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Unexpected high mortality associated with very low lipoprotein(a) after acute myocardial infarction: Identifying the unknown

  • Felicita Andreotti
    Correspondence
    Corresponding author at: Direzione Scientifica, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, Rome 00168, Italy.
    Affiliations
    Direzione Scientifica e Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, Largo A. Gemelli 8, Rome 00168, Italy

    Università Cattolica del Sacro Cuore, Rome, Italy
    Search for articles by this author
  • Massimo Massetti
    Affiliations
    Università Cattolica del Sacro Cuore, Rome, Italy

    Dipartimento di Scienze Cardiovascolari, Fondazione Policlinico Universitario A. Gemelli IRCCS, Rome, Italy
    Search for articles by this author
  • Aldo P Maggioni
    Affiliations
    ANMCO Research Center, Fondazione per il Tuo cuore, Florence, Italy

    GVM Care & Research, Maria Cecilia Hospital, Cotignola, Italy
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Published:August 02, 2021DOI:https://doi.org/10.1016/j.ejim.2021.07.006
      Plasma or serum concentrations of lipoprotein(a) - Lp(a) - are an established marker of risk for atherothrombotic cardiovascular disease (CVD) and for degenerative aortic valve stenosis (
      • Wohlfahrt P.
      • Jenča D.
      • Melenovský V.
      • Franeková J.
      • Jabor A.
      • Šramko M.
      • Staněk V.
      • Želízko M.
      • Poledne R.
      • Piťha J.
      • Adámková V.
      • Kautzner J.
      Very low lipoprotein(a) and increased mortality risk after myocardial infarction.
      ). Mechanistic experiments, prospective observations, and genetic studies strongly support a causal role of Lp(a) for CVD development (
      • Wohlfahrt P.
      • Jenča D.
      • Melenovský V.
      • Franeková J.
      • Jabor A.
      • Šramko M.
      • Staněk V.
      • Želízko M.
      • Poledne R.
      • Piťha J.
      • Adámková V.
      • Kautzner J.
      Very low lipoprotein(a) and increased mortality risk after myocardial infarction.
      ,
      • Maher L.L.
      • Tokgözoğlu S.L.
      • Sanchez E.J.
      • Underberg J.A.
      • Guyton J.R.
      JCL roundtable: global think tank on lipoprotein(a).
      ,
      • Andreotti F.
      • Maggioni A.P.
      Lipoprotein(a) reduction in persons with cardiovascular disease.
      ). Apolipoprotein(a) is synthesised mostly in the liver and is exclusively bound to low-density lipoprotein (LDL) to form Lp(a). The latter contributes to arterial lipid deposits (
      • Reblin T.
      • Meyer N.
      • Labeur C.
      • Henne-Bruns D.
      • Beisiegel U.
      Extraction of lipoprotein(a), apo B, and apo E from fresh human arterial wall and atherosclerotic plaques.
      ) and can inhibit endogenous fibrinolysis by competing with plasminogen for fibrin binding (
      • Andreotti F.
      • Maggioni A.P.
      Lipoprotein(a) reduction in persons with cardiovascular disease.
      ). Significant reductions of circulating Lp(a) by monoclonal antibodies against interleukin(IL)−6 (ziltivekimab) (
      • Ridker P.M.
      • Devalaraja M.
