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The neuropeptide galanin promotes an anti-thrombotic phenotype on endocardial endothelial cells from heart failure patients

      Abstract

      Thromboembolic complications are a significant cause of mortality and re-hospitalization in heart failure (HF) patients. One source of thrombi is the ventricular endocardial surface that becomes increasingly pro-thrombotic as HF progresses. Anticoagulation comes with bleeding risks so identifying therapeutic agents for improving cardiac endothelial health are of critical clinical importance.
      Endocardial endothelial cells are closely apposed to cardiac sympathetic nerves. In HF, cardiac sympathetic nerves are dysregulated and promote disease progression. Whether endocardial endothelial health and function is impacted by sympathetic dysregulation in HF is unknown. Also unexplored is the impact of neuropeptides, such as galanin and neuropeptide Y (NPY), co-released from sympathetic nerve terminals, on endothelial health.
      In this study we examined the effect of sympathetic nerve-released neurotransmitters and neuropeptides on the procoagulant phenotype of cultured human endocardial endothelial cells from HF patients. As a functional readout of procoagulant state we examined thrombin-mediated von Willebrand factor (vWF) extrusion and multimer expression. We demonstrate that vWF extrusion and multimer expression is promoted by thrombin, that isoproterenol (a beta-adrenergic receptor agonist) augments this effect, whereas co-treatment with the beta-blockers propranolol and carvedilol blocks this effect. We also show that vWF extrusion and multimer expression is attenuated by treatment with the neuropeptide galanin, but not with NPY.
      Our results are consistent with a protective role of beta-blockers and galanin on endocardial endothelial health in heart failure. Improving endothelial health through galanin therapy is a future clinical application of this study.

      Abbreviations:

      EEC (endocardial endothelial cell), EPCR (endothelial protein C receptor), FIIa (thrombin), HF (heart failure), LVAD (left ventricular assist device), NGF (nerve growth factor), NPY (neuropeptide Y), TM (thrombomodulin), vWF (von Willebrand factor)

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      References

        • Abdelmoneim S.S.
        • Pellikka P.A.
        • Mulvagh S.L.
        Contrast echocardiography for assessment of left ventricular thrombi.
        J. Ultrasound Med. 2014; 33 (doi:33/8/1337 [pii]): 1337-1344https://doi.org/10.7863/ultra.33.8.1337
        • Abdel-Samad D.
        • Perreault C.
        • Ahmarani L.
        • Avedanian L.
        • Bkaily G.
        • Magder S.
        • D'Orleans-Juste P.
        • Jacques D.
        Differences in neuropeptide Y-induced secretion of endothelin-1 in left and right human endocardial endothelial cells.
        Neuropeptides. 2012; 46 (doi:S0143-4179(12)00099-6 [pii]): 373-382https://doi.org/10.1016/j.npep.2012.09.003
        • Ahnert A.M.
        • Freudenberger R.S.
        What do we know about anticoagulation in patients with heart failure?.
        Curr. Opin. Cardiol. 2008; 23 (00001573-200805000-00010 [pii]): 228-232https://doi.org/10.1097/HCO.0b013e3282fcd64d
        • Anderson D.E.
        • Glynn J.J.
        • Song H.K.
        • Hinds M.T.
        Engineering an endothelialized vascular graft: a rational approach to study design in a non-human primate model.
        PLoS One. 2014; 9 (PONE-D-14-19106 [pii])e115163https://doi.org/10.1371/journal.pone.0115163
        • Azevedo E.R.
        • Kubo T.
        • Mak S.
        • Al-Hesayen A.
        • Schofield A.
        • Allan R.
        • Kelly S.
        • Newton G.E.
        • Floras J.S.
        • Parker J.D.
        Nonselective versus selective beta-adrenergic receptor blockade in congestive heart failure: differential effects on sympathetic activity.
        Circulation. 2001; 104: 2194-2199
        • Beemath A.
        • Stein P.D.
        • Skaf E.
        • Al Sibae M.R.
        • Alesh I.
        Risk of venous thromboembolism in patients hospitalized with heart failure.
        Am. J. Cardiol. 2006; 98 (doi:S0002-9149(06)01075-7 [pii]): 793-795https://doi.org/10.1016/j.amjcard.2006.03.064
        • Bettari L.
        • Fiuzat M.
        • Becker R.
        • Felker G.M.
        • Metra M.
        • O'Connor C.M.
        Thromboembolism and antithrombotic therapy in patients with heart failure in sinus rhythm: current status and future directions.
