Cardiac resynchronization therapy-induced left ventricular reverse remodelling is associated with reduced plasma annexin A5.
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.
Ravassa
Susana
S
Division of Cardiovascular Sciences, Centre for Applied Medical Research, University of Navarra, Avda. Pío XII 55, 31008 Pamplona, Spain.
García-Bolao
Ignacio
I
Zudaire
Amaia
A
Macías
Alfonso
A
Gavira
Juan J
JJ
Beaumont
Javier
J
Arias
Teresa
T
Huerta
Ana
A
Díez
Javier
J
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
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