Gender Differences in 10-Year Mortality in Patients with Coronary Artery Disease with Elevated Lipoprotein(a): In Search of Invisible Guardian Angel

ORIGINAL ARTICLE
Aleksandr B. Shek, Rano B. Alieva, Alisher A. Abdullaev, Khurshid G. Fozilov, Shavkat U. Khoshimov, Feruza M. Bekmetova, Ulugbek I. Nizamov, Adolat V. Ziyaeva

 
International Journal of Biomedicine. 2022;12(2):209-217.
DOI: 10.21103/Article12(2)_OA1
Originally published June 5, 2022

Abstract: 

The objective of our study was to examine the contribution of elevated Lp(a) to 10-year mortality in 140 CAD patients, depending on gender, baseline lipid levels, ApoA-I, ApoB, and  the ApoA1, ApoE, and ApoB gene polymorphisms.
Methods and Results: The study included 140 patients (75 men and 65 women) of the Uzbek population, hospitalized with diagnosis “CAD, unstable angina (IIB class, E. Braunwald et al., 1989)” (main group) in the period between January 2009 and February 2011. The endpoints at 10-year follow-up were death from cardiovascular causes (fatal myocardial infarction and sudden cardiac death). In the studied cohort of CAD patients, Lp(a) distribution was skewed to the right, the median was 16.9mg/dL, and the mean was 34.3mg/dL. At the same time, Lp(a) value greater than the 75th percentile was >41mg/dL. In this regard, we compared the baseline values in 2 groups of patients: Group 1 (Lp(a)<41mg/dL) and Group 2 (Lp(a)>41mg/dL).
The 10-year cardiovascular mortality rate was higher significantly in Group 2 (RR =3.67; 95% CI: 1.67-8.11; P=0.0013). Cardiovascular mortality was significantly higher (P<0.001) in men of Group 2 than in men of Group 1 (RR=5.31; 95% CI: 2.03-13.88; P<0.001), while in women, the 10-year mortality in the compared groups did not differ significantly. Cardiovascular mortality was lower in patients with ApoA-1≥140mg/dL, the majority of whom were women.
Conclusion: In the absence of targeted Lp(a) therapy, long exposure to a level of Lp(a) of >41mg/dL is a factor that increases 10-year mortality in CAD patients.

Highlights

  • 10-year cardiovascular mortality was higher in CAD patients with Lp(a)>41mg/dL.
  • However, the increase in mortality due to high Lp(a) was statistically significant in men than in women.
  • The ApoA-I level was higher in women than in men.
  • Cardiovascular mortality was lower in patients with ApoA-I≥140mg/dL, most of whom were women.   
Keywords: 
lipoprotein(a) • apolipoprotein • coronary artery disease
References: 
  1. Ference BA, Ginsberg HN, Graham I, Ray KK, Packard CJ, Bruckert E, Hegele RA, Krauss RM, Raal FJ, Schunkert H, Watts GF, Borén J, Fazio S, Horton JD, Masana L, Nicholls SJ, Nordestgaard BG, van de Sluis B, Taskinen MR, Tokgözoglu L, Landmesser U, Laufs U, Wiklund O, Stock JK, Chapman MJ, Catapano AL. Low-density lipoproteins cause atherosclerotic cardiovascular disease. 1. Evidence from genetic, epidemiologic, and clinical studies. A consensus statement from the European Atherosclerosis Society Consensus Panel. Eur Heart J. 2017 Aug 21;38(32):2459-2472. doi: 10.1093/eurheartj/ehx144. 
  2. Kronenberg F, Kronenberg MF, Kiechl S, Trenkwalder E, Santer P, Oberhollenzer F, Egger G, Utermann G, Willeit J. Role of lipoprotein(a) and apolipoprotein(a) phenotype in atherogenesis: prospective results from the Bruneck study. Circulation. 1999 Sep 14;100(11):1154-60. doi: 10.1161/01.cir.100.11.1154. 
  3. Nordestgaard BG, Langsted A. Lipoprotein (a) as a cause of cardiovascular disease: insights from epidemiology, genetics, and biology. J Lipid Res. 2016 Nov;57(11):1953-1975. doi: 10.1194/jlr.R071233. 
