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Thromb Haemost 2018; 118(02): 388-400
DOI: 10.1160/TH17-02-0103
Stroke, Systemic or Venous Thromboembolism
Schattauer GmbH Stuttgart

Assessment of Thrombotic Risk in Atrial Fibrillation with Ultrasound Molecular Imaging of P-Selectin

Yuanwen Jing   *
,
Yinlan Hu   *
,
Hairui Li
,
Junfen Wang
,
Xiaoyun Si
,
Hao Zheng
,
Jian Liu
,
Wangjun Liao
,
Yulin Liao
,
Jianping Bin
Further Information

Publication History

14 February 2017

29 November 2017

Publication Date:
29 January 2018 (online)

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Abstract

Molecular imaging of inflammatory mediators in atria may contribute to thrombotic risk assessment of atrial fibrillation (AF). We investigated the feasibility of ultrasound molecular imaging (UMI) targeted to P-selectin to assess thrombotic risk in AF. Rat AF models were established with rapid atrial pacing. Microbubbles targeted to P-selectin were injected into the rats, followed by left atrial (LA) UMI examination. Furthermore, P-selectin, platelets (PLTs), fibrin and tissue factor (TF) of LA were detected by histopathology and scanning electron microscopy. Plasma levels of P-selectin, thrombin-antithrombin complex (TAT) and prothrombin fragment 1 + 2 (F1 + 2) were measured by enzyme-linked immunosorbent assay. The data showed that P-selectin in LA was correlated with PLT, fibrin and TF (r = 0.735, p < 0.05; r = 0.827, p < 0.05; r = 0.785, p < 0.05, respectively). The plasma level of P-selectin was correlated with the expression of TAT and F1 + 2 (r = 0.866, p < 0.05; r = 0.916, p < 0.05, respectively). The contrast video intensity of adhered microbubbles targeted to P-selectin was correlated with the levels of P-selectin, PLT and fibrin in LA (r = 0.768, p < 0.05; r = 0.798, p < 0.05; r = 0.745, p < 0.05, respectively). In conclusion, P-selectin may serve as a biomarker for thrombotic risk in AF and can be quantified by UMI to assess thrombotic risk.

Keywords

P-selectin - ultrasound molecular imaging - atrial fibrillation - thrombotic risk

Financial Support

This work was supported by grants from the National Natural Science Foundation of China (nos. 81571698, 81227801 and 81271640), National Basic Research Program of China (973 Program) (no. 2013CB733804), and the Team Program of Natural Science Foundation of Guangdong Province, China (S2011030003134).


Authors' Contributions

Yuanwen Jing and Yinlan Hu wrote the article, performed the experiments and analysed the data; Hairui Li, Xiaoyun Si and Hao Zheng performed the experiments and analysed the data, Junfen Wang and Jian Liu wrote the article; Wangjun Liao, Yulin Liao designed the research; Jianping Bin designed the research and wrote the article.


* These authors contributed equally to this work.


Supplementary Material

 