        Circ. Heart Fail. 2011; 4 (doi:4/3/361 [pii]): 361-368https://doi.org/10.1161/CIRCHEARTFAILURE.110.959957
        • Bohm M.
        • La Rosee K.
        • Schwinger R.H.
        • Erdmann E.
        Evidence for reduction of norepinephrine uptake sites in the failing human heart.
        J. Am. Coll. Cardiol. 1995; 25 (doi:0735-1097(94)00353-R [pii]): 146-153
        • Brutsaert D.L.
        • Meulemans A.L.
        • Sipido K.R.
        • Sys S.U.
        Effects of damaging the endocardial surface on the mechanical performance of isolated cardiac muscle.
        Circ. Res. 1988; 62: 358-366
        • Cervero J.
        • Segura V.
        • Macias A.
        • Gavira J.J.
        • Montes R.
        • Hermida J.
        Atrial fibrillation in pigs induces left atrial endocardial transcriptional remodelling.
        Thromb. Haemost. 2012; 108 (doi:12-05-0285 [pii]): 742-749https://doi.org/10.1160/TH12-05-0285
        • Chung I.
        • Lip G.Y.
        Platelets and heart failure.
        Eur. Heart J. 2006; 27 (doi:ehl305 [pii]): 2623-2631https://doi.org/10.1093/eurheartj/ehl305
        • Clarke G.L.
        • Bhattacherjee A.
        • Tague S.E.
        • Hasan W.
        • Smith P.G.
        b-Adrenoceptor blockers increase cardiac sympathetic innervation by inhibiting autoreceptor suppression of axon growth.
        J. Neurosci. 2010; 30 (doi:30/37/12446 [pii]): 12446-12454https://doi.org/10.1523/JNEUROSCI.1667-10.2010
        • Cleland J.G.
        • Findlay I.
        • Jafri S.
        • Sutton G.
        • Falk R.
        • Bulpitt C.
        • Prentice C.
        • Ford I.
        • Trainer A.
        • Poole-Wilson P.A.
        The Warfarin/Aspirin Study in Heart failure (WASH): a randomized trial comparing antithrombotic strategies for patients with heart failure.
        Am. Heart J. 2004; 148 (S000287030400136X [pii]): 157-164https://doi.org/10.1016/j.ahj.2004.03.010
        • Dahlback B.
        The tale of protein S and C4b-binding protein, a story of affection.
        Thromb. Haemost. 2007; 98 (doi:07070090 [pii]): 90-96
        • De Lima L.G.
        • Soares B.G.
        • Saconato H.
        • Atallah A.N.
        • da Silva E.M.
        Beta-blockers for preventing stroke recurrence.
        Cochrane Database Syst. Rev. 2013; 5: CD007890https://doi.org/10.1002/14651858.CD007890.pub2
        • De Lorenzo F.
        • Saba N.
        • Kakkar V.V.
        Blood coagulation in patients with chronic heart failure: evidence for hypercoagulable state and potential for pharmacological intervention.
        Drugs. 2003; 63 (doi:6364 [pii]): 565-576
        • Diet F.
        • Erdmann E.
        Thromboembolism in heart failure: who should be treated?.
        Eur. J. Heart Fail. 2000; 2 (doi:S1388984200001264 [pii]): 355-363
        • Du X.J.
        • Cox H.S.
        • Dart A.M.
        • Esler M.D.
        Sympathetic activation triggers ventricular arrhythmias in rat heart with chronic infarction and failure.
        Cardiovasc. Res. 1999; 43: 919
        • Englert III, J.A.
        • Davis J.A.
        • Krim S.R.
        Mechanical circulatory support for the failing heart: continuous-flow left ventricular assist devices.
        Ochsner J. 2016; 16: 263-269
        • Ensley A.E.
        • Nerem R.M.
        • Anderson D.E.
        • Hanson S.R.
        • Hinds M.T.
        Fluid shear stress alters the hemostatic properties of endothelial outgrowth cells.
        Tissue Eng. A. 2012; 18: 127-136https://doi.org/10.1089/ten.TEA.2010.0290
        • Favaloro E.J.
        Von Willebrand factor collagen-binding (activity) assay in the diagnosis of von Willebrand disease: a 15-year journey.
        Semin. Thromb. Hemost. 2002; 28: 191-202https://doi.org/10.1055/s-2002-27821
        • Ferro A.
        • Queen L.R.
        • Priest R.M.
        • Xu B.
        • Ritter J.M.
        • Poston L.
        • Ward J.P.
        Activation of nitric oxide synthase by beta 2-adrenoceptors in human umbilical vein endothelium in vitro.
