Online first
Research Paper
Published online: 2024-05-20

open access

Page views 270
Article views/downloads 203
Get Citation

Connect on Social Media

Connect on Social Media

Lipoprotein (a) concentration as a risk factor for ischaemic stroke and its subtypes

Antonia Lackova1, Zuzana Gdovinova2, Miriam Kozarova3, Dominik Koreň2, Marek Lacko4

Abstract

Aim of the study. To investigate the relationship between serum lipoprotein (a) [Lp(a)] concentration and the risk of ischaemic stroke (IS) and its subtypes.

Clinical rationale for the study. Lp(a) plays a role in atherogenic, pro-thrombotic, and antifibrinolytic processes. Elevated plasma Lp(a) is a strong independent risk factor for the development and progression of atherosclerotic disease. The association between lipoproteins and IS is more complex than that reported for cardiovascular diseases, with inconsistent and contradictory results from epidemiological studies.

Material and methods. 231 patients with acute IS (defined as cases) and 163 age- and sex-matched control subjects were included in this prospective case-control study. Demographic and clinical variables (i.e. age, sex, smoking, presence of chronic diseases and concomitant medication) and laboratory data (i.e. concentrations of total cholesterol, high-density lipoprotein-cholesterol, low-density lipoprotein-cholesterol, triglycerides, Lp(a), apolipoprotein A1, apolipoprotein B) were recorded.


Results. The mean age and the percentage of men did not significantly differ between groups. Compared to controls, there was a significantly higher percentage of cases reported with concomitant diseases: diabetes mellitus, myocardial infarction, ischaemic heart disease, peripheral arterial disease, and atrial fibrillation. The study showed a significantly higher serum Lp(a) concentration in cases than in control subjects (81.81 nmol/L [c.32.7 mg/dL] vs. 59.75 nmol/L [c.23.9 mg/dL]; p = 0.036) and found an association between Lp(a) levels stratified by quartiles and the risk for ischaemic stroke (Q1 [Lp(a) < 13 nmol/L] vs. Q4 [Lp(a) > 117 nmol/L]: OR 2.23; 95% CI 1.23-4.03; p = 0.008). A subgroup analysis based on the TOAST classification of IS also showed a significant association between Lp(a) value of more than 75 nmol/L (30 mg/dL) and the risk of large-artery atherosclerosis stroke compared to the controls (OR 2.4; 95% CI 1.39-3.93; p = 0.001), as well as a statistically non-significant association with other subtypes of IS. The influence of Lp(a) remained significant even after adjusting for established risk factors for IS (OR 1.99; 95% CI 1.05-3.76; p = 0.04; respectively for the large-artery atherosclerotic subtype: OR 2.54; 95% CI 1.39-4.67; p = 0.003). 

Conclusion. We found that Lp(a) is an independent risk factor for ischaemic stroke, and for the large-artery atherosclerotic subtype of ischaemic stroke.