  • References

  • 1 Fuster V, Rydén LE, Cannom DS. , et al; American College of Cardiology/American Heart Association Task Force on Practice Guidelines; European Society of Cardiology Committee for Practice Guidelines; European Heart Rhythm Association; Heart Rhythm Society. ACC/AHA/ESC 2006 Guidelines for the Management of Patients with Atrial Fibrillation: a report of the American College of Cardiology/American Heart Association Task Force on Practice Guidelines and the European Society of Cardiology Committee for Practice Guidelines (Writing Committee to Revise the 2001 Guidelines for the Management of Patients With Atrial Fibrillation): developed in collaboration with the European Heart Rhythm Association and the Heart Rhythm Society. Circulation 2006; 114 (07) e257-e354
    CrossrefPubMedSearch in Google Scholar
  • 2 Freedman B, Potpara TS, Lip GY. Stroke prevention in atrial fibrillation. Lancet 2016; 388 (10046): 806-817
    CrossrefPubMedSearch in Google Scholar
  • 3 Voukalis C, Lip GY, Shantsila E. Emerging tools for stroke prevention in atrial fibrillation. EBioMedicine 2016; 4: 26-39
    CrossrefPubMedSearch in Google Scholar
  • 4 Chao TF, Liu CJ, Chen SJ. , et al. Atrial fibrillation and the risk of ischemic stroke: does it still matter in patients with a CHA2DS2-VASc score of 0 or 1?. Stroke 2012; 43 (10) 2551-2555
    CrossrefPubMedSearch in Google Scholar
  • 5 Szymanski FM, Lip GY, Filipiak KJ, Platek AE, Hrynkiewicz-Szymanska A, Opolski G. Stroke risk factors beyond the CHA2DS2-VASc score: Can we improve our identification of “high stroke risk” patients with atrial fibrillation?. Am J Cardiol 2015; 116 (11) 1781-1788
    CrossrefPubMedSearch in Google Scholar
  • 6 Watson T, Shantsila E, Lip GY. Mechanisms of thrombogenesis in atrial fibrillation: Virchow's triad revisited. Lancet 2009; 373 (9658): 155-166
    CrossrefPubMedSearch in Google Scholar
  • 7 Michels A, Albánez S, Mewburn J. , et al. Histones link inflammation and thrombosis through the induction of Weibel-Palade body exocytosis. J Thromb Haemost 2016; 14 (11) 2274-2286
    CrossrefPubMedSearch in Google Scholar
  • 8 Watson T, Arya A, Sulke N, Lip GY. Relationship of indices of inflammation and thrombogenesis to arrhythmia burden in paroxysmal atrial fibrillation. Chest 2010; 137 (04) 869-876
    CrossrefPubMedSearch in Google Scholar
  • 9 Vandendries ER, Furie BC, Furie B. Role of P-selectin and PSGL-1 in coagulation and thrombosis. Thromb Haemost 2004; 92 (03) 459-466
    Thieme ConnectPubMedSearch in Google Scholar
  • 10 Merten M, Thiagarajan P. P-selectin expression on platelets determines size and stability of platelet aggregates. Circulation 2000; 102 (16) 1931-1936
    CrossrefPubMedSearch in Google Scholar
  • 11 Jin H, Gebska MA, Blokhin IO. , et al. Endothelial PPAR-γ protects against vascular thrombosis by downregulating P-selectin expression. Arterioscler Thromb Vasc Biol 2015; 35 (04) 838-844
    CrossrefPubMedSearch in Google Scholar
  • 12 Falati S, Liu Q, Gross P. , et al. Accumulation of tissue factor into developing thrombi in vivo is dependent upon microparticle P-selectin glycoprotein ligand 1 and platelet P-selectin. J Exp Med 2003; 197 (11) 1585-1598
    CrossrefPubMedSearch in Google Scholar
  • 13 Cambien B, Wagner DD. A new role in hemostasis for the adhesion receptor P-selectin. Trends Mol Med 2004; 10 (04) 179-186
    CrossrefPubMedSearch in Google Scholar
  • 14 Culmer DL, Diaz JA, Hawley AE. , et al. Circulating and vein wall P-selectin promote venous thrombogenesis during aging in a rodent model. Thromb Res 2013; 131 (01) 42-48
    CrossrefPubMedSearch in Google Scholar
  • 15 Bielinski SJ, Berardi C, Decker PA. , et al. P-selectin and subclinical and clinical atherosclerosis: the Multi-Ethnic Study of Atherosclerosis (MESA). Atherosclerosis 2015; 240 (01) 3-9
    CrossrefPubMedSearch in Google Scholar
  • 16 Inaba Y, Lindner JR. Molecular imaging of disease with targeted contrast ultrasound imaging. Transl Res 2012; 159 (03) 140-148
    CrossrefPubMedSearch in Google Scholar
  • 17 Kaufmann BA, Lewis C, Xie A, Mirza-Mohd A, Lindner JR. Detection of recent myocardial ischaemia by molecular imaging of P-selectin with targeted contrast echocardiography. Eur Heart J 2007; 28 (16) 2011-2017
    CrossrefPubMedSearch in Google Scholar
  • 18 Kaufmann BA, Carr CL, Belcik JT. , et al. Molecular imaging of the initial inflammatory response in atherosclerosis: implications for early detection of disease. Arterioscler Thromb Vasc Biol 2010; 30 (01) 54-59
    CrossrefPubMedSearch in Google Scholar
  • 19 Deshpande N, Lutz AM, Ren Y. , et al. Quantification and monitoring of inflammation in murine inflammatory bowel disease with targeted contrast-enhanced US. Radiology 2012; 262 (01) 172-180
    CrossrefPubMedSearch in Google Scholar
  • 20 Yamashita T, Murakawa Y, Hayami N. , et al. Short-term effects of rapid pacing on mRNA level of voltage-dependent K(+) channels in rat atrium: electrical remodeling in paroxysmal atrial tachycardia. Circulation 2000; 101 (16) 2007-2014
