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Thromb Haemost 2017; 117(09): 1816-1827
DOI: 10.1160/TH17-03-069
Atherosclerosis and Ischaemic Disease
Schattauer GmbH

Molecular signature of coronary stent thrombosis: oxidative stress and innate immunity cells

Judit Cubedo   *
1   Cardiovascular Science Institute – ICCC, Biomedical Research Institute Sant Pau (IIB-Sant Pau) and CiberCV, Barcelona, Spain
,
Ana Blasco   *
2   Invasive Cardiology Department Puerta de Hierro Hospital, Majadahonda, Madrid, Spain
,
Teresa Padró
1   Cardiovascular Science Institute – ICCC, Biomedical Research Institute Sant Pau (IIB-Sant Pau) and CiberCV, Barcelona, Spain
,
Ilaria Ramaiola
1   Cardiovascular Science Institute – ICCC, Biomedical Research Institute Sant Pau (IIB-Sant Pau) and CiberCV, Barcelona, Spain
,
Oriol Juan-Babot
1   Cardiovascular Science Institute – ICCC, Biomedical Research Institute Sant Pau (IIB-Sant Pau) and CiberCV, Barcelona, Spain
,
Javier Goicolea
2   Invasive Cardiology Department Puerta de Hierro Hospital, Majadahonda, Madrid, Spain
,
José Antonio Fernández-Díaz
2   Invasive Cardiology Department Puerta de Hierro Hospital, Majadahonda, Madrid, Spain
,
Juan Francisco Oteo
2   Invasive Cardiology Department Puerta de Hierro Hospital, Majadahonda, Madrid, Spain
,
Lina Badimon
1   Cardiovascular Science Institute – ICCC, Biomedical Research Institute Sant Pau (IIB-Sant Pau) and CiberCV, Barcelona, Spain
3   Cardiovascular Research Chair UAB, Barcelona, Spain
› Author Affiliations Financial support: This work was supported by grants from the Spanish Ministry of Economy and Competitiveness of Science [SAF2016–76819–R to L. B.]; Institute of Health Carlos III, ISCIII [TERCEL RD16/00110018 and CB16/11/0041 to L. B.; and FIS PI16/01915 to T. P.]; FEDER ˵Una Manera de Hacer Europa”; and “CERCA Programme/Generalitat de Catalunya” Spain. We thank FIC-Fundacion Jesús Serra, Barcelona, Spain, for their continuous support.
Further Information

Publication History

Received: 10 March 2017

Accepted after major revision: 13 May 2017

Publication Date:
28 November 2017 (online)

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Summary

The clinical impact of in-stent thrombosis is high because it is associated with high mortality and 20 % of the patients suffer a recurrent event within the two following years. The aim of this study was to characterise the morphologic and proteomic profile of in-stent thrombi (IST) in comparison to thrombi developed on native coronary arteries (CT) to identify a differential molecular signature. The study included 45 patients with ST-elevation-myocardial-infarction (STEMI) treated by primary-percutaneous-intervention and thrombus aspiration: 21 had IST and 24 had CT. Thrombi were characterised by morphologic immunohistochemical analysis and differential proteomic profiling (2-DE+MALDI-TOF/TOF). Bioinformatic analysis revealed differences in proteins related to oxidative-stress and cell death/survival. IST showed a higher content of structural proteins (gelsolin, actin-cytoplasmic-1, tropomyosin, and myosin) together with an imbalance in redox-homeostasis related proteins (increased superoxide-dismutase and decreased peroxiredoxin-2 thrombus content), and a coordinated increase of chaperones (HSP60 and HSC70) and cellular quality control-related proteins (26S–protease-regulatory-subunit-7). These changes were reflected into a significant decrease in HSC70 systemic levels and a significant increase in advanced-oxidation-protein-products (AOPP) indicative of increased oxidative stress-mediated protein damage in IST. Our results reveal an imbalance in redox-related proteins indicative of an exacerbated oxidative-stress that leads to an accumulation of AOPP serum levels in IST. Moreover, the coordinated increase in chaperones and regulatory proteins reflects the activation of intracellular protection mechanisms to maintain protein integrity in IST. The failure to counterbalance the stress situation could trigger cellular apoptosis leading to the destabilization of the thrombus and to a worse prognosis of IST-STEMI-patients.

Supplementary Material to this article is available online at www.thrombosis-online.com.

Keywords

Acute myocardial infarction - thrombus - in-stent thrombosis - oxidative stress - chaperones

* Both authors contributed equally to this paper.


