Advertisement

Therapy with high-dose statins reduces soluble P-selectin: The impact on plasma fibrin clot properties

  • Author Footnotes
    1 Authors equally contributed.
    Jakub Siudut
    Footnotes
    1 Authors equally contributed.
    Affiliations
    Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland

    Krakow Center for Medical Research and Technologies, John Paul II Hospital, Krakow, Poland
    Search for articles by this author
  • Author Footnotes
    1 Authors equally contributed.
    Joanna Pudło
    Footnotes
    1 Authors equally contributed.
    Affiliations
    Department of Diagnostics, John Paul II Hospital, Krakow, Poland
    Search for articles by this author
  • Małgorzata Konieczyńska
    Affiliations
    Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland

    Department of Diagnostics, John Paul II Hospital, Krakow, Poland
    Search for articles by this author
  • Maciej Polak
    Affiliations
    Department of Epidemiology and Population Studies, Institute of Public Health, Jagiellonian University Medical College, Krakow, Poland
    Search for articles by this author
  • Jacek Jawień
    Affiliations
    Department of Pharmacology, Jagiellonian University Medical College, Krakow, Poland
    Search for articles by this author
  • Anetta Undas
    Correspondence
    Corresponding author at: Institute of Cardiology, Jagiellonian University Medical College, 80 Pradnicka St., 31-202 Krakow, Poland.
    Affiliations
    Department of Thromboembolic Disorders, Institute of Cardiology, Jagiellonian University Medical College, Krakow, Poland

    Krakow Center for Medical Research and Technologies, John Paul II Hospital, Krakow, Poland
    Search for articles by this author
  • Author Footnotes
    1 Authors equally contributed.
Published:November 18, 2022DOI:https://doi.org/10.1016/j.ijcard.2022.11.026

      Highlights

      • High-dose statin therapy reduce plasma sP-selectin concentrations in CAD patients.
      • Decrease of sP-selectin is associated with the improvement in fibrin clot properties.
      • Platelet-related statin effect is independent from cholesterol lowering.

      Abstract

      Objective

      Studies on the effect of statins on platelets in patients with coronary artery disease (CAD) yielded inconsistent results. We sought to investigate whether high-dose statin therapy reduces plasma concentrations of soluble P-selectin (sP-selectin), a well-established platelet activation marker and if such changes can affect fibrin clot properties, which are unfavorably altered in CAD patients.

      Methods

      We studied 130 consecutive patients with advanced CAD who did not achieve the target LDL cholesterol on statins. At baseline and after 6–12 months of treatment with atorvastatin 80 mg/day or rosuvastatin 40 mg/day, soluble plasma sP-selectin, along with plasma fibrin clot permeability (Ks), clot lysis time (CLT), thrombin generation and fibrinolysis proteins were determined.

      Results

      Before high-intensity statin treatment, lower Ks and longer CLT values were associated with increased sP-selectin (β −0.27 [95% CI -0.44 to −0.10] and β 0.21 [95% CI 0.01 to 0.41]; both p < 0.05, respectively) also after adjustment for potential confounders. sP-selectin, alongside fibrin features and other variables at baseline showed no association with lipid profile. On high-dose statin therapy, there was 32% reduction in sP-selectin levels (p < 0.001). On-treatment change (Δ) in sP-selectin correlated with ΔKs and ΔCLT (r = −0.32, p < 0.001 and r = 0.22, p = 0.011, respectively), but not with cholesterol and C-reactive protein lowering. We did not observe any associations between post-treatment sP-selectin levels and lipids, fibrin clot properties or thrombin generation.

      Conclusions

      High-dose statin therapy reduces markedly sP-selectin levels in association with improved fibrin clot phenotype, which highlights the contribution of platelet-derived proteins to a prothrombotic state in hypercholesterolemia and statin-induced antithrombotic effects.

