114859
        • Serban M.C.
        • Sahebkar A.
        • Mikhailidis D.P.
        • Toth P.P.
        • Jones S.R.
        • Muntner P.
        • et al.
        Impact of L-carnitine on plasma lipoprotein(a) concentrations: a systematic review and meta-analysis of randomized controlled trials.
        Sci Rep. Jan 12 2016; 6: 19188https://doi.org/10.1038/srep19188
        • Sahebkar A.
        • Simental-Mendía L.E.
        • Stefanutti C.
        • Pirro M.
        Supplementation with coenzyme Q10 reduces plasma lipoprotein(a) concentrations but not other lipid indices: a systematic review and meta-analysis.
        Pharmacol Res. Mar 2016; 105: 198-209https://doi.org/10.1016/j.phrs.2016.01.030
        • Erqou S.
        • Kaptoge S.
        • Perry P.L.
        • Di Angelantonio E.
        • Thompson A.
        • et al.
        • Emerging Risk Factors Collaboration
        Lipoprotein(a) concentration and the risk of coronary heart disease, stroke, and nonvascular mortality.
        JAMA. Jul 22 2009; 302: 412-423https://doi.org/10.1001/jama.2009.1063
        • Li Y.
        • Luke M.M.
        • Shiffman D.
        • Devlin J.J.
        Genetic variants in the apolipoprotein(a) gene and coronary heart disease.
        Circ Cardiovasc Genet. Oct 2011; 4: 565-573https://doi.org/10.1161/CIRCGENETICS.111.959601
        • Kronenberg F.
        Human genetics and the causal role of lipoprotein(a) for various diseases.
        Cardiovasc Drugs Ther. Feb 2016; 30: 87-100https://doi.org/10.1007/s10557-016-6648-3
        • Kronenberg F.
        Human genetics and the causal role of lipoprotein(a) for various diseases.
        Cardiovasc Drugs Ther. Feb 2016; 30: 87-100https://doi.org/10.1007/s10557-016-6648-3
        • Manocha A.
        • Srivastava L.M.
        Lipoprotein (a): a unique independent risk factor for coronary artery disease.
        Indian J Clin Biochem. Mar 2016; 31: 13-20https://doi.org/10.1007/s12291–015–0483-3