Apoptosis, Bcl-2, and proliferating cell nuclear antigen in the failing human heart: observations made after implantation of left ventricular assist device.
BACKGROUND
Heart failure is characterized by progressive left ventricular remodeling, a complex process that results from cell growth and cell death. The quantitative contribution of apoptotic cells toward left ventricular remodeling has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has been responsive to angiotensin-converting enzyme inhibition in experimental heart failure, but the dynamics and responsiveness to chronic left ventricular unloading have not been studied.


RESULTS
We studied 8 patients with severe heart failure before and after chronic left ventricular unloading with a left ventricular assist device (LVAD). Tissue from the left ventricular apex removed at the time of LVAD implantation was examined for apoptosis using the technique of terminal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end-labeling (TUNEL) in 10 patients. These same hearts explanted at the time of cardiac transplantation were then examined for apoptosis after patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients with equally severe heart failure who underwent heart transplantation without the use of an LVAD served as controls. Eight hearts obtained at autopsy approximately 6 hours after death from patients who died of non-cardiovascular disease causes served as non-heart failure controls. Additionally, 6 hearts were examined by immunohistochemistry for the antiapoptotic protein, Bcl-2, and for the repair and/or proliferation marker, proliferating cell nuclear antigen (PCNA), before and after LVAD. Apoptosis was not detected in the tissue sections from the hearts of 8 patients at the time of LVAD implantation. Only 1 of these patients had limited apoptosis (< 1 apoptotic cell/1,000 myocytes) after LVAD insertion. Three of 10 patients with severe heart failure who did not receive an LVAD but underwent transplantation showed limited apoptosis (< 1 apoptotic cell/1,000 myocytes). Likewise, none of the control hearts from patients who died of noncardiovascular disease manifested apoptosis. Six of 6 patients overexpressed Bcl-2 at the time of LVAD insertion. In all these patients, Bcl-2 returned to negligible levels after chronic unloading of the heart. Likewise, PCNA was abundantly expressed in 5 of 6 failing hearts at the time of LVAD implantation and was reduced in 4 of 5 hearts after chronic unloading by LVAD.


CONCLUSIONS
Apoptosis is a rare or inconsistent finding in the failing human heart. Overexpression of such indicators of cellular stress and DNA replication and/or repair as Bcl-2 and PNCA in heart failure may be altered by optimizing left ventricular loading conditions by such mechanical devices as the LVAD.
Francis
G S
GS
Department of Medicine, Fairview University Hospital Medical Center and University of Minnesota Medical School, Minneapolis, USA.
Anwar
F
F
Bank
A J
AJ
Kubo
S H
SH
Jessurun
J
J
D000328:Adult; D017209:Apoptosis / Q000502:physiology*; D015415:Biomarkers / Q000032:analysis; D001707:Biopsy, Needle; D002311:Cardiomyopathy, Dilated / Q000473:pathology / Q000503:physiopathology* / Q000601:surgery*; D018450:Disease Progression; D005260:Female; D016027:Heart Transplantation; D006353:Heart-Assist Devices; D006801:Humans; D007150:Immunohistochemistry; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic / Q000379:methods; D018809:Proliferating Cell Nuclear Antigen / Q000032:analysis*; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000502:physiology*; D012016:Reference Values; D012720:Severity of Illness Index; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology / Q000601:surgery*
D015415:Biomarkers; D018809:Proliferating Cell Nuclear Antigen; D019253:Proto-Oncogene Proteins c-bcl-2