Download PDF
Thromb Haemost 2023; 123(06): 585-596
DOI: 10.1055/s-0043-1764353
Cellular Haemostasis and Platelets

Statin Treatment Is Associated with Alterations in the Platelet Lipidome

Tobias Harm
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
,
Moritz Frey
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
,
Kristina Dittrich
2   Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, Eberhard Karls University Tübingen, Tübingen, Germany
,
Andreas Goldschmied
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
,
Anne-Katrin Rohlfing
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
,
Xiaoqing Fu
2   Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, Eberhard Karls University Tübingen, Tübingen, Germany
,
Adrian Brun
2   Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, Eberhard Karls University Tübingen, Tübingen, Germany
,
Tatsiana Castor
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
,
Dominik Rath
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
,
Karin Müller
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
,
Michael Lammerhofer
2   Institute of Pharmaceutical Sciences, Pharmaceutical (Bio-)Analysis, Eberhard Karls University Tübingen, Tübingen, Germany
,
Meinrad Gawaz
1   Department of Cardiology and Angiology, University Hospital Tübingen, Eberhard Karls University Tübingen, Tübingen, Germany
› Author Affiliations Funding This project was supported in part by the German Research Foundation (DFG) KFO-274 and TRR 240.
› Further Information
Also available at
    Permissions and Reprints


Abstract

Background Platelets are key players in the pathophysiology of coronary artery disease (CAD) and platelet hyperreactivity leads to increased risk of developing adverse cardiovascular events. Further, significant changes in the platelet lipidome occur in patients with acute coronary syndrome (ACS) and critically regulated lipids lead to platelet hyperresponsiveness. Statin treatment is crucial in the treatment and prevention of patients with CAD by remodeling lipid metabolism.

Objective In this study, we investigate the platelet lipidome of CAD patients by untargeted lipidomics, highlighting significant changes between statin-treated and naïve patients.

Methods We characterized the platelet lipidome in a CAD cohort (n = 105) by an untargeted lipidomics approach using liquid chromatography coupled to mass spectrometry.

Results Among the annotated lipids, 41 lipids were significantly upregulated in statin-treated patients, whereas 6 lipids were downregulated compared to naïve patients. The most prominent upregulated lipids in statin-treated patients belong to the class of triglycerides, cholesteryl esters, palmitic acid, and oxidized phospholipids, whereas mainly glycerophospholipids were downregulated compared to untreated patients. A more pronounced effect of statin treatment on the platelet lipidome was observed in ACS patients. We further highlight a dose-dependent influence on the platelet lipidome.

Conclusion Our results reveal that the platelet lipidome is altered in CAD patients with statin treatment and upregulated lipids embody mainly characteristic triglycerides, whereas downregulated lipids mostly compromise glycerophospholipids, which may play a role in the pathophysiology of CAD. Results of this study may contribute to the understanding of statin treatment softening the lipid phenotype.

Keywords

platelets - lipidome - statins - coronary artery disease

Data Availability Statement

The data that support the findings of this study are available on reasonable request from the corresponding author.


Supplementary Material



Publication History

Received: 25 October 2022

Accepted: 31 January 2023

Article published online:
10 March 2023

© 2023. Thieme. All rights reserved.

Georg Thieme Verlag KG
Rüdigerstraße 14, 70469 Stuttgart, Germany

 

