Remote ischemic preconditioning inhibits platelet αIIb β3 activation in coronary artery disease patients receiving dual antiplatelet therapy: A randomized trial

Jerrett K Lau, Gabrielle J Pennings, Caroline J Reddel, Heather Campbell, Hai Po H Liang, Mathew Traini, Elizabeth E Gardiner, Andy S Yong, Vivien M Chen, Leonard Kritharides, Jerrett K Lau, Gabrielle J Pennings, Caroline J Reddel, Heather Campbell, Hai Po H Liang, Mathew Traini, Elizabeth E Gardiner, Andy S Yong, Vivien M Chen, Leonard Kritharides

Abstract

Objectives: We investigated whether remote ischemic preconditioning (RIPC) inhibits agonist-induced conformational activation of platelet αIIb β3 in patients with coronary artery disease already receiving conventional antiplatelet therapy.

Patients/methods: Consecutive patients with angiographically confirmed coronary artery disease were randomized to RIPC or sham treatment. Venous blood was collected before and immediately after RIPC/sham. Platelet aggregometry (ADP, arachidonic acid) and whole blood platelet flow cytometry was performed for CD62P, CD63, active αIIb β3 (PAC-1 binding) before and after stimulation with ADP, thrombin ± collagen, or PAR-1 thrombin receptor agonist.

Results: Patients (25 RIPC, 23 sham) were well matched, 83% male, age (mean ± standard deviation) 63.3 ± 13.2 years, 95% aspirin, 81% P2Y12 inhibitor. RIPC did not affect platelet aggregation, nor agonist-induced expression of CD62P, but selectively and significantly decreased αIIb β3 activation after stimulation with either PAR-1 agonist peptide or the combination of thrombin + collagen, but not after ADP nor thrombin alone. The effect of RIPC on platelet αIIb β3 activation was evident in patients receiving both aspirin and P2Y12 inhibitor, and was not associated with an increase in vasodilator-stimulated phosphoprotein phosphorylation.

Conclusions: Remote ischemic preconditioning inhibits conformational activation of platelet αIIb β3 in response to exposure to thrombin and collagen in patients with coronary artery disease receiving dual antiplatelet therapy. These findings indicate agonist-specific inhibition of platelet activation by RIPC in coronary artery disease that is not obviated by the prior use of P2Y12 inhibitors.

Keywords: coronary artery disease; ischemic preconditioning; platelet activation; platelet antagonists; platelet glycoprotein GPIIb-IIIa complex.

© 2020 International Society on Thrombosis and Haemostasis.

