Skip to main content
SpringerLink
Log in

Statin Use is Associated with a Significant Reduction in Cholesterol Content of Erythrocyte Membranes. A Novel Pleiotropic Effect?

  • Published:
Cardiovascular Drugs and Therapy Aims and scope Submit manuscript

Abstract

Purpose

High cholesterol content of erythrocyte membranes (CEM) levels is present in patients with acute coronary syndromes (ACS). Intraplaque hemorrhage and erythrocyte lysis contribute to the deposition of cholesterol on the atherosclerotic plaque and to plaque rupture. With the present study we assessed the effect of statin therapy on CEM levels, a novel marker of coronary artery disease (CAD) instability during a 1-year follow-up in CAD patients.

Methods

212 consecutive eligible (158 men, 62 ± 10 years) patients undergoing diagnostic coronary angiography for the assessment of angina pectoris were assessed. The study population comprised of 84 chronic stable angina (CSA) patients and 128 ACS patients. All study participants were commenced on statin treatment in equipotent doses and were followed for up to 1 year (at  − 1,  − 3,  − 6 and  − 12 months).

Results

Repeated measurements analysis of variance after appropriate adjustment showed a significant decrease (p < 0.001) in CEM content during follow up. CEM levels were decreasing at each time point (1 month : 100 ug/mg 95%CI 94.3–105.6, 3 months : 78.1 ug/mg 95%CI 73.2–83, 6 months : 67.2 ug/mg 95%CI 63.1–71.2, 1 year : 45.3 ug/mg 95%CI 42.2–48.3) compared to admission (112.1 ug/mg 95% CI 105.9–118.3) and to all previous measurements.

Conclusions

The present study showed, that use of statins is associated with a reduction in CEM, an emerging marker of clinical instability and plaque vulnerability in CAD patients. The pleiotropic effects of statins at the cell membrane level represent a promising novel direction for research in CAD.

This is a preview of subscription content, log in via an institution to check access.

Access this article

Log in via an institution

Price excludes VAT (USA)
Tax calculation will be finalised during checkout.

Instant access to the full article PDF.

Institutional subscriptions

Fig. 1
Fig. 2

Similar content being viewed by others

References

  1. Herrmann J, Lerman A. Atherosclerosis in the back yard. J Am Coll Cardiol. 2007;49:2102–4.

    Article  PubMed  Google Scholar 

  2. Kolodgie FD, Burke AP, Nakazawa G, Cheng Q, Xu X, Virmani R. Free cholesterol in atherosclerotic plaques: where does it come from? Curr Opin Lipidol. 2007;18:500–7.

    Article  CAS  PubMed  Google Scholar 

  3. Moreno PR, Purushothaman KR, Sirol M, Levy AP, Fuster V. Neovascularization in human atherosclerosis. Circulation. 2006;113:2245–52.

    Article  PubMed  Google Scholar 

  4. Virmani R, Kolodgie FD, Burke AP, Finn AV, Gold HK, Tulenko TN, et al. Atherosclerotic plaque progression and vulnerability to rupture. Angiogenesis as a source for intraplaque hemorrhage. Atheroscler Thromb Vasc Biol. 2005;25:2054–61.

    Article  CAS  Google Scholar 

  5. Arbustini E, Morbini P, D’Armini AM, Repetto A, Minzioni G, Piovella F, et al. Plaque composition in plexogenic and thromboembolic pulmonary hypertension: the critical role of thrombotic material in pultaceous core formation. Heart. 2002;88:177–82.

    Article  CAS  PubMed  Google Scholar 

  6. Kolodgie FD, Gold HK, Burke AP, Fowler DR, Kruth HS, Weber DK, et al. Intraplaque haemorrhage and progression of coronary atheroma. N Engl J Med. 2003;349:2316–25.

    Article  CAS  PubMed  Google Scholar 

  7. Yeagle PL. Cholesterol and the cell membrane. Biochim Biophys Acta. 1985;822:267–87.

    CAS  PubMed  Google Scholar 

  8. Tziakas D, Kaski JC, Chalikias GK, Romero C, Fredericks S, Tentes IK, et al. Total cholesterol content of erythrocyte membranes is increased in patients with acute coronary syndrome. J Am Coll Cardiol. 2007;49:2081–9.