Article available in PDF format

View PDF Download PDF file

References

  1. Fan J, Li X, Yu X, et al. Global Burden, Risk Factor Analysis, and Prediction Study of Ischemic Stroke, 1990-2030. Neurology. 2023; 101(2): e137–e150.
  2. Phipps MS, Cronin CA. Management of acute ischemic stroke. BMJ. 2020; 368: l6983.
  3. Benjamin EJ, Muntner P, Alonso A, et al. American Heart Association Council on Epidemiology and Prevention Statistics Committee and Stroke Statistics Subcommittee. Heart Disease and Stroke Statistics-2019 Update: A Report From the American Heart Association. Circulation. 2019; 139(10): e56–e5e528.
  4. Ding Q, Liu S, Yao Y, et al. Global, Regional, and National Burden of Ischemic Stroke, 1990-2019. Neurology. 2022; 98(3): e279–e290.
  5. Fu H, Zhang D, Zhu R, et al. Association between lipoprotein(a) concentration and the risk of stroke in the Chinese Han population: a retrospective case-control study. Ann Transl Med. 2020; 8(5): 212.
  6. Kronenberg F. Human Genetics and the Causal Role of Lipoprotein(a) for Various Diseases. Cardiovasc Drugs Ther. 2016; 30(1): 87–100.
  7. Fogacci F, Cicero AF, D'Addato S, et al. Brisighella Heart Study Group. 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.
  8. Mach F, Baigent C, Catapano AL, et al. ESC Scientific Document Group. 2019 ESC/EAS Guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk. Eur Heart J. 2020; 41(1): 111–188.
  9. Kronenberg F, Mora S, Stroes ESG. Consensus and guidelines on lipoprotein(a) - seeing the forest through the trees. Curr Opin Lipidol. 2022; 33(6): 342–352.
  10. Ruscica M, Sirtori CR, Corsini A, et al. Lipoprotein(a): Knowns, unknowns and uncertainties. Pharmacol Res. 2021; 173: 105812.
  11. Riches K, Porter KE. Lipoprotein(a): Cellular Effects and Molecular Mechanisms. Cholesterol. 2012; 2012: 923289.
  12. Lawn RM. Lipoprotein(a) in heart disease. Sci Am. 1992; 266(6): 54–60.
  13. Kamstrup PR, Tybjaerg-Hansen A, Steffensen R, et al. Genetically elevated lipoprotein(a) and increased risk of myocardial infarction. JAMA. 2009; 301(22): 2331–2339.
  14. Dahlén GH. Lp(a) lipoprotein in cardiovascular disease. Atherosclerosis. 1994; 108(2): 111–126.
  15. Konemori G. Lipoprotein(a) and other risk factors for cerebral infarction. Hiroshima J Med Sci. 1995; 44(3): 65–77.
  16. Kronenberg F, Mora S, Stroes ESG, et al. Lipoprotein(a) in atherosclerotic cardiovascular disease and aortic stenosis: a European Atherosclerosis Society consensus statement. Eur Heart J. 2022; 43(39): 3925–3946.
  17. Lewington S, Whitlock G, Clarke R, et al. Prospective Studies Collaboration. Blood cholesterol and vascular mortality by age, sex, and blood pressure: a meta-analysis of individual data from 61 prospective studies with 55,000 vascular deaths. Lancet. 2007; 370(9602): 1829–1839.
  18. Deedwania PC, Pedersen TR, DeMicco DA, et al. TNT, CARDS and IDEAL Steering Committees and Investigators. Differing predictive relationships between baseline LDL-C, systolic blood pressure, and cardiovascular outcomes. Int J Cardiol. 2016; 222: 548–556.
  19. van den Berg MJ, van der Graaf Y, de Borst GJ, et al. SMART Study Group. Low-Density Lipoprotein Cholesterol, Non-High-Density Lipoprotein Cholesterol, Triglycerides, and Apolipoprotein B and Cardiovascular Risk in Patients With Manifest Arterial Disease. Am J Cardiol. 2016; 118(6): 804–810.
  20. O'Donnell MJ, McQueen M, Sniderman A, et al. INTERSTROKE Investigators. Association of Lipids, Lipoproteins, and Apolipoproteins with Stroke Subtypes in an International Case Control Study (INTERSTROKE). J Stroke. 2022; 24(2): 224–235.
  21. Hatano S. Experience from a multicentre stroke register: a preliminary report. Bull World Health Organ. 1976; 54(5): 541–553.