        Br. J. Pharmacol. 1999; 126: 1872-1880https://doi.org/10.1038/sj.bjp.0702512
        • Fukuchi M.
        • Watanabe J.
        • Kumagai K.
        • Katori Y.
        • Baba S.
        • Fukuda K.
        • Yagi T.
        • Iguchi A.
        • Yokoyama H.
        • Miura M.
        • Kagaya Y.
        • Sato S.
        • Tabayashi K.
        • Shirato K.
        Increased von Willebrand factor in the endocardium as a local predisposing factor for thrombogenesis in overloaded human atrial appendage.
        J. Am. Coll. Cardiol. 2001; 37 (doi:S0735-1097(01)01125-1 [pii]): 1436-1442
        • Ghersi G.
        • Chen W.
        • Lee E.W.
        • Zukowska Z.
        Critical role of dipeptidyl peptidase IV in neuropeptide Y-mediated endothelial cell migration in response to wounding.
        Peptides. 2001; 22 (doi:S0196978101003400 [pii]): 453-458
        • Gibbs C.R.
        • Blann A.D.
        • Watson R.D.
        • Lip G.Y.
        Abnormalities of hemorheological, endothelial, and platelet function in patients with chronic heart failure in sinus rhythm: effects of angiotensin-converting enzyme inhibitor and beta-blocker therapy.
        Circulation. 2001; 103: 1746-1751
        • Gogia S.
        • Neelamegham S.
        Role of fluid shear stress in regulating VWF structure, function and related blood disorders.
        Biorheology. 2015; 52 (doi:BIR15061 [pii]): 319-335https://doi.org/10.3233/BIR-15061
        • Gray D.W.
        • Marshall I.
        Novel signal transduction pathway mediating endothelium-dependent beta-adrenoceptor vasorelaxation in rat thoracic aorta.
        Br. J. Pharmacol. 1992; 107: 684-690
        • Gruszecki M.
        • Rolkowski R.
        • Pawlak R.
        • Buczko W.
        Propranolol prevents the development of venous thrombosis in rats by a platelet-dependent mechanism.
        Pol. J. Pharmacol. 2001; 53: 5-10
        • Gu J.
        • Polak J.M.
        • Allen J.M.
        • Huang W.M.
        • Sheppard M.N.
        • Tatemoto K.
        • Bloom S.R.
        High concentrations of a novel peptide, neuropeptide Y, in the innervation of mouse and rat heart.
        J. Histochem. Cytochem. 1984; 32: 467-472
        • Gustafsson F.
        • Rogers J.G.
        Left ventricular assist device therapy in advanced heart failure: patient selection and outcomes.
        Eur. J. Heart Fail. 2017; https://doi.org/10.1002/ejhf.779
        • Hackeng T.M.
        • Maurissen L.F.
        • Castoldi E.
        • Rosing J.
        Regulation of TFPI function by protein S.
        J. Thromb. Haemost. 2009; 7 (doi:JTH3363 [pii]): 165-168https://doi.org/10.1111/j.1538-7836.2009.03363.x
        • Hasan W.
        Autonomic cardiac innervation: development and adult plasticity.
        Organ. 2013; 9 (doi:24892 [pii]): 176-193https://doi.org/10.4161/org.24892
        • Hasan W.
        • Pedchenko T.
        • Krizsan-Agbas D.
        • Baum L.
        • Smith P.G.
        Sympathetic neurons synthesize and secrete pro-nerve growth factor protein.
        J. Neurobiol. 2003; 57: 38-53https://doi.org/10.1002/neu.10250
        • Hasan W.
        • Smith H.J.
        • Ting A.Y.
        • Smith P.G.
        Estrogen alters trkA and p75 neurotrophin receptor expression within sympathetic neurons.
        J. Neurobiol. 2005; 65: 192-204https://doi.org/10.1002/neu.20183
        • van Hinsbergh V.W.
        Endothelium—role in regulation of coagulation and inflammation.
        Semin. Immunopathol. 2012; 34: 93-106https://doi.org/10.1007/s00281-011-0285-5
        • Iba T.
        • Mills I.
        • Sumpio B.E.
        Intracellular cyclic AMP levels in endothelial cells subjected to cyclic strain in vitro.
        J. Surg. Res. 1992; 52: 625-630
        • Jacques D.
        • Sader S.
        • Perreault C.
        • Abdel-Samad D.
        • Provost C.
        Roles of nuclear NPY and NPY receptors in the regulation of the endocardial endothelium and heart function.
        Can. J. Physiol. Pharmacol. 2006; 84 (doi:y05-162 [pii]): 695-705https://doi.org/10.1139/y05-162
        • Kleber M.E.