  4. Kronenberg F. Human Genetics and the Causal Role of Lipoprotein(a) for Various Diseases. Cardiovasc Drugs Ther. 2016 Feb;30(1):87-100. doi: 10.1007/s10557-016-6648-3. 
  5. Willeit P, Ridker PM, Nestel PJ, Simes J, Tonkin AM, Pedersen TR, Schwartz GG, Olsson AG, Colhoun HM, Kronenberg F, Drechsler C, Wanner C, Mora S, Lesogor A, Tsimikas S. Baseline and on-statin treatment lipoprotein(a) levels for prediction of cardiovascular events: individual patient-data meta-analysis of statin outcome trials. Lancet. 2018 Oct 13;392(10155):1311-1320. doi: 10.1016/S0140-6736(18)31652-0. 
  6. Grundy SM, Stone NJ, Bailey AL, Beam C, Birtcher KK, Blumenthal RS, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019 Jun 25;73(24):e285-e350. doi: 10.1016/j.jacc.2018.11.003. 
  7. Mach F, Baigent C, Catapano AL, Koskinas KC, Casula M, Badimon L, Chapman MJ, De Backer GG, Delgado V, Ference BA, Graham IM, Halliday A, Landmesser U, Mihaylova B, Pedersen TR, Riccardi G, Richter DJ, Sabatine MS, Taskinen MR, Tokgozoglu L, Wiklund O; ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020 Jan 1;41(1):111-188. doi: 10.1093/eurheartj/ehz455. Erratum in: Eur Heart J. 2020 Nov 21;41(44):4255. 
  8. Paul-Hayase H, Rosseneu M, Robinson D, Van Bervliet JP, Deslypere JP, Humphries SE. Polymorphisms in the apolipoprotein (apo) AI-CIII-AIV gene cluster: detection of genetic variation determining plasma apo AI, apo CIII and apo AIV concentrations. Hum Genet. 1992 Feb;88(4):439-46. doi: 10.1007/BF00215679.
  9. Sposito AC, Gonbert S, Turpin G, Chapman MJ, Thillet J. Common promoter C516T polymorphism in the ApoB gene is an independent predictor of carotid atherosclerotic disease in subjects presenting a broad range of plasma cholesterol levels. Arterioscler Thromb Vasc Biol. 2004 Nov;24(11):2192-5. doi: 10.1161/01.ATV.0000144810.10164.50.
  10. Lamb H, Christie J, Singleton AB, Leake A, Perry RH, Ince PG, McKeith IG, Melton LM, Edwardson JA, Morris CM. Apolipoprotein E and alpha-1 antichymotrypsin polymorphism genotyping in Alzheimer's disease and in dementia with Lewy bodies. Distinctions between diseases. Neurology. 1998 Feb;50(2):388-91. doi: 10.1212/wnl.50.2.388.
  11. Wenham PR, Price WH, Blandell G. Apolipoprotein E genotyping by one-stage PCR. Lancet. 1991 May 11;337(8750):1158-9. doi: 10.1016/0140-6736(91)92823-k. 
  12. Willeit P, Kiechl S, Kronenberg F, Witztum JL, Santer P, Mayr M, Xu Q, Mayr A, Willeit J, Tsimikas S. Discrimination and net reclassification of cardiovascular risk with lipoprotein(a): prospective 15-year outcomes in the Bruneck Study. J Am Coll Cardiol. 2014 Sep 2;64(9):851-60. doi: 10.1016/j.jacc.2014.03.061. Erratum in: J Am Coll Cardiol. 2016 Feb 16;67(6):737. 
  13. Verbeek R, Sandhu MS, Hovingh GK, Sjouke B, Wareham NJ, Zwinderman AH, Kastelein JJP, Khaw KT, Tsimikas S, Boekholdt SM. Lipoprotein(a) Improves Cardiovascular Risk Prediction Based on Established Risk Algorithms. J Am Coll Cardiol. 2017 Mar 21;69(11):1513-1515. doi: 10.1016/j.jacc.2017.01.017. 
  14. Cook NR, Mora S, Ridker PM. Lipoprotein(a) and Cardiovascular Risk Prediction Among Women. J Am Coll Cardiol. 2018 Jul 17;72(3):287-296. doi: 10.1016/j.jacc.2018.04.060. 