    Article  CAS  PubMed  Google Scholar 

  9. Martinez M, Vaya A, Marti R, Gil L, Lluch I, Carmena R, et al. Erythrocyte membrane cholesterol/phospolipid changes and haemorrheological modifications in familial hypercholesterolemia treated with lovastatin. Thromb Res. 1996;83:375–88.

    Article  CAS  PubMed  Google Scholar 

  10. Koter M, Brochel M, Chojnowska-Jezierska J, Klikczynska K, Franiak I. The effect of atorvastatin on erythrocyte membranes and serum lipids in patients with type-2 hypercholesterolemia. Eur J Clin Pharmacol. 2002;58:501–6.

    Article  CAS  PubMed  Google Scholar 

  11. Koter M, Franiak I, Bronchel M, Chojnowska-Jezierska J. Effects of simvastatin and pravastatin on peroxidation of erythrocyte plasma lipids in patients with type-2 hypercholesterolemia. Can J Physiol Pharmacol. 2003;81:485–92.

    Article  CAS  PubMed  Google Scholar 

  12. Arbustini E. Total erythrocyte membrane cholesterol. An innocent new marker or an active player in acute coronary syndromes ? J Am Coll Cardiol. 2007;49:2090–2.

    Article  CAS  PubMed  Google Scholar 

  13. Fox K, Garcia MA, Ardissino D, Buszman P, Camici PG, Crea F, et al. Task Force on the Management of Stable Angina Pectoris of the European Society of Cardiology. Eur Heart J. 2006;27:1341–81.

    Article  PubMed  Google Scholar 

  14. Van de Werf F, Ardissino D, Betriu A, Cokkinos DV, Falk E, Fox KA, et al. Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Management of acute myocardial infarction in patients presenting with ST-segment elevation. The Task Force on the Management of Acute Myocardial Infarction of the European Society of Cardiology. Eur Heart J. 2003;24:28–66.

    Article  PubMed  Google Scholar 

  15. Bassand JP, Hamm CW, Ardissino D, Boersma E, Budaj A, Fernández-Avilés F, et al. Task Force for Diagnosis and Treatment of Non-ST-Segment Elevation Acute Coronary Syndromes of European Society of Cardiology. Eur Heart J. 2007;28:1598–660.

    Article  CAS  PubMed  Google Scholar 

  16. Jones PH, Davidson MH, Stein EA, Bays HE, McKenney JM, Miller E, et al. STELLAR Study Group. Comparison of the efficacy and safety of rosuvastatin versus atorvastatin, simvastatin, and pravastatin across doses (STELLAR* Trial). Am J Cardiol. 2003;92:152–60.

    Article  CAS  PubMed  Google Scholar 

  17. Thygesen K, Alpert JS, White HD. Universal definition of myocardial infarction: Kristian Thygesen, Joseph S. Alpert and Harvey D. White on behalf of the Joint ESC/ACCF/AHA/WHF Task Force for the Redefinition of Myocardial Infarction. Eur Heart J. 2007;28:2525–38.

    Article  PubMed  Google Scholar 

  18. Braunwald E. Unstable angina: a classification. Circulation. 1989;80:410–4.

    CAS  PubMed  Google Scholar 

  19. Grundy SM, Cleeman JI, Merz NB, Brewer B Jr, Clark LT, Hunninghake DB, et al. for the Coordinating Committee of the National Cholesterol Education Program. Implications of recent clinical trials for the National Cholesterol Education Program Adult Treatment Panel III Guidelines. Circulation. 2004;110:227–39.

    Article  PubMed  Google Scholar 

  20. Scanlon PJ, Faxon DP, Audet AM, Scanlon PJ, Faxon DP, Audet AM, et al. ACC/AHA guidelines for coronary angiography. A report of the American College of Cardiology/American Heart Association Task Force on practice guidelines (Committee on Coronary Angiography). Developed in collaboration with the Society for Cardiac Angiography and Interventions. J Am Coll Cardiol. 1999;33:1756–824.