References

REFERENCES

    1. Wallentin L, Becker RC, Budaj A, et al. Ticagrelor versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2009;361(11):1045-1057.
    1. Wiviott SD, Braunwald E, McCabe CH, et al. Prasugrel versus clopidogrel in patients with acute coronary syndromes. N Engl J Med. 2007;357(20):2001-2015.
    1. Heusch G, Botker HE, Przyklenk K, Redington A, Yellon D. Remote ischemic conditioning. J Am Coll Cardiol. 2015;65(2):177-195.
    1. Heusch G. 25 years of remote ischemic conditioning: from laboratory curiosity to clinical outcome. Basic Res Cardiol. 2018;113(3):15.
    1. Leung CH, Wang L, Nielsen JM, et al. Remote cardioprotection by transfer of coronary effluent from ischemic preconditioned rabbit heart preserves mitochondrial integrity and function via adenosine receptor activation. Cardiovasc Drugs Ther. 2014;28(1):7-17.
    1. Skyschally A, Gent S, Amanakis G, Schulte C, Kleinbongard P, Heusch G. Across-species transfer of protection by remote ischemic preconditioning with species-specific myocardial signal transduction by reperfusion injury salvage kinase and survival activating factor enhancement pathways. Circ Res. 2015;117(3):279-288.
    1. Surendra H, Diaz RJ, Harvey K, et al. Interaction of delta and kappa opioid receptors with adenosine A1 receptors mediates cardioprotection by remote ischemic preconditioning. J Mol Cell Cardiol. 2013;60:142-150.
    1. Shimizu M, Tropak M, Diaz RJ, et al. Transient limb ischaemia remotely preconditions through a humoral mechanism acting directly on the myocardium: evidence suggesting cross-species protection. Clin Sci (Lond). 2009;117(5):191-200.
    1. Heusch G, Rassaf T. Time to give up on cardioprotection? A critical appraisal of clinical studies on ischemic pre-, post-, and remote conditioning. Circ Res. 2016;119(5):676-695.
    1. Hausenloy DJ, Kharbanda RK, Moller UK, et al. Effect of remote ischaemic conditioning on clinical outcomes in patients with acute myocardial infarction (CONDI-2/ERIC-PPCI): a single-blind randomised controlled trial. Lancet. 2019;394(10207):1415-1424.
    1. Hausenloy DJ, Candilio L, Evans R, et al. Remote ischemic preconditioning and outcomes of cardiac surgery. N Engl J Med. 2015;373(15):1408-1417.
    1. Meybohm P, Bein B, Brosteanu O, et al. A Multicenter trial of remote ischemic preconditioning for heart surgery. N Engl J Med. 2015;373(15):1397-1407.
    1. Zhao W, Meng R, Ma C, et al. Safety and efficacy of remote ischemic preconditioning in patients with severe carotid artery stenosis before carotid artery stenting: a proof-of-concept, randomized controlled trial. Circulation. 2017;135(14):1325-1335.
    1. Battipaglia I, Scalone G, Milo M, Di Franco A, Lanza GA, Crea F. Upper arm intermittent ischaemia reduces exercise-related increase of platelet reactivity in patients with obstructive coronary artery disease. Heart. 2011;97(16):1298-1303.
    1. Stazi A, Scalone G, Laurito M, et al. Effect of remote ischemic preconditioning on platelet activation and reactivity induced by ablation for atrial fibrillation. Circulation. 2014;129(1):11-17.
    1. Pedersen CM, Cruden NL, Schmidt MR, et al. Remote ischemic preconditioning prevents systemic platelet activation associated with ischemia-reperfusion injury in humans. J Thromb Haemost. 2011;9(2):404-407.
    1. Fullard JF. The role of the platelet glycoprotein IIb/IIIa in thrombosis and haemostasis. Curr Pharm Des. 2004;10(14):1567-1576.
    1. Lincoff AM, Califf RM, Anderson KM, et al. Evidence for prevention of death and myocardial infarction with platelet membrane glycoprotein IIb/IIIa receptor blockade by abciximab (c7E3 Fab) among patients with unstable angina undergoing percutaneous coronary revascularization. EPIC Investigators. Evaluation of 7E3 in Preventing Ischemic Complications. J Am Coll Cardiol. 1997;30(1):149-156.
    1. Oberkofler CE, Limani P, Jang JH, et al. Systemic protection through remote ischemic preconditioning is spread by platelet-dependent signaling in mice. Hepatology. 2014;60(4):1409-1417.
    1. Alpuche J, Quirino L, Sanchez-Vega JT, Yap J, Perez-Campos E, Cabrera-Fuentes HA. The role of platelets in ischemic conditioning. Cond Med. 2018;1(6):313-318.
    1. Lanza GA, Stazi A, Villano A, et al. Effect of remote ischemic preconditioning on platelet activation induced by coronary procedures. Am J Cardiol. 2016;117(3):359-365.
    1. Johnsen J, Pryds K, Salman R, Lofgren B, Kristiansen SB, Botker HE. The remote ischemic preconditioning algorithm: effect of number of cycles, cycle duration and effector organ mass on efficacy of protection. Basic Res Cardiol. 2016;111(2):10.
    1. Cohen MV, Downey JM. The impact of irreproducibility and competing protection from P2Y12 antagonists on the discovery of cardioprotective interventions. Basic Res Cardiol. 2017;112(6):64.
    1. Hoole SP, Heck PM, Sharples L, et al. Cardiac remote ischemic preconditioning in coronary stenting (CRISP Stent) study: a prospective, randomized control trial. Circulation. 2009;119(6):820-827.
    1. Luo SJ, Zhou YJ, Shi DM, Ge HL, Wang JL, Liu RF. Remote ischemic preconditioning reduces myocardial injury in patients undergoing coronary stent implantation. Can J Cardiol. 2013;29(9):1084-1089.
    1. Liu Z, Wang YL, Hua Q, Chu YY, Ji XM. Late remote ischemic preconditioning provides benefit to patients undergoing elective percutaneous coronary intervention. Cell Biochem Biophys. 2014;70(1):437-442.
    1. Yong AS, Pennings GJ, Chang M, et al. Intracoronary shear-related up-regulation of platelet P-selectin and platelet-monocyte aggregation despite the use of aspirin and clopidogrel. Blood. 2011;117(1):11-20.
    1. Yong AS, Ng AC, Brieger D, Lowe HC, Ng MK, Kritharides L. Three-dimensional and two-dimensional quantitative coronary angiography, and their prediction of reduced fractional flow reserve. Eur Heart J. 2011;32(3):345-353.
    1. Thygesen K, Alpert JS, Jaffe AS, et al. Third universal definition of myocardial infarction. Circulation. 2012;126(16):2020-2035.
    1. Pennings GJ, Yong AS, Kritharides L. Expression of EMMPRIN (CD147) on circulating platelets in vivo. J Thromb Haemost. 2010;8(3):472-481.
    1. Al-Tamimi M, Mu FT, Moroi M, Gardiner EE, Berndt MC, Andrews RK. Measuring soluble platelet glycoprotein VI in human plasma by ELISA. Platelets. 2009;20(3):143-149.
    1. Horstrup K, Jablonka B, Honig-Liedl P, Just M, Kochsiek K, Walter U. Phosphorylation of focal adhesion vasodilator-stimulated phosphoprotein at Ser157 in intact human platelets correlates with fibrinogen receptor inhibition. Eur J Biochem. 1994;225(1):21-27.
    1. Stalker TJ, Newman DK, Ma P, Wannemacher KM, Brass LF. Platelet signaling. Handb Exp Pharmacol. 2012;59-85.
    1. Roberts W, Riba R, Homer-Vanniasinkam S, Farndale RW, Naseem KM. Nitric oxide specifically inhibits integrin-mediated platelet adhesion and spreading on collagen. J Thromb Haemost. 2008;6(12):2175-2185.

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