        • Koller L.
        • Goliasch G.
        • Sulzgruber P.
        • Scharnagl H.
        • Silbernagel G.
        • Grammer T.B.
        • Delgado G.
        • Tomaschitz A.
        • Pilz S.
        • Marz W.
        • Niessner A.
        Von Willebrand factor improves risk prediction in addition to N-terminal pro-B-type natriuretic peptide in patients referred to coronary angiography and signs and symptoms of heart failure and preserved ejection fraction.
        Circ. Heart Fail. 2015; 8 (doi:CIRCHEARTFAILURE.114.001478 [pii]): 25-32https://doi.org/10.1161/CIRCHEARTFAILURE.114.001478
        • Kobayashi M.
        • Massiello A.
        • Karimov J.H.
        • Van Wagoner D.R.
        • Fukamachi K.
        Cardiac autonomic nerve stimulation in the treatment of heart failure.
        Ann. Thorac. Surg. 2013; 96 (doi:S0003-4975(13)00123-9 [pii]): 339-345https://doi.org/10.1016/j.athoracsur.2012.12.060
        • Krespi P.G.
        • Makris T.K.
        • Hatzizacharias A.N.
        • Triposkiadis P.
        • Tsoukala C.
        • Kyriaki D.
        • Votteas V.
        • Kyriakidis M.
        Moxonidine effect on microalbuminuria, thrombomodulin, and plasminogen activator inhibitor-1 levels in patients with essential hypertension.
        Cardiovasc. Drugs Ther. 1998; 12: 463-467
        • Kreusser M.M.
        • Buss S.J.
        • Krebs J.
        • Kinscherf R.
        • Metz J.
        • Katus H.A.
        • Haass M.
        • Backs J.
        Differential expression of cardiac neurotrophic factors and sympathetic nerve ending abnormalities within the failing heart.
        J. Mol. Cell. Cardiol. 2008; 44 (doi:S0022-2828(07)01285-0 [pii]): 380-387https://doi.org/10.1016/j.yjmcc.2007.10.019
        • Lecht S.
        • Foerster C.
        • Arien-Zakay H.
        • Marcinkiewicz C.
        • Lazarovici P.
        • Lelkes P.I.
        Cardiac microvascular endothelial cells express and release nerve growth factor but not fibroblast growth factor-2.
        In Vitro Cell. Dev. Biol. Anim. 2010; 46: 469-476https://doi.org/10.1007/s11626-009-9267-5
        • Ledford-Kraemer M.R.
        Analysis of von Willebrand factor structure by multimer analysis.
        Am. J. Hematol. 2010; 85: 510-514https://doi.org/10.1002/ajh.21739
        • Levesque M.J.
        • Nerem R.M.
        The elongation and orientation of cultured endothelial cells in response to shear stress.
        J. Biomech. Eng. 1985; 107: 341-347
        • Li K.
        • Rouleau J.L.
        • Calderone A.
        • Andries J.L.
        • Brutsaert D.L.
        Endocardial function in pacing-induced heart failure in the dog.
        J. Mol. Cell. Cardiol. 1993; 25 (doi:S0022-2828(83)71063-1 [pii]): 529-540https://doi.org/10.1006/jmcc.1993.1063
        • Lin P.Y.
        • Shen H.C.
        • Chen C.J.
        • Wu S.E.
        • Kao H.L.
        • Huang J.H.
        • Wang D.L.
        • Chen S.C.
        The inhibition in tumor necrosis factor-alpha-induced attenuation in endothelial thrombomodulin expression by carvedilol is mediated by nuclear factor-kappaB and reactive oxygen species.
        J. Thromb. Thrombolysis. 2010; 29: 52-59https://doi.org/10.1007/s11239-009-0318-2
        • Lip G.Y.
        • Piotrponikowski P.
        • Andreotti F.
        • Anker S.D.
        • Filippatos G.
        • Homma S.
        • Morais J.
        • Pullicino P.
        • Rasmussen L.H.
        • Marin F.
        • Lane D.A.
        Thromboembolism and antithrombotic therapy for heart failure in sinus rhythm: an executive summary of a joint consensus document from the ESC Heart Failure Association and the ESC Working Group on Thrombosis.
        Thromb. Haemost. 2012; 108 (doi:12-08-0578 [pii]): 1009-1022https://doi.org/10.1160/TH12-08-0578
        • Marron K.
        • Wharton J.
        • Sheppard M.N.
        • Gulbenkian S.
        • Royston D.
        • Yacoub M.H.