      Keywords

      To read this article in full you will need to make a payment

      Purchase one-time access:

      Academic & Personal: 24 hour online accessCorporate R&D Professionals: 24 hour online access
      One-time access price info
      • For academic or personal research use, select 'Academic and Personal'
      • For corporate R&D use, select 'Corporate R&D Professionals'

      Subscribe:

      Subscribe to International Journal of Cardiology
      Already a print subscriber? Claim online access
      Already an online subscriber? Sign in
      Institutional Access: Sign in to ScienceDirect

      References

        • André P.
        P-selectin in haemostasis.
        Br. J. Haematol. 2004; 126: 298-306https://doi.org/10.1111/j.1365-2141.2004.05032.x
        • Palabrica T.
        • Lobb R.
        • Furie B.C.
        • Aronovitz M.
        • Benjamin C.
        • Hsu Y.-M.
        • Sajer S.A.
        • Furie B.
        Leukocyte accumulation promoting fibrin deposition is mediated in vivo by P-selectin on adherent platelets.
        Nature. 1992; 359: 848-851https://doi.org/10.1038/359848a0
        • Barry O.P.
        • Praticò D.
        • Savani R.C.
        • FitzGerald G.A.
        Modulation of monocyte-endothelial cell interactions by platelet microparticles.
        J. Clin. Investig. 1998; 102: 136-144https://doi.org/10.1172/JCI2592
        • Romo G.M.
        • Dong J.-F.
        • Schade A.J.
        • Gardiner E.E.
        • Kansas G.S.
        • Li C.Q.
        • McIntire L.V.
        • Berndt M.C.
        • López J.A.
        The glycoprotein Ib-IX-V complex is a platelet counterreceptor for P-selectin.
        J. Exp. Med. 1999; 190: 803-814https://doi.org/10.1084/jem.190.6.803
        • Celi A.
        • Pellegrini G.
        • Lorenzet R.
        • A D.B.
        • Ready N.
        • Furie B.C.
        • Furie B.
        P-selectin induces the expression of tissue factor on monocytes.
        Proc. Natl. Acad. Sci. 1994; 91: 8767-8771https://doi.org/10.1073/pnas.91.19.8767
        • Gurbel P.A.
        • O’Connor C.M.
        • Dalesandro M.R.
        • Serebruany V.L.
        Relation of soluble and platelet p-selectin to early outcome in patients with acute myocardial infarction after thrombolytic therapy.
        Am. J. Cardiol. 2001; 87: 774-777https://doi.org/10.1016/S0002-9149(00)01502-2
        • Blann A.D.
        • Goode G.K.
        • Miller J.P.
        • McCollum C.N.
        Soluble P-selectin in hyperlipidaemia with and without symptomatic vascular disease: relationship with von Willebrand factor.
        Blood Coagul. Fibrinolysis. 1997; 8: 200-204https://doi.org/10.1097/00001721-199704000-00008
        • Kirk G.
        • McLaren M.
        • Muir A.H.
        • Stonebridge P.A.
        • Belch J.J.
        Decrease in P-selectin levels in patients with hypercholesterolaemia and peripheral arterial occlusive disease after lipid-lowering treatment.
        Vasc. Med. 1999; 4: 23-26https://doi.org/10.1177/1358836X9900400104
        • Ali F.Y.
        • Armstrong P.C.J.
        • Dhanji A.-R.A.
        • Tucker A.T.
        • Paul-Clark M.J.
        • Mitchell J.A.
        • Warner T.D.
        Antiplatelet actions of statins and fibrates are mediated by PPARs.
        Arterioscler. Thromb. Vasc. Biol. 2009; 29: 706-711https://doi.org/10.1161/ATVBAHA.108.183160
        • Pignatelli P.
        • Carnevale R.
        • Pastori D.
        • Cangemi R.
        • Napoleone L.
        • Bartimoccia S.
        • Nocella C.
        • Basili S.
        • Violi F.
        Immediate antioxidant and antiplatelet effect of atorvastatin via inhibition of Nox2.
        Circulation. 2012; 126: 92-103https://doi.org/10.1161/CIRCULATIONAHA.112.095554
        • Nenna A.
        • Nappi F.
        • Lusini M.
        • Satriano U.M.
        • Schilirò D.
        • Spadaccio C.