    Article  CAS  PubMed  Google Scholar 

  21. Kaski JC, Chester MR, Chen L, Katritsis D. Rapid angiographic progression of coronary artery disease in patients with angina pectoris. The role of complex stenosis morphology. Circulation. 1995;92:2058–65.

    CAS  PubMed  Google Scholar 

  22. Cazzola R, Rondanelli M, Russo-Volpe S, Ferrari E, Cestaro B. Decreased membrane fluidity and altered susceptibility to peroxidation and lipid composition in overweight and obese female erythrocytes. J Lipid Res. 2004;45:1846–51.

    Article  CAS  PubMed  Google Scholar 

  23. Miwa S, Inouye M, Ohmura C, Mitsuhashi N, Onuma T, Kawamori R. Relationship between carotid atherosclerosis and erythrocyte membrane cholesterol oxidation products in type 2 diabetic patients. Diabetes Res Clin Pract. 2003;61:81–8.

    Article  CAS  PubMed  Google Scholar 

  24. Bradford MM. A rapid and sensitive method for the quantitation of microgram quantities of protein uitilizing the principle of protein-dye binding. Anal Biochem. 1976;72:248–54.

    Article  CAS  PubMed  Google Scholar 

  25. Allain CC, Poon LS, Chan CSG, Richmond W, Fu PC. Enzymatic Determination of Total Serum Cholesterol. Clin Chem. 1974;20:470–5.

    CAS  PubMed  Google Scholar 

  26. Ray KK, Cannon CP. The potential relevance of the multiple lipid-independent (pleiotropic) effects of statins in the management of acute coronary syndromes. J Am Coll Cardiol. 2005;46:1425–33.

    Article  CAS  PubMed  Google Scholar 

  27. Calabro P, Yeh ET. The pleiotropic effects of statins. Curr Opin Cardiol. 2005;20:541–6.

    Article  PubMed  Google Scholar 

  28. Dietzen DJ, Page KL, Tetzloff TA, Bohrer A, Turk J. Inhibition of 3-hydroxy-3methylglutaryl coenzyme A (HMG CoA) reductase blunts factor VIIa/Tissue Factor and prothrombinase acitivities via effects on membrane phosphatidylserine. Arterioscler Thromb Vasc Biol. 2007;27:690–6.

    Article  CAS  PubMed  Google Scholar 

  29. Lin H-L, Xu X-S, Lu H-X, Zhang L, Li C-J, Tang M-X, et al. Pathological mechanisms and dose dependency of erythrocyte-induced vulnerability of atherosclerotic plaques. J Mol Cell Cardiol. 2007;43:272–80.

    Article  CAS  PubMed  Google Scholar 

  30. Caliskan S, Caliskan M, Kuralay F, Onvural B. Effect of simvastatin therapy on blood and tissue ATP levels and erythrocyte membrane lipid composition. Res Exp Med. 2000;199:189–94.

    CAS  Google Scholar 

  31. Uyuklu M, Meiselman HJ, Baskurt OK. Effect of decreased plasma cholesterol by atorvastatin treatment on erythrocyte mechanical properties. Clin Hemorheol Microcirc. 2007;36:25–33.

    CAS  PubMed  Google Scholar 

  32. Levy Y, Leibowitz R, Aviram M, Brook JG, Cogan U. Reduction of plasma cholesterol by lovastatin normalizes erythrocyte membrane fluidity in patients with severe hypercholesterolemia. Br J Clin Pharmacol. 1992;34:427–30.

    CAS  PubMed  Google Scholar 

  33. Lijnen P, Celis H, Fagard R, Staessen J, Amery A. Influence of cholesterol lowering on plasma membrane lipids and cationic transport systems. J Hypertens. 1994;12:59–64.

    Article  CAS  PubMed  Google Scholar 

  34. Pogue DH, Moravec CS, Roppelt C, Disch CH, Cressman MD, Bond M. Effect of lovastatin on cholesterol content of cardiac and red blood cell membranes in normal and cardiomyopathic hamsters. J Pharmacol Exp Ther. 1995;273:863–9.

