title: Endocardial Endothelial Dysfunction Progressively Disrupts Initially Anti then Pro-Thrombotic Pathways in Heart Failure Mice.
abstract: OBJECTIVE
  An experimental model of endocardial thrombosis has not been developed and endocardial endothelial dysfunction in heart failure (HF) is understudied. We sought to determine whether disruption of the endothelial anti-coagulant activated protein C (APC) pathway in CREBA133 HF mice promotes endocardial thrombosis in the acute decompensated phase of the disease, and whether alterations in von Willebrand factor (vWF) secretion from HF endocardium reduces thrombus formation as HF stabilizes.
  
  
  RESULTS
  Echocardiography was used to follow HF development and to detect endocardial thrombi in CREBA133 mice. Endocardial thrombi incidence was confirmed with immunohistochemistry and histology. In early and acute decompensated phases of HF, CREBA133 mice had the highest incidence of endocardial thrombi and these mice also had a shorter tail-bleeding index consistent with a pro-thrombotic milieu. Both APC generation, and expression of receptors that promote APC function (thrombomodulin, endothelial protein C receptor, protein S), were suppressed in the endocardium of acute decompensated HF mice. However, in stable compensated HF mice, an attenuation occurred for vWF protein content and secretion from endocardial endothelial cells, vWF-dependent platelet agglutination (by ristocetin), and thrombin generation on the endocardial surface.
  
  
  CONCLUSIONS
  CREBA133 mice develop HF and endocardial endothelial dysfunction. Attenuation of the anti-coagulant APC pathway promotes endocardial thrombosis in early and acute decompensated phases of HF. However, in stable compensated HF mice, disruptions in endothelial vWF expression and extrusion may actually reduce the incidence of endocardial thrombosis.
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Amanda
authors.initials: A
authors.lastname: Schoner
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Christina
authors.initials: C
authors.lastname: Tyrrell
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Melinda
authors.initials: M
authors.lastname: Wu
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Jill M
authors.initials: JM
authors.lastname: Gelow
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Alicia A
authors.initials: AA
authors.lastname: Hayes
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Jonathan R
authors.initials: JR
authors.lastname: Lindner
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Kent L
authors.initials: KL
authors.lastname: Thornburg
authors.affiliation: Knight Cardiovascular Institute, Oregon Health and Science University, Portland, Oregon, United States of America.
authors.forename: Wohaib
authors.initials: W
authors.lastname: Hasan
mesh_terms: D000818:Animals; D000925:Anticoagulants / Q000737:chemistry; D017362:Cyclic AMP Response Element-Binding Protein / Q000235:genetics; D004195:Disease Models, Animal; D004452:Echocardiography; D004699:Endocardium / Q000378:metabolism*; D042783:Endothelial Cells / Q000166:cytology; D005260:Female; D006331:Heart Diseases / Q000503:physiopathology*; D006333:Heart Failure / Q000503:physiopathology*; D006439:Hemodynamics; D007150:Immunohistochemistry; D008297:Male; D051379:Mice; D008822:Mice, Transgenic; D010641:Phenotype; D010974:Platelet Aggregation; D011486:Protein C / Q000378:metabolism*; D013917:Thrombin / Q000378:metabolism; D013927:Thrombosis / Q000378:metabolism / Q000503:physiopathology*; D014841:von Willebrand Factor / Q000378:metabolism*
chemical_list: D000925:Anticoagulants; C492004:Creb1 protein, mouse; D017362:Cyclic AMP Response Element-Binding Protein; D011486:Protein C; D014841:von Willebrand Factor; D013917:Thrombin