  22. Adams HP, Bendixen BH, Kappelle LJ, et al. Classification of subtype of acute ischemic stroke. Definitions for use in a multicenter clinical trial. TOAST. Trial of Org 10172 in Acute Stroke Treatment. Stroke. 1993; 24(1): 35–41.
  23. Smolders B, Lemmens R, Thijs V. Lipoprotein (a) and stroke: a meta-analysis of observational studies. Stroke. 2007; 38(6): 1959–1966.
  24. Nave AH, Lange KS, Leonards CO, et al. Lipoprotein (a) as a risk factor for ischemic stroke: a meta-analysis. Atherosclerosis. 2015; 242(2): 496–503.
  25. Kumar P, Swarnkar P, Misra S, et al. Lipoprotein (a) level as a risk factor for stroke and its subtype: A systematic review and meta-analysis. Sci Rep. 2021; 11(1): 15660.
  26. Nordestgaard BG, Chapman MJ, Ray K, et al. European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010; 31(23): 2844–2853.
  27. Loscalzo J, Weinfeld M, Fless GM, et al. Lipoprotein(a), fibrin binding, and plasminogen activation. Arteriosclerosis. 1990; 10(2): 240–245.
  28. Marcovina SM, Koschinsky ML. Evaluation of lipoprotein(a) as a prothrombotic factor: progress from bench to bedside. Curr Opin Lipidol. 2003; 14(4): 361–366.
  29. Ezratty A, Simon DI, Loscalzo J. Lipoprotein(a) binds to human platelets and attenuates plasminogen binding and activation. Biochemistry. 1993; 32(17): 4628–4633.
  30. Rand ML, Sangrar W, Hancock MA, et al. Apolipoprotein(a) enhances platelet responses to the thrombin receptor-activating peptide SFLLRN. Arterioscler Thromb Vasc Biol. 1998; 18(9): 1393–1399.
  31. Boffa MB. Beyond fibrinolysis: The confounding role of Lp(a) in thrombosis. Atherosclerosis. 2022; 349: 72–81.
  32. Caplice NM, Panetta C, Peterson TE, et al. Lipoprotein (a) binds and inactivates tissue factor pathway inhibitor: a novel link between lipoproteins and thrombosis. Blood. 2001; 98(10): 2980–2987.
  33. Boffa MB, Koschinsky ML. Lipoprotein (a): truly a direct prothrombotic factor in cardiovascular disease? J Lipid Res. 2016; 57(5): 745–757.
  34. Tomaszewska-Lampart I, Wiącek M, Bartosik-Psujek H. Risk factors for infarct growth and haemorrhagic or oedematous complications after endovascular treatment - a literature review. Neurol Neurochir Pol. 2022; 56(5): 389–398.
  35. Chen R, Ovbiagele B, Feng W. Diabetes and Stroke: Epidemiology, Pathophysiology, Pharmaceuticals and Outcomes. Am J Med Sci. 2016; 351(4): 380–386.
  36. Liang HJ, Zhang QY, Hu YT, et al. Hypertriglyceridemia: A Neglected Risk Factor for Ischemic Stroke? J Stroke. 2022; 24(1): 21–40.
  37. Schulz UGR, Rothwell PM. Differences in vascular risk factors between etiological subtypes of ischemic stroke: importance of population-based studies. Stroke. 2003; 34(8): 2050–2059.
  38. Tirschwell DL, Smith NL, Heckbert SR, et al. Association of cholesterol with stroke risk varies in stroke subtypes and patient subgroups. Neurology. 2004; 63(10): 1868–1875.
  39. Rigal M, Ruidavets JB, Viguier A, et al. Lipoprotein (a) and risk of ischemic stroke in young adults. J Neurol Sci. 2007; 252(1): 39–44.
  40. Anisetti B, Youssef H, Elkhair AM, et al. Association between within-visit blood pressure variability, stroke, coronary heart disease, and cardiovascular mortality. Neurol Neurochir Pol. 2023; 57(5): 423–429.
  41. Kozarova M, Lackova A, Kozelova Z, et al. Lipoprotein (a): A Novel Cardiovascular Risk Factor. Balkan Med J. 2023; 40(4): 234–235.
  42. Nordestgaard BG, Chapman MJ, Ray K, et al. European Atherosclerosis Society Consensus Panel. Lipoprotein(a) as a cardiovascular risk factor: current status. Eur Heart J. 2010; 31(23): 2844–2853.
  43. Grundy SM, Stone NJ, Bailey AL, et al. 2018 AHA/ACC/AACVPR/AAPA/ABC/ACPM/ADA/AGS/APhA/ASPC/NLA/PCNA Guideline on the Management of Blood Cholesterol: Executive Summary: A Report of the American College of Cardiology/American Heart Association Task Force on Clinical Practice Guidelines. J Am Coll Cardiol. 2019; 73(24): 3168–3209.



Neurologia i Neurochirurgia Polska