        • Chello M.
        Effect of statins on platelet activation and function: from molecular pathways to clinical effects.
        Biomed. Res. Int. 2021; 2021: 1-10https://doi.org/10.1155/2021/6661847
        • Yemisci M.
        • Ay H.
        • Kocaefe Ç.
        • Qui J.
        • Topalkara K.
        • Özgüç M.
        • Kirazli Ş.
        • Özcebe O.
        • Moskowitz M.A.
        • Dalkara T.
        Statin potentiates human platelet eNOS activity without enhancing eNOS mRNA and protein levels.
        Cerebrovasc. Dis. 2008; 26: 190-198https://doi.org/10.1159/000145327
        • Violi F.
        • Pignatelli P.
        Statins as regulators of redox signaling in platelets.
        Antioxid. Redox Signal. 2014; 20: 1300-1312https://doi.org/10.1089/ars.2013.5527
        • Violi F.
        • Calvieri C.
        • Ferro D.
        • Pignatelli P.
        Statins as antithrombotic drugs.
        Circulation. 2013; 127: 251-257https://doi.org/10.1161/CIRCULATIONAHA.112.145334
        • Xu D.
        • Shu J.
        • Huang Q.
        • Wasti B.
        • Chen C.
        • Liu L.
        • Zhao S.
        Evaluation of the lipid lowering ability, anti-inflammatory effects and clinical safety of intensive therapy with Zhibitai, a Chinese traditional medicine.
        Atherosclerosis. 2010; 211: 237-241https://doi.org/10.1016/j.atherosclerosis.2010.01.044
        • Zinellu A.
        • Mangoni A.A.
        Systematic review and meta-analysis of the effect of statins on circulating E-selectin, L-selectin, and P-selectin.
        Biomedicines. 2021; 9: 1707https://doi.org/10.3390/biomedicines9111707
        • Siudut J.
        • Ząbczyk M.
        • Wołkow P.
        • Polak M.
        • Undas A.
        • Jawień J.
        Intensive low-density lipoprotein cholesterol lowering improves fibrin clot properties: association with lipoproteins and C-reactive protein.
        Vasc. Pharmacol. 2022; 144106977https://doi.org/10.1016/j.vph.2022.106977
        • Catapano A.L.
        • Graham I.
        • de Backer G.
        • Wiklund O.
        • Chapman M.J.
        • Drexel H.
        • Hoes A.W.
        • Jennings C.S.
        • Landmesser U.
        • Pedersen T.R.
        • Reiner Ž.
        • Riccardi G.
        • Taskinen M.-R.
        • Tokgozoglu L.
        • Verschuren W.M.M.
        • Vlachopoulos C.
        • Wood D.A.
        • Zamorano J.L.
        ESC/EAS guidelines for the management of dyslipidaemias.
        Eur. Heart J. 2016; 37: 2999-3058https://doi.org/10.1093/eurheartj/ehw272
        • de Luca L.
        • Corsini A.
        • Uguccioni M.
        • Colivicchi F.
        Statins plus ezetimibe in the era of proprotein convertase subtilisin/ kexin type 9 inhibitors.
        Kardiol. Pol. 2020; 78: 850-860https://doi.org/10.33963/KP.15529
        • Matusik P.T.
        • Leśniak W.J.
        • Heleniak Z.
        • Undas A.
        Thromboembolism and bleeding in patients with atrial fibrillation and stage 4 chronic kidney disease: impact of biomarkers.
        Kardiol. Pol. 2021; 79: 1086-1092https://doi.org/10.33963/KP.a2021.0088
        • Undas A.
        • Zawilska K.
        • Ciesla-Dul M.
        • Lehmann-Kopydlowska A.
        • Skubiszak A.
        • Ciepluch K.
        • Tracz W.
        Altered fibrin clot structure/function in patients with idiopathic venous thromboembolism and in their relatives.
        Blood. 2009; 114: 4272-4278https://doi.org/10.1182/blood-2009-05-222380
        • Seljeflot I.
        • Tonstad S.
        • Hjermann I.
        • Arnesen H.
        Reduced expression of endothelial cell markers after 1 year treatment with simvastatin and atorvastatin in patients with coronary heart disease.
        Atherosclerosis. 2002; 162: 179-185https://doi.org/10.1016/S0021-9150(01)00696-7
        • Larsen J.B.
        • Hvas A.-M.