  15. Ariyo AA, Thach C, Tracy R; Cardiovascular Health Study Investigators. Lp(a) lipoprotein, vascular disease, and mortality in the elderly. N Engl J Med. 2003 Nov 27;349(22):2108-15. doi: 10.1056/NEJMoa001066. 
  16. Wild SH, Fortmann SP, Marcovina SM. A prospective case-control study of lipoprotein(a) levels and apo(a) size and risk of coronary heart disease in Stanford Five-City Project participants. Arterioscler Thromb Vasc Biol. 1997 Feb;17(2):239-45. doi: 10.1161/01.atv.17.2.239. Erratum in: Arterioscler Throm Vasc Biol 1997 May;17(5):1010. 
  17. Seman LJ, DeLuca C, Jenner JL, Cupples LA, McNamara JR, Wilson PW, Castelli WP, Ordovas JM, Schaefer EJ. Lipoprotein(a)-cholesterol and coronary heart disease in the Framingham Heart Study. Clin Chem. 1999 Jul;45(7):1039-46.
  18. Gordon T, Castelli WP, Hjortland MC, Kannel WB, Dawber TR. High density lipoprotein as a protective factor against coronary heart disease. The Framingham Study. Am J Med. 1977 May;62(5):707-14. doi: 10.1016/0002-9343(77)90874-9. 
  19. Assmann G, Funke H, Schriewer H. The relationship of HDL-apolipoprotein A-I and HDL-Cholesterol to risk factors of coronary heart disease: initial results of the prospective epidemiological study in company employees in Westfalia. J Clin Chem Clin Biochem. 1982 May;20(5):287-9. doi: 10.1515/cclm.1982.20.5.287. 
  20. Nagano M, Yamashita S, Hirano K, Takano M, Maruyama T, Ishihara M, Sagehashi Y, Kujiraoka T, Tanaka K, Hattori H, Sakai N, Nakajima N, Egashira T, Matsuzawa Y. Molecular mechanisms of cholesteryl ester transfer protein deficiency in Japanese. J Atheroscler Thromb. 2004;11(3):110-21. doi: 10.5551/jat.11.110. 
  21. Madsen CM, Varbo A, Nordestgaard BG. Extreme high high-density lipoprotein cholesterol is paradoxically associated with high mortality in men and women: two prospective cohort studies. Eur Heart J. 2017 Aug 21;38(32):2478-2486. doi: 10.1093/eurheartj/ehx163.
  22. AIM-HIGH Investigators. The role of niacin in raising high-density lipoprotein cholesterol to reduce cardiovascular events in patients with atherosclerotic cardiovascular disease and optimally treated low-density lipoprotein cholesterol: baseline characteristics of study participants. The Atherothrombosis Intervention in Metabolic syndrome with low HDL/high triglycerides: impact on Global Health outcomes (AIM-HIGH) trial. Am Heart J. 2011 Mar;161(3):538-43. doi: 10.1016/j.ahj.2010.12.007. E
  23. Schwartz GG, Olsson AG, Abt M, Ballantyne CM, Barter PJ, Brumm J, Chaitman BR, Holme IM, Kallend D, Leiter LA, Leitersdorf E, McMurray JJ, Mundl H, Nicholls SJ, Shah PK, Tardif JC, Wright RS; dal-OUTCOMES Investigators. Effects of dalcetrapib in patients with a recent acute coronary syndrome. N Engl J Med. 2012 Nov 29;367(22):2089-99. doi: 10.1056/NEJMoa1206797. 
  24. Voight BF, Peloso GM, Orho-Melander M, Frikke-Schmidt R, Barbalic M, Jensen MK, et al. Plasma HDL cholesterol and risk of myocardial infarction: a mendelian randomisation study. Lancet. 2012 Aug 11;380(9841):572-80. doi: 10.1016/S0140-6736(12)60312-2. Epub 2012 May 17. Erratum in: Lancet. 2012 Aug 11;380(9841):564. 
  25. Haase CL, Tybjærg-Hansen A, Qayyum AA, Schou J, Nordestgaard BG, Frikke-Schmidt R. LCAT, HDL cholesterol and ischemic cardiovascular disease: a Mendelian randomization study of HDL cholesterol in 54,500 individuals. J Clin Endocrinol Metab. 2012 Feb;97(2):E248-56. doi: 10.1210/jc.2011-1846. 