  • References

  • 1 Droppa M, Tschernow D, Müller KAL. et al. Evaluation of clinical risk factors to predict high on-treatment platelet reactivity and outcome in patients with stable coronary artery disease (PREDICT-STABLE). PLoS One 2015; 10 (03) e0121620
    CrossrefPubMedSearch in Google Scholar
  • 2 Geisler T, Zürn C, Simonenko R. et al. Early but not late stent thrombosis is influenced by residual platelet aggregation in patients undergoing coronary interventions. Eur Heart J 2010; 31 (01) 59-66
    CrossrefPubMedSearch in Google Scholar
  • 3 Geisler T, Langer H, Wydymus M. et al. Low response to clopidogrel is associated with cardiovascular outcome after coronary stent implantation. Eur Heart J 2006; 27 (20) 2420-2425
    CrossrefPubMedSearch in Google Scholar
  • 4 Gawaz M. Does uncontrolled platelet activation promote coronary artery disease?. JACC Cardiovasc Imaging 2016; 9 (07) 855-857
    CrossrefPubMedSearch in Google Scholar
  • 5 Gawaz M, Langer H, May AE. Platelets in inflammation and atherogenesis. J Clin Invest 2005; 115 (12) 3378-3384
    CrossrefPubMedSearch in Google Scholar
  • 6 Bentzon JF, Otsuka F, Virmani R, Falk E. Mechanisms of plaque formation and rupture. Circ Res 2014; 114 (12) 1852-1866
    CrossrefPubMedSearch in Google Scholar
  • 7 Arroyo LH, Lee RT. Mechanisms of plaque rupture: mechanical and biologic interactions. Cardiovasc Res 1999; 41 (02) 369-375
    CrossrefPubMedSearch in Google Scholar
  • 8 Collet J-P, Thiele H, Barbato E. et al; ESC Scientific Document Group. 2020 ESC guidelines for the management of acute coronary syndromes in patients presenting without persistent ST-segment elevation. Eur Heart J 2021; 42 (14) 1289-1367
    CrossrefPubMedSearch in Google Scholar
  • 9 Ibanez B, James S, Agewall S. et al; ESC Scientific Document Group. 2017 ESC Guidelines for the management of acute myocardial infarction in patients presenting with ST-segment elevation: the Task Force for the management of acute myocardial infarction in patients presenting with ST-segment elevation of the European Society of Cardiology (ESC). Eur Heart J 2018; 39 (02) 119-177
    CrossrefPubMedSearch in Google Scholar
  • 10 Reny JL, Fontana P, Hochholzer W. et al. Vascular risk levels affect the predictive value of platelet reactivity for the occurrence of MACE in patients on clopidogrel. Systematic review and meta-analysis of individual patient data. Thromb Haemost 2016; 115 (04) 844-855
    PubMedSearch in Google Scholar
  • 11 Stellos K, Sauter R, Fahrleitner M. et al. Binding of oxidized low-density lipoprotein on circulating platelets is increased in patients with acute coronary syndromes and induces platelet adhesion to vascular wall in vivo–brief report. Arterioscler Thromb Vasc Biol 2012; 32 (08) 2017-2020
    CrossrefPubMedSearch in Google Scholar
  • 12 May AE, Geisler T, Gawaz M. Individualized antithrombotic therapy in high risk patients after coronary stenting. A double-edged sword between thrombosis and bleeding. Thromb Haemost 2008; 99 (03) 487-493
    Thieme ConnectPubMedSearch in Google Scholar
  • 13 Vinik AI, Erbas T, Park TS, Nolan R, Pittenger GL. Platelet dysfunction in type 2 diabetes. Diabetes Care 2001; 24 (08) 1476-1485
    CrossrefPubMedSearch in Google Scholar
  • 14 Chatterjee M, Rath D, Schlotterbeck J. et al. Regulation of oxidized platelet lipidome: implications for coronary artery disease. Eur Heart J 2017; 38 (25) 1993-2005
    CrossrefPubMedSearch in Google Scholar