        Fibrin clot properties in coronary artery disease: new determinants and prognostic markers.
        Pol. Arch. Intern. Med. 2021; 131https://doi.org/10.20452/pamw.16113
        • Mitsios J.V.
        • Papathanasiou A.I.
        • Goudevenos J.A.
        • Tselepis A.D.
        The antiplatelet and antithrombotic actions of statins.
        Curr. Pharm. Des. 2010; 16: 3808-3814https://doi.org/10.2174/138161210794455120
        • Collet J.P.
        • Allali Y.
        • Lesty C.
        • Tanguy M.L.
        • Silvain J.
        • Ankri A.
        • Blanchet B.
        • Dumaine R.
        • Gianetti J.
        • Payot L.
        • Weisel J.W.
        • Montalescot G.
        Altered fibrin architecture is associated with hypofibrinolysis and premature coronary atherothrombosis.
        Arterioscler. Thromb. Vasc. Biol. 2006; 26: 2567-2573https://doi.org/10.1161/01.ATV.0000241589.52950.4c
        • Ząbczyk M.
        • Natorska J.
        • Undas A.
        Fibrin clot properties in atherosclerotic vascular disease: from pathophysiology to clinical outcomes.
        J. Clin. Med. 2021; 10: 2999https://doi.org/10.3390/jcm10132999
        • Bryk A.
        • Natorska J.
        • Ząbczyk M.
        • Zettl K.
        • Wiśniewski J.R.
        Plasma fibrin clot proteomics in patients with acute pulmonary embolism : association with clot properties.
        J. Proteome. 2020; 229103946https://doi.org/10.1016/j.jprot.2020.103946
        • Stachowicz A.
        • Siudut J.
        • Suski M.
        • Olszanecki R.
        • Korbut R.
        • Undas A.
        • Wiśniewski J.R.
        Optimization of quantitative proteomic analysis of clots generated from plasma of patients with venous thromboembolism.
        Clin. Proteomics. 2017; 14: 38https://doi.org/10.1186/s12014-017-9173-x
        • Małecki R.
        • Gacka M.
        • Kuliszkiewicz-Janus M.
        • Jakobsche-Policht U.
        • Kwiatkowski J.
        • Adamiec R.
        • Undas A.
        Altered plasma fibrin clot properties in essential thrombocythemia.
        Platelets. 2015; 7104: 1-7https://doi.org/10.3109/09537104.2015.1042967
        • Sadowski M.
        • Ząbczyk M.
        • Undas A.
        Coronary thrombus composition: links with inflammation, platelet and endothelial markers.
        Atherosclerosis. 2014; 237: 555-561https://doi.org/10.1016/j.atherosclerosis.2014.10.020
        • Mobarrez F.
        • He S.
        • Bröijersen A.
        • Wiklund B.
        • Antovic A.
        • Antovic J.
        • Egberg N.
        • Jörneskog G.
        • Wallén H.
        Atorvastatin reduces thrombin generation and expression of tissue factor, P-selectin and GPIIIa on platelet-derived microparticles in patients with peripheral arterial occlusive disease.
        Thromb. Haemost. 2011; 106: 344-352https://doi.org/10.1160/TH10-12-0810
        • Zhou Q.
        • Liao J.K.
        Pleiotropic effects of statins - basic research and clinical perspectives.
        Circ. J. 2010; 74: 818-826https://doi.org/10.1253/circj.CJ-10-0110
        • Eccles K.A.
        • Sowden H.
        • Porter K.E.
        • Parkin S.M.
        • Homer-Vanniasinkam S.
        • Graham A.M.
        Simvastatin alters human endothelial cell adhesion molecule expression and inhibits leukocyte adhesion under flow.
        Atherosclerosis. 2008; 200: 69-79https://doi.org/10.1016/j.atherosclerosis.2007.12.018
        • Graham A.
        • Eccles K.A.
        • Porter K.
        • Homer-Vanniasinkham S.
        Potential mechanisms of the anti-inflammatory effects of simvastatin in an in vitro flow model of inflammation.
        FASEB J. 2007; 21https://doi.org/10.1096/fasebj.21.6.A1152-d
        • Mach F.
        • Baigent C.
        • Catapano A.L.
        • Koskinas K.C.
        • Casula M.
        • Badimon L.
        • Chapman M.J.
        • de Backer G.G.
        • Delgado V.