  26. von Eckardstein A, Nofer JR, Assmann G. High density lipoproteins and arteriosclerosis. Role of cholesterol efflux and reverse cholesterol transport. Arterioscler Thromb Vasc Biol. 2001 Jan;21(1):13-27. doi: 10.1161/01.atv.21.1.13.
  27. Rohatgi A, Khera A, Berry JD, Givens EG, Ayers CR, Wedin KE, Neeland IJ, Yuhanna IS, Rader DR, de Lemos JA, Shaul PW. HDL cholesterol efflux capacity and incident cardiovascular events. N Engl J Med. 2014 Dec 18;371(25):2383-93. doi: 10.1056/NEJMoa1409065. 
  28. Gillard BK, Rosales C, Xu B, Gotto AM Jr, Pownall HJ. Rethinking reverse cholesterol transport and dysfunctional high-density lipoproteins. J Clin Lipidol. 2018 Jul-Aug;12(4):849-856. doi: 10.1016/j.jacl.2018.04.001. 
  29. Nicholls SJ, Puri R, Ballantyne CM, Jukema JW, Kastelein JJP, Koenig W, Wright RS, Kallend D, Wijngaard P, Borgman M, Wolski K, Nissen SE. Effect of Infusion of High-Density Lipoprotein Mimetic Containing Recombinant Apolipoprotein A-I Milano on Coronary Disease in Patients With an Acute Coronary Syndrome in the MILANO-PILOT Trial: A Randomized Clinical Trial. JAMA Cardiol. 2018 Sep 1;3(9):806-814. doi: 10.1001/jamacardio.2018.2112. 
  30. Nicholls SJ, Andrews J, Kastelein JJP, Merkely B, Nissen SE, Ray KK, Schwartz GG, Worthley SG, Keyserling C, Dasseux JL, Griffith L, Kim SW, Janssan A, Di Giovanni G, Pisaniello AD, Scherer DJ, Psaltis PJ, Butters J. Effect of Serial Infusions of CER-001, a Pre-β High-Density Lipoprotein Mimetic, on Coronary Atherosclerosis in Patients Following Acute Coronary Syndromes in the CER-001 Atherosclerosis Regression Acute Coronary Syndrome Trial: A Randomized Clinical Trial. JAMA Cardiol. 2018 Sep 1;3(9):815-822. doi: 10.1001/jamacardio.2018.2121. 
  31. Rader DJ. Apolipoprotein A-I Infusion Therapies for Coronary Disease: Two Outs in the Ninth Inning and Swinging for the Fences. JAMA Cardiol. 2018 Sep 1;3(9):799-801. doi: 10.1001/jamacardio.2018.2168. 
  32. Didichenko SA, Navdaev AV, Cukier AM, Gille A, Schuetz P, Spycher MO, Thérond P, Chapman MJ, Kontush A, Wright SD. Enhanced HDL Functionality in Small HDL Species Produced Upon Remodeling of HDL by Reconstituted HDL, CSL112: Effects on Cholesterol Efflux, Anti-Inflammatory and Antioxidative Activity. Circ Res. 2016 Sep 2;119(6):751-63. doi: 10.1161/CIRCRESAHA.116.308685. 
  33. Gille A, D'Andrea D, Tortorici MA, Hartel G, Wright SD. CSL112 (Apolipoprotein A-I [Human]) Enhances Cholesterol Efflux Similarly in Healthy Individuals and Stable Atherosclerotic Disease Patients. Arterioscler Thromb Vasc Biol. 2018 Apr;38(4):953-963. doi: 10.1161/ATVBAHA.118.310538. 
  34. Haase CL, Tybjærg-Hansen A, Grande P, Frikke-Schmidt R. Genetically elevated apolipoprotein A-I, high-density lipoprotein cholesterol levels, and risk of ischemic heart disease. J Clin Endocrinol Metab. 2010 Dec;95(12):E500-10. doi: 10.1210/jc.2010-0450. 