  • 15 Harm T, Bild A, Dittrich K. et al. Acute coronary syndrome is associated with a substantial change in the platelet lipidome. Cardiovasc Res 2022; 118 (08) 1904-1916
    CrossrefPubMedSearch in Google Scholar
  • 16 Nenna A, Nappi F, Lusini M. et al. Effect of statins on platelet activation and function: from molecular pathways to clinical effects. BioMed Res Int 2021; 2021: 6661847
    CrossrefPubMedSearch in Google Scholar
  • 17 Peng B, Geue S, Coman C. et al. Identification of key lipids critical for platelet activation by comprehensive analysis of the platelet lipidome. Blood 2018; 132 (05) e1-e12
    CrossrefPubMedSearch in Google Scholar
  • 18 Sposito AC, Chapman MJ. Statin therapy in acute coronary syndromes: mechanistic insight into clinical benefit. Arterioscler Thromb Vasc Biol 2002; 22 (10) 1524-1534
    CrossrefPubMedSearch in Google Scholar
  • 19 Lopes RD, de Barros E Silva PGM, Damiani LP. et al. Major adverse cardiovascular events after 12 months among patients with acute coronary syndrome receiving loading doses of atorvastatin prior to planned PCI. JAMA 2020; 323 (08) 787-789
    CrossrefPubMedSearch in Google Scholar
  • 20 Øvrehus KA, Diederichsen A, Grove EL. et al. Reduction of myocardial infarction and all-cause mortality associated to statins in patients without obstructive CAD. JACC Cardiovasc Imaging 2021; 14 (12) 2400-2410
    CrossrefPubMedSearch in Google Scholar
  • 21 Hulten E, Jackson JL, Douglas K, George S, Villines TC. The effect of early, intensive statin therapy on acute coronary syndrome: a meta-analysis of randomized controlled trials. Arch Intern Med 2006; 166 (17) 1814-1821
    CrossrefPubMedSearch in Google Scholar
  • 22 Mihaylova B, Emberson J, Blackwell L. et al; Cholesterol Treatment Trialists' (CTT) Collaborators. The effects of lowering LDL cholesterol with statin therapy in people at low risk of vascular disease: meta-analysis of individual data from 27 randomised trials. Lancet 2012; 380 (9841): 581-590
    CrossrefPubMedSearch in Google Scholar
  • 23 Slatter DA, Aldrovandi M, O'Connor A. et al. Mapping the human platelet lipidome reveals cytosolic phospholipase A2 as a regulator of mitochondrial bioenergetics during activation. Cell Metab 2016; 23 (05) 930-944
    CrossrefPubMedSearch in Google Scholar
  • 24 O'Donnell VB, Murphy RC, Watson SP. Platelet lipidomics: modern day perspective on lipid discovery and characterization in platelets. Circ Res 2014; 114 (07) 1185-1203
    CrossrefPubMedSearch in Google Scholar
  • 25 Magtanong L, Ko PJ, To M. et al. Exogenous monounsaturated fatty acids promote a ferroptosis-resistant cell state. Cell Chem Biol 2019; 26 (03) 420.e9-432.e9
    CrossrefPubMedSearch in Google Scholar
  • 26 Li D, Li Y. The interaction between ferroptosis and lipid metabolism in cancer. Signal Transduct Target Ther 2020; 5 (01) 108
    CrossrefPubMedSearch in Google Scholar
  • 27 Yamaja Setty BN, Berger M, Stuart MJ. 13-Hydroxyoctadeca-9,11-dienoic acid (13-HODE) inhibits thromboxane A2 synthesis, and stimulates 12-HETE production in human platelets. Biochem Biophys Res Commun 1987; 148 (02) 528-533
    CrossrefPubMedSearch in Google Scholar
  • 28 McEwen BJ, Morel-Kopp MC, Chen W, Tofler GH, Ward CM. Effects of omega-3 polyunsaturated fatty acids on platelet function in healthy subjects and subjects with cardiovascular disease. Semin Thromb Hemost 2013; 39 (01) 25-32
    Thieme ConnectPubMedSearch in Google Scholar
  • 29 Lagarde M, Guichardant M, Bernoud-Hubac N, Calzada C, Véricel E. Oxygenation of polyunsaturated fatty acids and oxidative stress within blood platelets. Biochim Biophys Acta Mol Cell Biol Lipids 2018; 1863 (06) 651-656