        • Ference B.A.
        • Graham I.M.
        • Halliday A.
        • Landmesser U.
        • Mihaylova B.
        • Pedersen T.R.
        • Riccardi G.
        • Richter D.J.
        • Sabatine M.S.
        • Taskinen M.R.
        • Tokgozoglu L.
        • Wiklund O.
        • Mueller C.
        • Drexel H.
        • Aboyans V.
        • Corsini A.
        • Doehner W.
        • Farnier M.
        • Gigante B.
        • Kayikcioglu M.
        • Krstacic G.
        • Lambrinou E.
        • Lewis B.S.
        • Masip J.
        • Moulin P.
        • Petersen S.
        • Petronio A.S.
        • Piepoli M.F.
        • Pinto X.
        • Raber L.
        • Ray K.K.
        • Reiner Z.
        • Riesen W.F.
        • Roffi M.
        • Schmid J.P.
        • Shlyakhto E.
        • Simpson I.A.
        • Stroes E.
        • Sudano I.
        • Tselepis A.D.
        • Viigimaa M.
        • Vindis C.
        • Vonbank A.
        • Vrablik M.
        • Vrsalovic M.
        • Gomez J.L.Z.
        • Collet J.P.
        • Windecker S.
        • Dean V.
        • Fitzsimons D.
        • Gale C.P.
        • Grobbee D.E.
        • Halvorsen S.
        • Hindricks G.
        • Iung B.
        • Jüni P.
        • Katus H.A.
        • Leclercq C.
        • Lettino M.
        • Merkely B.
        • Sousa-Uva M.
        • Touyz R.M.
        • Nibouche D.
        • Zelveian P.H.
        • Siostrzonek P.
        • Najafov R.
        • van de Borne P.
        • Pojskic B.
        • Postadzhiyan A.
        • Kypris L.
        • Spinar J.
        • Larsen M.L.
        • Eldin H.S.
        • Strandberg T.E.
        • Ferrières J.
        • Agladze R.
        • Laufs U.
        • Rallidis L.
        • Bajnok L.
        • Gudjonsson T.
        • Maher V.
        • Henkin Y.
        • Gulizia M.M.
        • Mussagaliyeva A.
        • Bajraktari G.
        • Kerimkulova A.
        • Latkovskis G.
        • Hamoui O.
        • Slapikas R.
        • Visser L.
        • Dingli P.
        • Ivanov V.
        • Boskovic A.
        • Nazzi M.
        • Visseren F.
        • Mitevska I.
        • Retterstøl K.
        • Jankowski P.
        • Fontes-Carvalho R.
        • Gaita D.
        • Ezhov M.
        • Foscoli M.
        • Giga V.
        • Pella D.
        • Fras Z.
        • de Isla L.P.
        • Hagström E.
        • Lehmann R.
        • Abid L.
        • Ozdogan O.
        • Mitchenko O.
        • Patel R.S.
        ESC/EAS guidelines for the management of dyslipidaemias: lipid modification to reduce cardiovascular risk.
        Eur. Heart J. 2019; 41: 111-188https://doi.org/10.1093/eurheartj/ehz455
        • Kotseva K.
        • de Backer G.
        • de Bacquer D.
        • Rydén L.
        • Hoes A.
        • Grobbee D.
        • Maggioni A.
        • Marques-Vidal P.
        • Jennings C.
        • Abreu A.
        • Aguiar C.
        • Badariene J.
        • Bruthans J.
        • Castro Conde A.
        • Cifkova R.
        • Crowley J.
        • Davletov K.
        • Deckers J.
        • de Smedt D.
        • de Sutter J.
        • Dilic M.
        • Dolzhenko M.
        • Dzerve V.
        • Erglis A.
        • Fras Z.
        • Gaita D.
        • Gotcheva N.
        • Heuschmann P.
        • Hasan-Ali H.
        • Jankowski P.
        • Lalic N.
        • Lehto S.
        • Lovic D.
        • Mancas S.
        • Mellbin L.
        • Milicic D.
        • Mirrakhimov E.
        • Oganov R.
        • Pogosova N.
        • Reiner Z.
        • Stöerk S.
        • Tokgözoğlu L.
        • Tsioufis C.
        • Vulic D.
        • Wood D.
        Lifestyle and impact on cardiovascular risk factor control in coronary patients across 27 countries: results from the European Society of Cardiology ESC-EORP EUROASPIRE V registry.
        Eur. J. Prev. Cardiol. 2019; 26: 824-835https://doi.org/10.1177/2047487318825350
        • Pracoń R.