 

  • References

  • 1 Huber K, De Caterina R, Kristensen SD. et al. Pre-hospital reperfusion therapy: a strategy to improve therapeutic outcome in patients with ST-elevation myocardial infarction. Eur Heart J 2005; 26: 2063-2074.
    CrossrefPubMedGoogle Scholar
  • 2 Burzotta F, De Vita M, Gu YL. et al. Clinical impact of thrombectomy in acute ST-elevation myocardial infarction: an individual patient-data pooled analysis of 11 trials. Eur Heart J 2009; 30: 2193-2203.
    CrossrefPubMedGoogle Scholar
  • 3 Silva-Orrego P, Colombo P, Bigi R. et al. Thrombus aspiration before primary angioplasty improves myocardial reperfusion in acute myocardial infarction: the DEAR-MI (Dethrombosis to Enhance Acute Reperfusion in Myocardial Infarction) study. J Am Coll Cardiol 2006; 48: 1552-1559.
    PubMedGoogle Scholar
  • 4 De Luca G, Dirksen MT, Spaulding C. Time course, predictors and clinical implications of stent thrombosis following primary angioplasty. Insights from the DESERT cooperation. Thromb Haemost 2013; 110: 826-833.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 5 Iakovou I, Schmidt T, Bonizzoni E. et al. Incidence, predictors, and outcome of thrombosis after successful implantation of drug-eluting stents. J Am Med Assoc 2005; 293: 2126-2130.
    CrossrefPubMedGoogle Scholar
  • 6 Doyle B, Rihal CS, O’Sullivan CJ. et al. Outcomes of stent thrombosis and restenosis during extended follow-up of patients treated with bare-metal coronary stents. Circulation 2007; 116: 2391-2398.
    CrossrefPubMedGoogle Scholar
  • 7 Arakawa K, Yasuda S, Hao H. et al. Significant association between neutrophil aggregation in aspirated thrombus and myocardial damage in patients with ST-segment elevation acute myocardial infarction. Circ J 2009; 73: 139-144.
    CrossrefPubMedGoogle Scholar
  • 8 Yunoki K, Naruko T, Sugioka K. et al. Erythrocyte-rich thrombus aspirated from patients with ST-elevation myocardial infarction: association with oxidative stress and its impact on myocardial reperfusion. Eur Heart J 2012; 33: 1480-1490.
    CrossrefPubMedGoogle Scholar
  • 9 Yunoki K, Naruko T, Inoue T. et al. Relationship of thrombus characteristics to the incidence of angiographically visible distal embolization in patients with ST-segment elevation myocardial infarction treated with thrombus aspiration. JACC Cardiovasc Interv 2013; 06: 377-385.
    CrossrefPubMedGoogle Scholar
  • 10 Iwata H, Sata M, Ando J. et al. Impact of primitive cells in intracoronary thrombi on lesion prognosis: temporal analysis of cellular constituents of thrombotic material obtained from patients with acute coronary syndrome. Heart 2010; 96: 748-755.
    CrossrefPubMedGoogle Scholar
  • 11 Ramaiola I, Padro T, Pena E. et al. Changes in thrombus composition and profilin-1 release in acute myocardial infarction. Eur Heart J 2015; 36: 965-975.
    CrossrefPubMedGoogle Scholar
  • 12 Kramer MC, van der Wal AC, Koch KT. et al. Presence of older thrombus is an independent predictor of long-term mortality in patients with ST-elevation myocardial infarction treated with thrombus aspiration during primary percutaneous coronary intervention. Circulation 2008; 118: 1810-1816.
    CrossrefPubMedGoogle Scholar
  • 13 Silvain J, Collet JP, Nagaswami C. et al. Composition of coronary thrombus in acute myocardial infarction. J Am Coll Cardiol 2011; 57: 1359-1367.
    CrossrefPubMedGoogle Scholar
  • 14 Mingo S, Goicolea J, Nombela L. et al. Primary percutaneous angioplasty. An analysis of reperfusion delays, their determining factors and their prognostic implications. Rev Esp Cardiol 2009; 62: 15-22.
    CrossrefPubMedGoogle Scholar
  • 15 Blasco A, Bellas C, Goicolea L. et al. Immunohistological Analysis of Intracoronary Thrombus Aspirate in STEMI Patients: Clinical Implications of Pathological Findings. Rev Esp Cardiol. 2016 Epub ahead of print
    PubMedGoogle Scholar
  • 16 Martin-Ventura JL, Madrigal-Matute J, Martinez-Pinna R. et al. Erythrocytes, leukocytes and platelets as a source of oxidative stress in chronic vascular diseases: detoxifying mechanisms and potential therapeutic options. Thromb Haemost 2012; 108: 435-442.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 17 Svilaas T, Vlaar PJ, van der Horst IC. et al. Thrombus aspiration during primary percutaneous coronary intervention. N Engl J Med 2008; 358: 557-567.