    CrossrefPubMedSearch in Google Scholar
  • 30 Shaikh SR, Edidin M. Polyunsaturated fatty acids and membrane organization: elucidating mechanisms to balance immunotherapy and susceptibility to infection. Chem Phys Lipids 2008; 153 (01) 24-33
    CrossrefPubMedSearch in Google Scholar
  • 31 Harayama T, Riezman H. Understanding the diversity of membrane lipid composition. Nat Rev Mol Cell Biol 2018; 19 (05) 281-296
    CrossrefPubMedSearch in Google Scholar
  • 32 Lu J, Jilling T, Li D, Caplan MS. Polyunsaturated fatty acid supplementation alters proinflammatory gene expression and reduces the incidence of necrotizing enterocolitis in a neonatal rat model. Pediatr Res 2007; 61 (04) 427-432
    CrossrefPubMedSearch in Google Scholar
  • 33 Galicia-Garcia U, Jebari S, Larrea-Sebal A. et al. Statin treatment-induced development of type 2 diabetes: from clinical evidence to mechanistic insights. Int J Mol Sci 2020; 21 (13) 4725
    CrossrefPubMedSearch in Google Scholar
  • 34 Olzmann JA, Carvalho P. Dynamics and functions of lipid droplets. Nat Rev Mol Cell Biol 2019; 20 (03) 137-155
    CrossrefPubMedSearch in Google Scholar
  • 35 Cannon CP, Braunwald E, McCabe CH. et al; Pravastatin or Atorvastatin Evaluation and Infection Therapy-Thrombolysis in Myocardial Infarction 22 Investigators. Intensive versus moderate lipid lowering with statins after acute coronary syndromes. N Engl J Med 2004; 350 (15) 1495-1504
    CrossrefPubMedSearch in Google Scholar
  • 36 Violi F, Calvieri C, Ferro D, Pignatelli P. Statins as antithrombotic drugs. Circulation 2013; 127 (02) 251-257
    CrossrefPubMedSearch in Google Scholar
  • 37 Sikora J, Kostka B, Marczyk I, Krajewska U, Chałubiński M, Broncel M. Effect of statins on platelet function in patients with hyperlipidemia. Arch Med Sci 2013; 9 (04) 622-628
    CrossrefPubMedSearch in Google Scholar
  • 38 Pignatelli P, Sanguigni V, Lenti L. et al. Oxidative stress-mediated platelet CD40 ligand upregulation in patients with hypercholesterolemia: effect of atorvastatin. J Thromb Haemost 2007; 5 (06) 1170-1178
    CrossrefPubMedSearch in Google Scholar
  • 39 Blann AD, Gurney D, Hughes E, Buggins P, Silverman SH, Lip GYH. Influence of pravastatin on lipoproteins, and on endothelial, platelet, and inflammatory markers in subjects with peripheral artery disease. Am J Cardiol 2001; 88 (01) A7-A8 , 89–92
    CrossrefPubMedSearch in Google Scholar
  • 40 Serebruany VL, Miller M, Pokov AN. et al. Effect of statins on platelet PAR-1 thrombin receptor in patients with the metabolic syndrome (from the PAR-1 inhibition by statins [PARIS] study). Am J Cardiol 2006; 97 (09) 1332-1336
    CrossrefPubMedSearch in Google Scholar
  • 41 Patti G, Pasceri V, Colonna G. et al. Atorvastatin pretreatment improves outcomes in patients with acute coronary syndromes undergoing early percutaneous coronary intervention: results of the ARMYDA-ACS randomized trial. J Am Coll Cardiol 2007; 49 (12) 1272-1278
    CrossrefPubMedSearch in Google Scholar
  • 42 Cortellaro M, Cofrancesco E, Arbustini E. et al. Atorvastatin and thrombogenicity of the carotid atherosclerotic plaque: the ATROCAP study. Thromb Haemost 2002; 88 (01) 41-47
    PubMedSearch in Google Scholar
  • 43 Schuurman AR, Léopold V, Pereverzeva L. et al. The platelet lipidome is altered in patients with COVID-19 and correlates with platelet reactivity. Thromb Haemost 2022; 122 (10) 1683-1692
    Thieme ConnectPubMedSearch in Google Scholar