title: Cardiac resynchronization therapy-induced left ventricular reverse remodelling is associated with reduced plasma annexin A5.
abstract: OBJECTIVE
  Cardiac resynchronization therapy (CRT) diminishes cardiac apoptosis and improves systolic function in heart failure (HF) patients with ventricular dyssynchrony. Plasma annexin A5 (AnxA5), a protein related to cellular damage, is associated with systolic dysfunction. We investigated whether the response to CRT is associated with plasma AnxA5. We also studied AnxA5 overexpression effects in HL-1 cardiomyocytes.
  
  
  RESULTS
  AnxA5 ELISA was performed in plasma from 57 patients with HF and ventricular dyssynchrony at baseline and after 1 year of CRT. Patients were categorized as responders if they presented both a reduction in left ventricular (LV) end-systolic volume index (LVESVi) >10% and an increase in LV ejection fraction (LVEF) >10%. HL-1 cells were transfected with human AnxA5 cDNA, and AnxA5, PKC, Akt, p38MAPK, Bcl-2, mitochondrial integrity, caspase-3, and ATP were assessed. At baseline, an increased plasma AnxA5 level was associated with decreased LVEF and increased LVEDVi values (P < 0.05). No differences in baseline AnxA5 were observed between responders and non-responders. After CRT, AnxA5 decreased (P = 0.001) in responders but remained unchanged in non-responders. Final values of AnxA5 were independently associated with LVEF (r = -0.387, P = 0.003) and LVESVi (r = 0.403, P = 0.004) in all patients. Compared with control cells, AnxA5-transfected cells exhibited AnxA5 overexpression, decreased PKC and Akt and increased p38MAPK and Bcl-2 phosphorylation, loss of mitochondrial integrity, caspase-3 activation, and decreased ATP.
  
  
  CONCLUSIONS
  CRT-induced LV reverse remodelling is associated with reduction in plasma AnxA5. The excess of AnxA5 is detrimental for HL-1 cardiomyocytes. Collectively, these data suggest that the beneficial effects of CRT might be related to an AnxA5 decrease.
authors.affiliation: Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain.
authors.forename: Susana
authors.initials: S
authors.lastname: Ravassa
authors.forename: Ignacio
authors.initials: I
authors.lastname: García-Bolao
authors.forename: Amaia
authors.initials: A
authors.lastname: Zudaire
authors.forename: Alfonso
authors.initials: A
authors.lastname: Macías
authors.forename: Juan J
authors.initials: JJ
authors.lastname: Gavira
authors.forename: Javier
authors.initials: J
authors.lastname: Beaumont
authors.forename: Teresa
authors.initials: T
authors.lastname: Arias
authors.forename: Ana
authors.initials: A
authors.lastname: Huerta
authors.forename: Javier
authors.initials: J
authors.lastname: Díez
mesh_terms: D000255:Adenosine Triphosphate / Q000378:metabolism; D000368:Aged; D000818:Animals; D017304:Annexin A5 / Q000097:blood* / Q000235:genetics; D015415:Biomarkers / Q000097:blood; D058406:Cardiac Resynchronization Therapy; D016022:Case-Control Studies; D053148:Caspase 3 / Q000378:metabolism; D002460:Cell Line; D016009:Chi-Square Distribution; D015536:Down-Regulation; D004797:Enzyme-Linked Immunosorbent Assay; D005260:Female; D006801:Humans; D016014:Linear Models; D008297:Male; D051379:Mice; D008875:Middle Aged; D008929:Mitochondria, Heart / Q000378:metabolism / Q000473:pathology; D032383:Myocytes, Cardiac / Q000378:metabolism / Q000473:pathology; D010766:Phosphorylation; D011493:Protein Kinase C / Q000378:metabolism; D051057:Proto-Oncogene Proteins c-akt / Q000378:metabolism; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000378:metabolism; D013030:Spain; D013318:Stroke Volume; D013997:Time Factors; D014162:Transfection; D016896:Treatment Outcome; D018487:Ventricular Dysfunction, Left / Q000097:blood / Q000473:pathology / Q000503:physiopathology / Q000628:therapy*; D016277:Ventricular Function, Left; D020257:Ventricular Remodeling; D048051:p38 Mitogen-Activated Protein Kinases / Q000378:metabolism
chemical_list: D017304:Annexin A5; D015415:Biomarkers; D019253:Proto-Oncogene Proteins c-bcl-2; D000255:Adenosine Triphosphate; D051057:Proto-Oncogene Proteins c-akt; D011493:Protein Kinase C; D048051:p38 Mitogen-Activated Protein Kinases; C505409:Casp3 protein, mouse; D053148:Caspase 3