      • Baeres F.M.M.
      • Engelmann M.D.M.
      • Hovingh G.K.
      • Ivkovic M.
      • Lo L.
      • Kling D.
      • Pergola P.
      • Raj D.
      • Libby P.
      • Davidson M.
      • Investigators RESCUE
      IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.
      ) and IL-1β (canakinumab) (
      • Choudhury R.P.
      • Birks J.S.
      • Mani V.
      • Biasiolli L.
      • Robson M.D.
      • L'Allier P.L.
      • Gingras M.A.
      • Alie N.
      • McLaughlin M.A.
      • Basson C.T.
      • Schecter A.D.
      • Svensson E.C.
      • Zhang Y.
      • Yates D.
      • Tardif J.C.
      • Fayad Z.A
      Arterial effects of canakinumab in patients with atherosclerosis and type 2 diabetes or glucose intolerance.
      ) suggest involvement of Lp(a) in the nod-like receptor protein-3 inflammasome cascade that generates IL-6, IL-1β and C-reactive protein. Circulating levels of Lp(a) are considered relatively stable and largely genetically determined; laboratory measurements are evolving toward a global standardization (
      • Maher L.L.
      • Tokgözoğlu S.L.
      • Sanchez E.J.
      • Underberg J.A.
      • Guyton J.R.
      JCL roundtable: global think tank on lipoprotein(a).
      ); at least one lifetime measure is recommended to assess CVD risk which is considered significant for Lp(a) values ≥125 nM (
      • Wohlfahrt P.
      • Jenča D.
      • Melenovský V.
      • Franeková J.
      • Jabor A.
      • Šramko M.
      • Staněk V.
      • Želízko M.
      • Poledne R.
      • Piťha J.
      • Adámková V.
      • Kautzner J.
      Very low lipoprotein(a) and increased mortality risk after myocardial infarction.
      ). Oral niacin and subcutaneous proprotein convertase subtilisin/kexin type 9 inhibitors induce moderate Lp(a) reduction, with concomitant effects on LDL-cholesterol concentrations (
      • Maher L.L.
      • Tokgözoğlu S.L.
      • Sanchez E.J.
      • Underberg J.A.
      • Guyton J.R.
      JCL roundtable: global think tank on lipoprotein(a).
      ); more intense and specific pharmacological interventions to lower Lp(a) include inhibition of apolipoprotein(a) synthesis by the hepatocyte-directed antisense oligonucleotide pelacarsen and by the short interfering RNAs olpasiran and SLN360 (
      • Maher L.L.
      • Tokgözoğlu S.L.
      • Sanchez E.J.
      • Underberg J.A.
      • Guyton J.R.
      JCL roundtable: global think tank on lipoprotein(a).
      ,
      • Andreotti F.
      • Maggioni A.P.
      Lipoprotein(a) reduction in persons with cardiovascular disease.
      ). Lp(a)HORIZON (NCT04023552) is the first ongoing large randomized CVD outcome trial comparing subcutaneous pelacarsen (TQJ230) 80 mg monthly versus placebo; the study plans to enrol 7680 patients with a history of myocardial infarction (MI) or ischemic stroke or significant peripheral artery disease and with baseline Lp(a) >140 nM in order to accrue 993 events; completion date is estimated in June 2024 (
      • Maher L.L.
      • Tokgözoğlu S.L.
      • Sanchez E.J.
      • Underberg J.A.
      • Guyton J.R.
      JCL roundtable: global think tank on lipoprotein(a).
      ).