    CAS  PubMed  Google Scholar 

  35. Dwight JF, Mendes Ribeiro AC, Hendry BM. Effects of HMG-CoA reductase inhibition on erythrocyte membrane cholesterol and acyl chain composition. Clin Chim Acta. 1996;256:53–63.

    Article  CAS  PubMed  Google Scholar 

  36. Miossec P, Zkhiri F, Paries J, David-Dufilho M, Devynck MA, Valensi PE. Effect of pravastatin on erythrocyte rheological and biochemical properties in poorly controlled type-2 diabetic patients. Diabet Med. 1999;16:424–30.

    Article  CAS  PubMed  Google Scholar 

  37. Rabini RA, Polenta M, Staffolani R, Tocchini M, Signore R, Testa I, et al. Effect of hydroxymethylglutaryl-CoA reductase inhibitors on the functional properties of erythrocyte membranes. Exp Mol Pathol. 1993;59:51–7.

    Article  CAS  PubMed  Google Scholar 

  38. Lijnen P, Fagard R, Staessen J, Thijs L, Amery A. Erythrocyte membrane lipids and cationic transport systems in men. J Hypertens. 1992;10:1205–11.

    Article  CAS  PubMed  Google Scholar 

  39. Schick BP, Schick PK. Cholesterol exchange in platelets, erythrocytes, and megakaryocytes. Biochim Biophys Acta. 1985;833:281–90.

    CAS  PubMed  Google Scholar 

  40. Chabanel A, Flamm M, Sung KL, Lee MM, Schachter SL, Chien S. Influence of cholesterol content on red cell membrane viscoelasticity and fluidity. Biophys J. 1983;44:171–6.

    Article  CAS  PubMed  Google Scholar 

  41. Kanakaraj P, Singh M. Influence of hypercholesterolemia on morphological and rheological characteristics of erythrocytes. Atherosclerosis. 1989;76:209–18.

    Article  CAS  PubMed  Google Scholar 

  42. London IM, Schwarz H. Erythrocyte metabolism. The metabolic behavior of the cholesterol of human erythrocytes. J Clin Invest. 1992;32:1248–52.

    Article  Google Scholar 

  43. Gold JC, Phillips MC. Effects of membrane lipid composition on the kinetics of cholesterol exchange between lipoproteins and different species of red blood cells. Biochim Biophys Acta. 1990;1027:85–92.

    Article  CAS  PubMed  Google Scholar 

  44. Rothblat GH, Arbogast LY, Ray EK. Stimulation of esterified cholesterol accumulation in tissue culture cells exposed to high density lipoproteins enriched in free cholesterol. J Lipid Res. 1978;19:350–8.

    CAS  PubMed  Google Scholar 

  45. d’Hollander F, Chavallier F. Movement of cholesterol in vitro in rat blood and quantitation of the exchange of free cholesterol between plasma and erythrocytes. J Lipid Res. 1972;13:733–44.

    Google Scholar 

  46. Gottlieb MH. Rates of cholesterol exchange between human erythrocytes and plasma lipoproteins. Biochim Biophys Acta. 1980;600:530–41.

    Article  CAS  PubMed  Google Scholar 

  47. Quarfordt SH, Hilderman HL. Quantitation of the in vitro free cholesterol exchange of human red cells and lipoproteins. J Lipid Res. 1970;11:528–35.

    CAS  PubMed  Google Scholar 

  48. Kuypers FA, Roelofsen B, Op Den Kamp JAF, Van Deenen LLM. The membrane of intact human erythrocyte tolerates only limited changes in the fatty acid composition of its phosphatidylcholine. Biochim Biophys Acta. 1984;769:337–47.

    Article  CAS  PubMed  Google Scholar 

  49. Hagve TA, Lie O, Gronn M. The effect of dietary n-3 fatty acids on osmotic fragility and membrane fluidity of human erythrocytes. Scand J Clin Lab Invest. 1993;53(Suppl 215):75–84.

    Article  CAS  Google Scholar 

  50. Hui DY, Noel JG, Harmony JAK. Binding of plasma low density lipoproteins to erythrocytes. Biochim Biophys Acta. 1981;664:513–26.