  35. Karjalainen MK, Holmes MV, Wang Q, Anufrieva O, Kähönen M, Lehtimäki T, Havulinna AS, Kristiansson K, Salomaa V, Perola M, Viikari JS, Raitakari OT, Järvelin MR, Ala-Korpela M, Kettunen J. Apolipoprotein A-I concentrations and risk of coronary artery disease: A Mendelian randomization study. Atherosclerosis. 2020 Apr;299:56-63. doi: 10.1016/j.atherosclerosis.2020.02.002.
  36. Richardson TG, Sanderson E, Palmer TM, Ala-Korpela M, Ference BA, Davey Smith G, Holmes MV. Evaluating the relationship between circulating lipoprotein lipids and apolipoproteins with risk of coronary heart disease: A multivariable Mendelian randomisation analysis. PLoS Med. 2020 Mar 23;17(3):e1003062. doi: 10.1371/journal.pmed.1003062. 
  37. Wang XL, Liu SX, McCredie RM, Wilcken DE. Polymorphisms at the 5'-end of the apolipoprotein AI gene and severity of coronary artery disease. J Clin Invest. 1996 Jul 15;98(2):372-7. doi: 10.1172/JCI118802. 
  38. Smith JD, Brinton EA, Breslow JL. Polymorphism in the human apolipoprotein A-I gene promoter region. Association of the minor allele with decreased production rate in vivo and promoter activity in vitro. J Clin Invest. 1992 Jun;89(6):1796-800. doi: 10.1172/JCI115783. 
  39. Gerdes LU, Gerdes C, Kervinen K, Savolainen M, Klausen IC, Hansen PS, Kesäniemi YA, Faergeman O. The apolipoprotein epsilon4 allele determines prognosis and the effect on prognosis of simvastatin in survivors of myocardial infarction : a substudy of the Scandinavian simvastatin survival study. Circulation. 2000 Mar 28;101(12):1366-71. doi: 10.1161/01.cir.101.12.1366. 
  40. van 't Hooft FM, Jormsjö S, Lundahl B, Tornvall P, Eriksson P, Hamsten A. A functional polymorphism in the apolipoprotein B promoter that influences the level of plasma low density lipoprotein. J Lipid Res. 1999 Sep;40(9):1686-94. 
  41. Frikke-Schmidt R, Nordestgaard BG, Agerholm-Larsen B, Schnohr P, Tybjaerg-Hansen A. Context-dependent and invariant associations between lipids, lipoproteins, and apolipoproteins and apolipoprotein E genotype. J Lipid Res. 2000 Nov;41(11):1812-22. 
  42. Pászty C, Maeda N, Verstuyft J, Rubin EM. Apolipoprotein AI transgene corrects apolipoprotein E deficiency-induced atherosclerosis in mice. J Clin Invest. 1994 Aug;94(2):899-903. doi: 10.1172/JCI117412.
  43. Karathanasis SK, Freeman LA, Gordon SM, Remaley AT. The Changing Face of HDL and the Best Way to Measure It. Clin Chem. 2017 Jan;63(1):196-210. doi: 10.1373/clinchem.2016.257725. 
  44. Spence JD, Koschinsky M. Mechanisms of lipoprotein(a) pathogenicity: prothrombotic, proatherosclerotic, or both? Arterioscler Thromb Vasc Biol. 2012 Jul;32(7):1550-1. doi: 10.1161/ATVBAHA.112.251306. 
  45. Tsimikas S. A Test in Context: Lipoprotein(a): Diagnosis, Prognosis, Controversies, and Emerging Therapies. J Am Coll Cardiol. 2017 Feb 14;69(6):692-711. doi: 10.1016/j.jacc.2016.11.042. 
  46. Liu AC, Lawn RM, Verstuyft JG, Rubin EM. Human apolipoprotein A-I prevents atherosclerosis associated with apolipoprotein[a] in transgenic mice. J Lipid Res. 1994 Dec;35(12):2263-7. 
  47. Matthews KA, Crawford SL, Chae CU, Everson-Rose SA, Sowers MF, Sternfeld B, Sutton-Tyrrell K. Are changes in cardiovascular disease risk factors in midlife women due to chronological aging or to the menopausal transition? J Am Coll Cardiol. 2009 Dec 15;54(25):2366-73. doi: 10.1016/j.jacc.2009.10.009.

Download Article
Received March 19, 2022.
Accepted May 9, 2022.
©2022 International Medical Research and Development Corporation.