      Keywords

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      References

        • Wohlfahrt P.
        • Jenča D.
        • Melenovský V.
        • Franeková J.
        • Jabor A.
        • Šramko M.
        • Staněk V.
        • Želízko M.
        • Poledne R.
        • Piťha J.
        • Adámková V.
        • Kautzner J.
        Very low lipoprotein(a) and increased mortality risk after myocardial infarction.
        Eur J Intern Med. 2021; S0953-6205 (00135-7)https://doi.org/10.1016/j.ejim.2021.04.012
        • Maher L.L.
        • Tokgözoğlu S.L.
        • Sanchez E.J.
        • Underberg J.A.
        • Guyton J.R.
        JCL roundtable: global think tank on lipoprotein(a).
        J Clin Lipidol. 2021; 15 (10.1016/j.jacl.2021.06.00): 387-393
        • Andreotti F.
        • Maggioni A.P.
        Lipoprotein(a) reduction in persons with cardiovascular disease.
        N Engl J Med. 2020; 382: e65https://doi.org/10.1056/NEJMc2004861
        • Reblin T.
        • Meyer N.
        • Labeur C.
        • Henne-Bruns D.
        • Beisiegel U.
        Extraction of lipoprotein(a), apo B, and apo E from fresh human arterial wall and atherosclerotic plaques.
        Atherosclerosis. 1995; 113: 179-188https://doi.org/10.1016/0021-9150(94)05445-o
        • Ridker P.M.
        • Devalaraja M.
        • Baeres F.M.M.
        • Engelmann M.D.M.
        • Hovingh G.K.
        • Ivkovic M.
        • Lo L.
        • Kling D.
        • Pergola P.
        • Raj D.
        • Libby P.
        • Davidson M.
        • Investigators RESCUE
        IL-6 inhibition with ziltivekimab in patients at high atherosclerotic risk (RESCUE): a double-blind, randomised, placebo-controlled, phase 2 trial.
        Lancet. 2021; 397: 2060-2069
        • Choudhury R.P.
        • Birks J.S.
        • Mani V.
        • Biasiolli L.
        • Robson M.D.
        • L'Allier P.L.
        • Gingras M.A.
        • Alie N.
        • McLaughlin M.A.
        • Basson C.T.
        • Schecter A.D.
        • Svensson E.C.
        • Zhang Y.
        • Yates D.
        • Tardif J.C.
        • Fayad Z.A
        Arterial effects of canakinumab in patients with atherosclerosis and type 2 diabetes or glucose intolerance.
        J Am Coll Cardiol. 2016; 68: 1769-1780https://doi.org/10.1016/j.jacc.2016.07.768
        • Yusuf S.
        • Hawken S.
        • Ounpuu S.
        • Dans T.
        • Avezum A.
        • Lanas F.
        • McQueen M.
        • Budaj A.
        • Pais P.
        • Varigos J.
        • Lisheng L.
        • INTERHEART Study Investigators
        Effect of potentially modifiable risk factors associated with myocardial infarction in 52 countries (the INTERHEART study): case-control study.
        Lancet. 2004; 364: 937-952https://doi.org/10.1016/S0140-6736(04)17018-9
        • Andreotti F.
        • Rio T.
        • Lavorgna A.
        Body fat and cardiovascular risk: understanding the obesity paradox.
        Eur Heart J. 2009; 30: 752-754https://doi.org/10.1093/eurheartj/ehp081
        • Figtree G.A.
        • Vernon S.T.
        • Hadziosmanovic N.
        • Sundström J.
        • Alfredsson J.
        • Arnott C.
        • Delatour V.
        • Leósdóttir M.
        • Hagström E.
        Mortality in STEMI patients without standard modifiable risk factors: a sex-disaggregated analysis of SWEDEHEART registry data.
        Lancet. 2021; 397: 1085-1094https://doi.org/10.1016/S0140-6736(21)00272-5
        • Haider A.W.
        • Andreotti F.
        • Thompson G.R.
        • Kluft C.
        • Maseri A.
        • Davies G.J.
        Serum lipoprotein(a) level is related to thrombin generation and spontaneous intermittent coronary occlusion in patients with acute myocardial infarction.
        Circulation. 1996; 94: 2072-2076https://doi.org/10.1161/01.cir.94.9.2072
        • Andreotti F.
        • Pasceri V.
        • Hackett D.R.
        • Davies G.J.
        • Haider A.W.
        • Maseri A
        Preinfarction angina as a predictor of more rapid coronary thrombolysis in patients with acute myocardial infarction.
        N Engl J Med. 1996; 334: 7-12https://doi.org/10.1056/NEJM199601043340102.12
        • Andreotti F.
        • Sciahbasi A.
        • De Marco E.
        • Maseri A.
        Preinfarction angina and improved reperfusion of the infarct-related artery.
        Thromb Haemost. 1999; 82 (PMID: 10695490): 68-72
        • Andreotti F.
        • Becker R.C.
        Atherothrombotic disorders: new insights from hematology.
        Circulation. 2005; 111: 1855-1863https://doi.org/10.1161/01.CIR.0000160361.73423.23
        • White H.D.
        Deconstructing the paradox of smoking and improved short-term cardiovascular outcomes after myocardial infarction.
        J Am Coll Cardiol. 2020; 75: 1755-1757https://doi.org/10.1016/j.jacc.2020.02.044
        • Vaccarino V.
        • Parsons L.
        • Every N.R.
        • Barron H.V.
        • Krumholz H.M.
        Sex-based differences in early mortality after myocardial infarction. National registry of myocardial infarction 2 participants.
        N Engl J Med. 1999; 341: 217-225https://doi.org/10.1056/NEJM199907223410401