    CAS  PubMed  Google Scholar 

  51. Lange Y, Swaisgood MH, Ramos BV, Steck TL. Plasma membranes contain half the phospholipid and 90% of the cholesterol and sphingomyelin in cultured human fibroblasts. J Biol Chem. 1989;264:3786–93.

    CAS  PubMed  Google Scholar 

  52. Ohvo-Rekila H, Ramstedt B, Leppimaki P, Slotte P. Cholesterol interactions with phospholipids in membranes. Prog Lipid Res. 2002;41:66–97.

    Article  CAS  PubMed  Google Scholar 

  53. Chen H, Born E, Mathur SN, Field FJ. Cholesterol and sphingomyelin syntheses are regulated independently in cultured human intestinal cells, CaCo-2: role of membrane cholesterol and sphingomyelin content. J Lipid Res. 1993;34:2159–67.

    CAS  PubMed  Google Scholar 

  54. Chen H, Born E, Mathur SN, Johlin FC Jr, Field FJ. Sphingomyelin content of intestinal cell membranes regulates cholesterol absorption. Biochem J. 1992;286:771–7.

    CAS  PubMed  Google Scholar 

  55. Slotte JP, Bierman EL. Depletion of plasma —membrane sphingomyelin rapidly alters the distribution of cholesterol between plasma membranes and intracellular cholesterol pools in cultured fibroblasts. Biochem J. 1988;250:653–8.

    CAS  PubMed  Google Scholar 

Download references

Conflict of interest

None declared

Author information

Authors and Affiliations

  1. University Cardiology Department, Medical School, Democritus University of Thrace, Voulgaroktonou 23, 68100, Alexandroupolis, Greece

    Dimitrios N. Tziakas, Georgios K. Chalikias, Dimitrios Stakos, Adina Thomaidi, Sofia Chatzikyriakou, Konstantina Mitrousi & Stavros Konstantinides

  2. Biochemistry Department, Medical School, Democritus University of Thrace, Alexandroupolis, Greece

    Ioannis K. Tentes & Alexandros X. Kortsaris

  3. Cardiovascular Biology Research Centre, St George’s Hospital, University of London, London, UK

    Juan Carlos Kaski

  4. Center for Clinical Research, Foundation of Biomedical Research, Academy of Athens, Athens, Greece

    Harisios Boudoulas

Authors
  1. Dimitrios N. Tziakas
    View author publications

    You can also search for this author in PubMed Google Scholar

  2. Georgios K. Chalikias
    View author publications

    You can also search for this author in PubMed Google Scholar

  3. Dimitrios Stakos
    View author publications

    You can also search for this author in PubMed Google Scholar

  4. Ioannis K. Tentes
    View author publications

    You can also search for this author in PubMed Google Scholar

  5. Adina Thomaidi
    View author publications

    You can also search for this author in PubMed Google Scholar

  6. Sofia Chatzikyriakou
    View author publications

    You can also search for this author in PubMed Google Scholar

  7. Konstantina Mitrousi
    View author publications

    You can also search for this author in PubMed Google Scholar

  8. Alexandros X. Kortsaris
    View author publications

    You can also search for this author in PubMed Google Scholar

  9. Juan Carlos Kaski
    View author publications

    You can also search for this author in PubMed Google Scholar

  10. Harisios Boudoulas
    View author publications

    You can also search for this author in PubMed Google Scholar

  11. Stavros Konstantinides
    View author publications

    You can also search for this author in PubMed Google Scholar

Corresponding author

Correspondence to Dimitrios N. Tziakas.

Rights and permissions

Reprints and permissions

About this article

Cite this article

Tziakas, D.N., Chalikias, G.K., Stakos, D. et al. Statin Use is Associated with a Significant Reduction in Cholesterol Content of Erythrocyte Membranes. A Novel Pleiotropic Effect?. Cardiovasc Drugs Ther 23, 471–480 (2009). https://doi.org/10.1007/s10557-009-6202-7

Download citation

  • Published:

  • Issue Date:

  • DOI: https://doi.org/10.1007/s10557-009-6202-7

Key words

Search

Navigation