        • Demkow M.
        • Anthopolos R.
        • Mazurek T.
        • Drożdż J.
        • Witkowski A.
        • Gajos G.
        • Pruszczyk P.
        • Roik M.
        • Łoboz-Grudzień K.
        • Lesiak M.
        • Reczuch K.
        • Kalarus Z.
        • Kryczka K.
        • Henzel J.
        • Kaczmarska-Dyrda E.
        • Maksym J.
        • Jonik S.
        • Krekora J.
        • Celińska-Spodar M.
        • Jaroch J.
        • Łanocha M.
        • Szulik M.
        • Szwed H.
        • Rużyłło W.
        Optimal medical therapy in patients with stable coronary artery disease in Poland: the ISCHEMIA trial experience.
        Pol. Arch. Intern. Med. 2021; 131https://doi.org/10.20452/pamw.16100
        • Ridker P.M.
        • Buring J.E.
        • Rifai N.
        Soluble P-selectin and the risk of future cardiovascular events.
        Circulation. 2001; 103: 491-495https://doi.org/10.1161/01.CIR.103.4.491
        • Blann A.D.
        • Faragher E.B.
        • McCollum C.N.
        Increased soluble P-selectin following myocardial infarction: a new marker for the progression of atherosclerosis.
        Blood Coagul. Fibrinolysis. 1997; 8: 383-390
        • Bochenek M.
        • Zalewski J.
        • Sadowski J.
        • Undas A.
        Type 2 diabetes as a modifier of fibrin clot properties in patients with coronary artery disease.
        J. Thromb. Thrombolysis. 2013; 35: 264-270https://doi.org/10.1007/s11239-012-0821-8
        • Tscharre M.
        • Vogel B.
        • Tentzeris I.
        • Freynhofer M.
        • Rohla M.
        • Wojta J.
        • Weiss T.
        • Ay C.
        • Huber K.
        • Farhan S.
        Prognostic impact of soluble P-selectin on long-term adverse cardiovascular outcomes in patients undergoing percutaneous coronary intervention.
        Thromb. Haemost. 2019; 119: 340-347https://doi.org/10.1055/s-0038-1676563
        • Schmitt C.
        • Abt M.
        • Ciorciaro C.
        • Kling D.
        • Jamois C.
        • Schick E.
        • Solier C.
        • Benghozi R.
        • Gaudreault J.
        First-in-man study with inclacumab, a human monoclonal antibody against P-selectin.
        J. Cardiovasc. Pharmacol. 2015; 65: 611-619https://doi.org/10.1097/FJC.0000000000000233
        • Tardif J.-C.
        • Tanguay J.-F.
        • Wright S.R.
        • Duchatelle V.
        • Petroni T.
        • Grégoire J.C.
        • Ibrahim R.
        • Heinonen T.M.
        • Robb S.
        • Bertrand O.F.
        • Cournoyer D.
        • Johnson D.
        • Mann J.
        • Guertin M.-C.
        • L’Allier P.L.
        Effects of the P-selectin antagonist Inclacumab on myocardial damage after percutaneous coronary intervention for non–ST-segment elevation myocardial infarction.
        J. Am. Coll. Cardiol. 2013; 61: 2048-2055https://doi.org/10.1016/j.jacc.2013.03.003
        • Stähli B.E.
        • Gebhard C.
        • Duchatelle V.
        • Cournoyer D.
        • Petroni T.
        • Tanguay J.
        • Robb S.
        • Mann J.
        • Guertin M.
        • Wright R.S.
        • L’Allier P.L.
        • Tardif J.
        Effects of the P-selectin antagonist inclacumab on myocardial damage after percutaneous coronary intervention according to timing of infusion: insights from the SELECT-ACS trial.
        J. Am. Heart Assoc. 2016; 5https://doi.org/10.1161/JAHA.116.004255
        • Stähli B.E.
        • Tardif J.-C.
        • Carrier M.
        • Gallo R.
        • Emery R.W.
        • Robb S.
        • Cournoyer D.
        • Blondeau L.
        • Johnson D.
        • Mann J.
        • Lespérance J.
        • Guertin M.-C.
        • L’Allier P.L.
        Effects of P-selectin antagonist Inclacumab in patients undergoing coronary artery bypass graft surgery.
        J. Am. Coll. Cardiol. 2016; 67: 344-346https://doi.org/10.1016/j.jacc.2015.10.071