Reversible activation of nuclear factor-kappaB in human end-stage heart failure after left ventricular mechanical support.
OBJECTIVE
Left ventricular assist devices (LVAD) have been used to 'bridge' patients with end-stage heart failure to transplantation. Although several reports have suggested that the native ventricular function recovers after long-term LVAD support, a process called 'reverse remodeling', the underlying biological mechanisms are still unknown. As the transcription factor nuclear factor-kappaB (NF-kappaB) has been shown to be active in the failing human heart, we examined whether its activity is altered under LVAD support, and may thus contribute to the dynamic process of 'reverse remodeling'.


METHODS
The activity of NF-kappaB was studied in 16 patients with end-stage heart failure (eight with dilated cardiomyopathy, six with ischemic heart disease, one with myocarditis, and one with congenital heart disease) before and after LVAD support by immunohistochemistry using an antibody against active NF-kappaB. Gel-shifts for NF-kappaB DNA-binding activity were performed with paired human myocardial tissue from four patients. The mean cardiomyocyte diameter before and after mechanical unloading was measured with an image analyzer system.


RESULTS
15 patients out of 16 showed a significant decrease in the number of NF-kappaB positive cardiomyocyte nuclei after LVAD support in the left ventricular myocardium. The NF-kappaB DNA-binding activity also decreased after LVAD support as measured by gel-shift analysis. While the number of positive cardiomyocytes was significantly higher in the subendocardium than in the subepicardium at the time of LVAD implantation, this difference was no longer present at the time of LVAD explantation. The diameter of cardiomyocytes in the left ventricle decreased significantly as a parameter of structural reverse remodeling.


CONCLUSIONS
LVAD support decreases the extent of NF-kappaB activation in failing human hearts, suggesting that NF-kappaB may be involved in the process of 'reverse remodeling'.
Grabellus
Florian
F
The Gerhard-Domagk-Institute of Pathology, University of Münster, Domagkstrasse 17, 48149 Münster, Germany.
Levkau
Bodo
B
Sokoll
Andrea
A
Welp
Hendryk
H
Schmid
Christof
C
Deng
Mario C
MC
Takeda
Atsushi
A
Breithardt
Günter
G
Baba
Hideo A
HA
D000328:Adult; D001345:Autoradiography; D002311:Cardiomyopathy, Dilated / Q000150:complications / Q000378:metabolism / Q000628:therapy; D004591:Electrophoresis, Polyacrylamide Gel; D024202:Electrophoretic Mobility Shift Assay; D005260:Female; D006333:Heart Failure / Q000209:etiology / Q000378:metabolism* / Q000628:therapy*; D006353:Heart-Assist Devices; D006801:Humans; D008297:Male; D008875:Middle Aged; D017202:Myocardial Ischemia / Q000150:complications / Q000378:metabolism / Q000628:therapy; D009205:Myocarditis / Q000150:complications / Q000378:metabolism / Q000628:therapy; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D016328:NF-kappa B / Q000032:analysis / Q000378:metabolism*; D013771:Tetralogy of Fallot / Q000150:complications / Q000378:metabolism / Q000628:therapy
D016328:NF-kappa B