    CrossrefPubMedGoogle Scholar
  • 18 Cubedo J, Ramaiola I, Padro T. et al. High-molecular-weight kininogen and the intrinsic coagulation pathway in patients with de novo acute myocardial infarction. Thromb Haemost 2013; 110: 1121-1134.
    Article in Thieme ConnectPubMedGoogle Scholar
  • 19 Zilberman M, Eberhart RC. Drug-eluting bioresorbable stents for various applications. Annu Rev Biomed Eng 2006; 08: 153-180.
    CrossrefPubMedGoogle Scholar
  • 20 Chaabane C, Otsuka F, Virmani R. et al. Biological responses in stented arteries. Cardiovasc Res 2013; 99: 353-363.
    CrossrefPubMedGoogle Scholar
  • 21 Riegger J, Byrne RA, Joner M. et al. Histopathological evaluation of thrombus in patients presenting with stent thrombosis. A multicenter European study: a report of the prevention of late stent thrombosis by an interdisciplinary global European effort consortium. Eur Heart J 2016; 37: 1538-1549.
    PubMedGoogle Scholar
  • 22 Cook S, Ladich E, Nakazawa G. et al. Correlation of intravascular ultrasound findings with histopathological analysis of thrombus aspirates in patients with very late drug-eluting stent thrombosis. Circulation 2009; 120: 391-399.
    CrossrefPubMedGoogle Scholar
  • 23 Niccoli G, Menozzi A, Capodanno D. et al. Relationship between Serum Inflammatory Biomarkers and Thrombus Characteristics in Patients with ST Segment Elevation Myocardial Infarction. Cardiology 2017; 137: 27-35.
    CrossrefPubMedGoogle Scholar
  • 24 Inoue T, Croce K, Morooka T. et al. Vascular inflammation and repair: implications for re-endothelialization, restenosis, and stent thrombosis. JACC Cardiovasc Interv 2011; 04: 1057-1066.
    CrossrefPubMedGoogle Scholar
  • 25 Inoue T, Sata M, Hikichi Y. et al. Mobilization of CD34-positive bone marrow-derived cells after coronary stent implantation: impact on restenosis. Circulation 2007; 115: 553-561.
    CrossrefPubMedGoogle Scholar
  • 26 Suades R, Padro T, Vilahur G. et al. Growing thrombi release increased levels of CD235a(+) microparticles and decreased levels of activated platelet-derived microparticles. Validation in ST-elevation myocardial infarction patients. J Thromb Haemost 2015; 13: 1776-1786.
    CrossrefPubMedGoogle Scholar
  • 27 Brasen JH, Kivela A, Roser K. et al. Angiogenesis, vascular endothelial growth factor and platelet-derived growth factor-BB expression, iron deposition, and oxidation-specific epitopes in stented human coronary arteries. Arterioscler Thromb Vasc Biol 2001; 21: 1720-1726.
    CrossrefPubMedGoogle Scholar
  • 28 Hare GM, Mu A, Romaschin A. et al. Plasma methemoglobin as a potential biomarker of anemic stress in humans. Can J Anaesth 2012; 59: 348-356.
    CrossrefPubMedGoogle Scholar
  • 29 Juni RP, Duckers HJ, Vanhoutte PM. et al. Oxidative stress and pathological changes after coronary artery interventions. J Am Coll Cardiol 2013; 61: 1471-1481.
    CrossrefPubMedGoogle Scholar
  • 30 Yubisui T, Takeshita M, Yoneyama Y. Reduction of methemoglobin through flavin at the physiological concentration by NADPH-flavin reductase of human erythrocytes. J Biochem 1980; 87: 1715-1720.
    CrossrefPubMedGoogle Scholar
  • 31 Rhee SG, Woo HA, Kil IS. et al. Peroxiredoxin functions as a peroxidase and a regulator and sensor of local peroxides. J Biol Chem 2012; 287: 4403-4410.
    CrossrefPubMedGoogle Scholar
  • 32 Fukai T, Ushio-Fukai M. Superoxide dismutases: role in redox signaling, vascular function, and diseases. Antioxid Redox Signal 2011; 15: 1583-1606.
    CrossrefPubMedGoogle Scholar
  • 33 Raisanen SR, Lehenkari P, Tasanen M. et al. Carbonic anhydrase III protects cells from hydrogen peroxide-induced apoptosis. FASEB J 1999; 13: 513-522.
    CrossrefPubMedGoogle Scholar
  • 34 Aaronson RM, Graven KK, Tucci M. et al. Non-neuronal enolase is an endothelial hypoxic stress protein. J Biol Chem 1995; 270: 27752-27757.
    CrossrefPubMedGoogle Scholar
  • 35 Tarone G, Brancaccio M. Keep your heart in shape: molecular chaperone networks for treating heart disease. Cardiovasc Res 2014; 102: 346-361.
    CrossrefPubMedGoogle Scholar