        • Anderson R.H.
        • Polak J.M.
        Human endocardial innervation and its relationship to the endothelium: an immunohistochemical, histochemical, and quantitative study.
        Cardiovasc. Res. 1994; 28 (doi:0008-6363(94)90193-7 [pii]): 1490-1499
        • Marron K.
        • Wharton J.
        • Sheppard M.N.
        • Fagan D.
        • Royston D.
        • Kuhn D.M.
        • de Leval M.R.
        • Whitehead B.F.
        • Anderson R.H.
        • Polak J.M.
        Distribution, morphology, and neurochemistry of endocardial and epicardial nerve terminal arborizations in the human heart.
        Circulation. 1995; 92: 2343-2351
        • Massie B.M.
        • Collins J.F.
        • Ammon S.E.
        • Armstrong P.W.
        • Cleland J.G.
        • Ezekowitz M.
        • Jafri S.M.
        • Krol W.F.
        • O'Connor C.M.
        • Schulman K.A.
        • Teo K.
        • Warren S.R.
        Randomized trial of warfarin, aspirin, and clopidogrel in patients with chronic heart failure: the Warfarin and Antiplatelet Therapy in Chronic Heart Failure (WATCH) trial.
        Circulation. 2009; 119 (doi:CIRCULATIONAHA.108.801753 [pii]): 1616-1624https://doi.org/10.1161/CIRCULATIONAHA.108.801753
        • Meredith I.T.
        • Broughton A.
        • Jennings G.L.
        • Esler M.D.
        Evidence of a selective increase in cardiac sympathetic activity in patients with sustained ventricular arrhythmias.
        N. Engl. J. Med. 1991; 325: 618-624https://doi.org/10.1056/NEJM199108293250905
        • Miranda S.M.
        • Moscavitch S.D.
        • Carestiato L.R.
        • Felix R.M.
        • Rodrigues R.C.
        • Messias L.R.
        • Azevedo J.C.
        • Nobrega A.C.
        • Mesquita E.T.
        • Mesquita C.T.
        Cardiac I123-MIBG correlates better than ejection fraction with symptoms severity in systolic heart failure.
        Arq. Bras. Cardiol. 2013; 101 (doi:S0066-782X2013002700003 [pii]): 4-8https://doi.org/10.5935/abc.20130111
        • Momi S.
        • Caracchini R.
        • Falcinelli E.
        • Evangelista S.
        • Gresele P.
        Stimulation of platelet nitric oxide production by nebivolol prevents thrombosis.
        Arterioscler. Thromb. Vasc. Biol. 2014; 34 (doi:ATVBAHA.114.303290 [pii]): 820-829https://doi.org/10.1161/ATVBAHA.114.303290
        • Mourik M.J.
        • Valentijn J.A.
        • Voorberg J.
        • Koster A.J.
        • Valentijn K.M.
        • Eikenboom J.
        von Willebrand factor remodeling during exocytosis from vascular endothelial cells.
        J. Thromb. Haemost. 2013; 11: 2009-2019https://doi.org/10.1111/jth.12401
        • Nakayama K.
        • Watanabe N.
        • Yamazawa T.
        • Takeshita N.
        • Tanaka Y.
        • Yanaihara N.
        Effects of porcine galanin on the mesenteric microcirculation and arteriolar smooth muscle in the rat.
        Eur. J. Pharmacol. 1991; 193: 75-80
        • Ng T.M.
        • Tsai F.
        • Khatri N.
        • Barakat M.N.
        • Elkayam U.
        Venous thromboembolism in hospitalized patients with heart failure: incidence, prognosis, and prevention.
        Circ. Heart Fail. 2010; 3 (doi:3/1/165 [pii]): 165-173https://doi.org/10.1161/CIRCHEARTFAILURE.109.892349
        • Olas B.
        Gasomediators (·NO, CO, and H(2)S) and their role in hemostasis and thrombosis.
        Clin. Chim. Acta. 2015; 445 (doi:S0009-8981(15)00171-0 [pii]): 115-121https://doi.org/10.1016/j.cca.2015.03.027
        • Ostadal B.
        • Schiebler T.H.
        • Rychter Z.
        Relations between development of the capillary wall and myoarchitecture of the rat heart.
        Adv. Exp. Med. Biol. 1975; 53: 375-388
        • Packer M.
        • Coats A.J.
        • Fowler M.B.
        • Katus H.A.
        • Krum H.
        • Mohacsi P.
        • Rouleau J.L.
        • Tendera M.
        • Castaigne A.
        • Roecker E.B.
        • Schultz M.K.