    CrossrefPubMedSearch in Google Scholar
  • 21 Sugiyama A, Takahara A, Honsho S, Nakamura Y, Hashimoto K. A simple in vivo atrial fibrillation model of rat induced by transesophageal atrial burst pacing. J Pharmacol Sci 2005; 98 (03) 315-318
    CrossrefPubMedSearch in Google Scholar
  • 22 Yamashita T, Sekiguchi A, Iwasaki YK. , et al. Thrombomodulin and tissue factor pathway inhibitor in endocardium of rapidly paced rat atria. Circulation 2003; 108 (20) 2450-2452
    CrossrefPubMedSearch in Google Scholar
  • 23 Arzbaecher R, Jenkins JM. A review of the theoretical and experimental bases of transesophageal atrial pacing. J Electrocardiol 2002; 35 (Suppl): 137-141
    CrossrefPubMedSearch in Google Scholar
  • 24 Xie J, Liao Y, Yang L. , et al. Ultrasound molecular imaging of angiogenesis induced by mutant forms of hypoxia-inducible factor-1α. Cardiovasc Res 2011; 92 (02) 256-266
    CrossrefPubMedSearch in Google Scholar
  • 25 Koo TK, Li MY. A guideline of selecting and reporting intraclass correlation coefficients for reliability research. J Chiropr Med 2016; 15 (02) 155-163
    Search in Google Scholar
  • 26 Alonso A, Della Martina A, Stroick M. , et al. Molecular imaging of human thrombus with novel abciximab immunobubbles and ultrasound. Stroke 2007; 38 (05) 1508-1514
    CrossrefPubMedSearch in Google Scholar
  • 27 Takeuchi M, Ogunyankin K, Pandian NG. , et al. Enhanced visualization of intravascular and left atrial appendage thrombus with the use of a thrombus-targeting ultrasonographic contrast agent (MRX-408A1): In vivo experimental echocardiographic studies. J Am Soc Echocardiogr 1999; 12 (12) 1015-1021
    CrossrefPubMedSearch in Google Scholar
  • 28 Wang X, Hagemeyer CE, Hohmann JD. , et al. Novel single-chain antibody-targeted microbubbles for molecular ultrasound imaging of thrombosis: validation of a unique noninvasive method for rapid and sensitive detection of thrombi and monitoring of success or failure of thrombolysis in mice. Circulation 2012; 125 (25) 3117-3126
    CrossrefPubMedSearch in Google Scholar
  • 29 Luo ZQ, Hao XH, Li JH, Dai J, Liu KY, Lai YQ. Left atrial endocardial dysfunction and platelet activation in patients with atrial fibrillation and mitral stenosis. J Thorac Cardiovasc Surg 2014; 148 (05) 1970-1976
    CrossrefPubMedSearch in Google Scholar
  • 30 Li-Saw-Hee FL, Blann AD, Gurney D, Lip GY. Plasma von Willebrand factor, fibrinogen and soluble P-selectin levels in paroxysmal, persistent and permanent atrial fibrillation. Effects of cardioversion and return of left atrial function. Eur Heart J 2001; 22 (18) 1741-1747
    CrossrefPubMedSearch in Google Scholar
  • 31 Nair PM, Pidcoke HF, Cap AP, Ramasubramanian AK. Effect of cold storage on shear-induced platelet aggregation and clot strength. J Trauma Acute Care Surg 2014; 77 (03) (Suppl. 02) S88-S93
    CrossrefPubMedSearch in Google Scholar
  • 32 Faraday N, Rosenfeld BA. In vitro hypothermia enhances platelet GPIIb-IIIa activation and P-selectin expression. Anesthesiology 1998; 88 (06) 1579-1585
    CrossrefPubMedSearch in Google Scholar
  • 33 Ramacciotti E, Hawley AE, Farris DM. , et al. Leukocyte- and platelet-derived microparticles correlate with thrombus weight and tissue factor activity in an experimental mouse model of venous thrombosis. Thromb Haemost 2009; 101 (04) 748-754
    Thieme ConnectPubMedSearch in Google Scholar
  • 34 Kelchtermans H, Pelkmans L, Bouwhuis A. , et al. Simultaneous measurement of thrombin generation and fibrin formation in whole blood under flow conditions. Thromb Haemost 2016; 116 (01) 134-145
    Thieme ConnectPubMedSearch in Google Scholar
  • 35 Ferrante EA, Pickard JE, Rychak J, Klibanov A, Ley K. Dual targeting improves microbubble contrast agent adhesion to VCAM-1 and P-selectin under flow. J Control Release 2009; 140 (02) 100-107
    CrossrefPubMedSearch in Google Scholar
  • 36 Behm CZ, Lindner JR. Cellular and molecular imaging with targeted contrast ultrasound. Ultrasound Q 2006; 22 (01) 67-72
    PubMedSearch in Google Scholar
  • 37 Chung NA, Belgore F, Li-Saw-Hee FL, Conway DS, Blann AD, Lip GY. Is the hypercoagulable state in atrial fibrillation mediated by vascular endothelial growth factor?. Stroke 2002; 33 (09) 2187-2191
    CrossrefPubMedSearch in Google Scholar
  • 38 Cerletti C, Tamburrelli C, Izzi B, Gianfagna F, de Gaetano G. Platelet-leukocyte interactions in thrombosis. Thromb Res 2012; 129 (03) 263-266
    CrossrefPubMedSearch in Google Scholar
  • 39 Chugh SS, Havmoeller R, Narayanan K. , et al. Worldwide epidemiology of atrial fibrillation: a Global Burden of Disease 2010 Study. Circulation 2014; 129 (08) 837-847
    CrossrefPubMedSearch in Google Scholar
  • 40 Wang X, Gkanatsas Y, Palasubramaniam J. , et al. Thrombus-targeted theranostic microbubbles: a new technology towards concurrent rapid ultrasound diagnosis and bleeding-free fibrinolytic treatment of thrombosis. Theranostics 2016; 6 (05) 726-738
    CrossrefPubMedSearch in Google Scholar