        • DeMets D.L.
        Effect of carvedilol on survival in severe chronic heart failure.
        N. Engl. J. Med. 2001; 344: 1651-1658https://doi.org/10.1056/NEJM200105313442201
        • Panjala S.R.
        • Steinle J.J.
        Insulin and beta-adrenergic receptors inhibit retinal endothelial cell apoptosis through independent pathways.
        Neurochem. Res. 2011; 36: 604-612https://doi.org/10.1007/s11064-010-0303-3
        • de Peuter O.R.
        • Kok W.E.
        • Torp-Pedersen C.
        • Buller H.R.
        • Kamphuisen P.W.
        Systolic heart failure: a prothrombotic state.
        Semin. Thromb. Hemost. 2009; 35: 497-504https://doi.org/10.1055/s-0029-1234145
        • de Peuter O.R.
        • Souverein P.C.
        • Klungel O.H.
        • Buller H.R.
        • de Boer A.
        • Kamphuisen P.W.
        Non-selective vs. selective beta-blocker treatment and the risk of thrombo-embolic events in patients with heart failure.
        Eur. J. Heart Fail. 2011; 13 (doi:hfq176 [pii]): 220-226https://doi.org/10.1093/eurjhf/hfq176
        • Prom R.
        • Usedom J.E.
        • Dull R.B.
        Antithrombotics in heart failure with reduced ejection fraction and normal sinus rhythm: an evidence appraisal.
        Ann. Pharmacother. 2014; 48 (doi:1060028013511058 [pii]): 226-237https://doi.org/10.1177/1060028013511058
        • Rahbar E.
        • Cardenas J.C.
        • Baimukanova G.
        • Usadi B.
        • Bruhn R.
        • Pati S.
        • Ostrowski S.R.
        • Johansson P.I.
        • Holcomb J.B.
        • Wade C.E.
        Endothelial glycocalyx shedding and vascular permeability in severely injured trauma patients.
        J. Transl. Med. 2015; 13 (10.1186/s12967-015-0481-5 [pii]): 117https://doi.org/10.1186/s12967-015-0481-5
        • Ramchandra R.
        • Hood S.G.
        • Denton D.A.
        • Woods R.L.
        • McKinley M.J.
        • McAllen R.M.
        • May C.N.
        Basis for the preferential activation of cardiac sympathetic nerve activity in heart failure.
        Proc. Natl. Acad. Sci. U. S. A. 2009; 106 (doi:0811929106 [pii]): 924-928https://doi.org/10.1073/pnas.0811929106
        • Red-Horse K.
        • Ueno H.
        • Weissman I.L.
        • Krasnow M.A.
        Coronary arteries form by developmental reprogramming of venous cells.
        Nature. 2010; 464 (doi:nature08873 [pii]): 549-553https://doi.org/10.1038/nature08873
        • Reiner M.F.
        • Breitenstein A.
        • Holy E.W.
        • Glanzmann M.
        • Amstalden H.
        • Stampfli S.F.
        • Bonetti N.R.
        • Falk V.
        • Keller S.
        • Savarese G.
        • Benussi S.
        • Maisano F.
        • Luscher T.F.
        • Beer J.H.
        • Steffel J.
        • Camici G.G.
        Ticagrelor, but not clopidogrel active metabolite, displays antithrombotic properties in the left atrial endocardium.
        Eur. Heart J. 2017; (doi:ehw578 [pii])https://doi.org/10.1093/eurheartj/ehw578
        • Rider J.E.
        • Polster S.P.
        • Lee S.
        • Charles N.J.
        • Adhikari N.
        • Mariash A.
        • Tadros G.
        • Stangland J.
        • Smolenski R.T.
        • Terracciano C.M.
        • Barton P.J.
        • Birks E.J.
        • Yacoub M.H.
        • Miller L.W.
        • Hall J.L.
        Chronic treatment with clenbuterol modulates endothelial progenitor cells and circulating factors in a murine model of cardiomyopathy.
        J. Cardiovasc. Transl. Res. 2009; 2: 182-190https://doi.org/10.1007/s12265-009-9089-6
        • Riewald M.
        • Schuepbach R.A.
        Protective signaling pathways of activated protein C in endothelial cells.
        Arterioscler. Thromb. Vasc. Biol. 2008; 28 (doi:28/1/1 [pii]): 1-3https://doi.org/10.1161/ATVBAHA.107.157321
        • Roberts W.C.
        • Siegel R.J.
        • McManus B.M.
        Idiopathic dilated cardiomyopathy: analysis of 152 necropsy patients.
        Am. J. Cardiol. 1987; 60: 1340-1355
        • Rundqvist B.
        • Elam M.
        • Bergmann-Sverrisdottir Y.
        • Eisenhofer G.
        • Friberg P.
        Increased cardiac adrenergic drive precedes generalized sympathetic activation in human heart failure.
        Circulation. 1997; 95: 169-175
        • Saric M.
        • Armour A.C.
        • Arnaout M.S.
        • Chaudhry F.A.
        • Grimm R.A.
        • Kronzon I.
        • Landeck B.F.
        • Maganti K.
        • Michelena H.I.
        • Tolstrup K.
        Guidelines for the use of echocardiography in the evaluation of a cardiac source of embolism.
        J. Am. Soc. Echocardiogr. 2016; 29 (doi:S0894-7317(15)00728-2 [pii]): 1-42https://doi.org/10.1016/j.echo.2015.09.011
        • Schmidhuber S.M.
        • Santic R.
        • Tam C.W.
        • Bauer J.W.
        • Kofler B.
        • Brain S.D.
        Galanin-like peptides exert potent vasoactive functions in vivo.
        J. Invest. Dermatol. 2007; 127 (doi:S0022-202X(15)33288-7 [pii]): 716-721https://doi.org/10.1038/sj.jid.5700569
        • Schoner A.
        • Tyrrell C.
        • Wu M.
        • Gelow J.M.
        • Hayes A.A.
        • Lindner J.R.
        • Thornburg K.L.
        • Hasan W.
        Endocardial endothelial dysfunction progressively disrupts initially anti then pro-thrombotic pathways in heart failure mice.
        PLoS One. 2015; 10 (PONE-D-15-35329 [pii])e0142940https://doi.org/10.1371/journal.pone.0142940
        • Shivkumar K.
        • Ajijola O.A.
        • Anand I.
        • Armour J.A.
        • Chen P.S.
        • Esler M.
        • De Ferrari G.M.
        • Fishbein M.C.
        • Goldberger J.J.
        • Harper R.M.
        • Joyner M.J.
        • Khalsa S.S.
        • Kumar R.
        • Lane R.
        • Mahajan A.
        • Po S.
        • Schwartz P.J.
        • Somers V.K.
        • Valderrabano M.
        • Vaseghi M.
        • Zipes D.P.
        Clinical neurocardiology defining the value of neuroscience-based cardiovascular therapeutics.
        J. Physiol. 2016; 594: 3911-3954https://doi.org/10.1113/JP271870
        • Sornelli F.
        • Lambiase A.
        • Mantelli F.
        • Aloe L.
        NGF and NGF-receptor expression of cultured immortalized human corneal endothelial cells.
        Mol. Vis. 2010; 16 (doi:157 [pii]): 1439-1447
        • Spindler V.
        • Waschke J.
        Beta-adrenergic stimulation contributes to maintenance of endothelial barrier functions under baseline conditions.
        Microcirculation. 2011; 18: 118-127https://doi.org/10.1111/j.1549-8719.2010.00072.x
        • Stockschlaeder M.
        • Schneppenheim R.
        • Budde U.
        Update on von Willebrand factor multimers: focus on high-molecular-weight multimers and their role in hemostasis.
        Blood Coagul. Fibrinolysis. 2014; 25: 206-216https://doi.org/10.1097/MBC.0000000000000065
        • Stratton J.R.
        • Resnick A.D.
        Increased embolic risk in patients with left ventricular thrombi.
        Circulation. 1987; 75: 1004-1011
        • Subramaniam V.
        • Davis R.C.
        • Shantsila E.
        • Lip G.Y.
        Antithrombotic therapy for heart failure in sinus rhythm.
        Fundam. Clin. Pharmacol. 2009; 23 (doi:FCP776 [pii]): 705-717https://doi.org/10.1111/j.1472-8206.2009.00776.x
        • Sugi Y.
        • Markwald R.R.
        Formation and early morphogenesis of endocardial endothelial precursor cells and the role of endoderm.
        Dev. Biol. 1996; 175 (doi:S0012-1606(96)90096-2 [pii]): 66-83https://doi.org/10.1006/dbio.1996.0096
        • Triposkiadis F.
        • Karayannis G.
        • Giamouzis G.
        • Skoularigis J.
        • Louridas G.
        • Butler J.
        The sympathetic nervous system in heart failure physiology, pathophysiology, and clinical implications.
        J. Am. Coll. Cardiol. 2009; 54 (doi:S0735-1097(09)01689-1 [pii]): 1747-1762https://doi.org/10.1016/j.jacc.2009.05.015
        • Tsutamoto T.
        • Nishiyama K.
        • Sakai H.
        • Tanaka T.
        • Fujii M.
        • Yamamoto T.
        • Yamaji M.
        • Horie M.
        Transcardiac increase in norepinephrine and prognosis in patients with chronic heart failure.
        Eur. J. Heart Fail. 2008; 10 (doi:S1388-9842(08)00457-1 [pii]): 1208-1214https://doi.org/10.1016/j.ejheart.2008.09.011
        • Uretsky B.F.
        • Thygesen K.
        • Armstrong P.W.
        • Cleland J.G.
        • Horowitz J.D.
        • Massie B.M.
        • Packer M.
        • Poole-Wilson P.A.
        • Ryden L.
        Acute coronary findings at autopsy in heart failure patients with sudden death: results from the assessment of treatment with lisinopril and survival (ATLAS) trial.
        Circulation. 2000; 102: 611-616
        • Van de Wouwer M.
        • Collen D.
        • Conway E.M.
        Thrombomodulin-protein C-EPCR system: integrated to regulate coagulation and inflammation.
        Arterioscler. Thromb. Vasc. Biol. 2004; 24 (01.ATV.0000134298.25489.92 [pii]): 1374-1383https://doi.org/10.1161/01.ATV.0000134298.25489.92
        • Vestweber D.
        VE-cadherin: the major endothelial adhesion molecule controlling cellular junctions and blood vessel formation.
        Arterioscler. Thromb. Vasc. Biol. 2008; 28 (doi:ATVBAHA.107.158014 [pii]): 223-232https://doi.org/10.1161/ATVBAHA.107.158014
        • Vestweber D.
        • Winderlich M.
        • Cagna G.
        • Nottebaum A.F.
        Cell adhesion dynamics at endothelial junctions: VE-cadherin as a major player.
        Trends Cell Biol. 2009; 19 (doi:S0962-8924(08)00261-4 [pii]): 8-15https://doi.org/10.1016/j.tcb.2008.10.001
        • Watson A.M.
        • Hood S.G.
        • May C.N.
        Mechanisms of sympathetic activation in heart failure.
        Clin. Exp. Pharmacol. Physiol. 2006; 33 (doi:CEP4523 [pii]): 1269-1274https://doi.org/10.1111/j.1440-1681.2006.04523.x
        • Weksler B.B.
        • Gillick M.
        • Pink J.
        Effect of propranolol on platelet function.
        Blood. 1977; 49: 185-196
        • Wood J.P.
        • Ellery P.E.
        • Maroney S.A.
        • Mast A.E.
        Biology of tissue factor pathway inhibitor.
        Blood. 2014; 123 (doi:blood-2013-11-512764 [pii]): 2934-2943https://doi.org/10.1182/blood-2013-11-512764
        • Yamamoto H.
        • Arai T.
        • Ben S.
        • Iguchi K.
        • Hoshino M.
        Expression of galanin and galanin receptor mRNA in skin during the formation of granulation tissue.
        Endocrine. 2011; 40: 400-407https://doi.org/10.1007/s12020-011-9529-3
        • Yokota Y.
        • Kawanishi H.
        • Hayakawa M.
        • Kumaki T.
        • Takarada A.
        • Nakanishi O.
        • Fukuzaki H.
        Cardiac thrombus in dilated cardiomyopathy. Relationship between left ventricular pathophysiology and left ventricular thrombus.
        Jpn. Heart J. 1989; 30: 1-11
        • Yuan H.
        • Deng N.
        • Zhang S.
        • Cao Y.
        • Wang Q.
        • Liu X.
        • Zhang Q.
        The unfolded von Willebrand factor response in bloodstream: the self-association perspective.
        J. Hematol. Oncol. 2012; 5 (doi:1756-8722-5-65 [pii]): 65https://doi.org/10.1186/1756-8722-5-65
        • Zannad F.
        • Stough W.G.
        • Regnault V.
        • Gheorghiade M.
        • Deliargyris E.
        • Gibson C.M.
        • Agewall S.
        • Berkowitz S.D.
        • Burton P.
        • Calvo G.
        • Goldstein S.
        • Verheugt F.W.
        • Koglin J.
        • O'Connor C.M.
        Is thrombosis a contributor to heart failure pathophysiology? Possible mechanisms, therapeutic opportunities, and clinical investigation challenges.
        Int. J. Cardiol. 2013; 167 (doi:S0167-5273(12)01647-6 [pii]): 1772-1782https://doi.org/10.1016/j.ijcard.2012.12.018