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 r emodeling has varied widely in tissue removed from cardiomyopathic hearts. Apoptosis has been responsive to angiotensin-converting enzyme inhibition i n experimental heart failure, but the dynamics and responsiveness to chroni c left ventricular unloading have not been studied. Methods and Results: We studied 8 patients with severe heart failure before and after chronic left ventricular unloading with a left ventricular assis t device (LVAD). Tissue from the left ventricular apex removed at the time of LVAD implantation was examined for apoptosis using the technique of term inal deoxynucleotidyl transferase deoxyuridine triphosphate-biotin nick end -labeling (TUNEL) in 10 patients. These same hearts explanted at the time o f cardiac transplantation were then examined for apoptosis Lifter patients had been on the LVAD for 99 +/- 20 (SEM) days. An additional 10 patients wi th equally severe heart failure who underwent heart transplantation without the use of an LVAD served as controls. Eight hearts obtained at autopsy ap proximately 6 hours after death from patients who died of non-cardiovascula r disease causes served us non-heart failure controls. Additionally, 6 hear ts were examined by immunohistochemistry for the antiapoptotic protein, Bcl -2, and for the repair and/or proliferation marker, proliferating cell nucl ear antigen (PCNA), before and after LVAD. Apoptosis was not detected in th e tissue sections from the hearts of 8 patients at the time of LVAD implant ation. Only 1 of these patients had limited apoptosis (1 apoptotic cell/1,0 00 myocytes) after LVAD insertion. Three of 10 patients with severe heart f ailure who did not receive an LVAD but underwent transplantation showed lim ited apoptosis (< 1 apoptotic cell/1,000 myocytes). Likewise, none of the c ontrol hearts from patients who died of noncardiovascular disease manifeste d apoptosis. Six of 6 patients overexpressed Bcl-2 at the rime of LVAD inse rtion. In all these patients, Bcl-2 returned to negligible levels after chr onic unloading of the heart. Likewise, PCNA was abundantly expressed in 5 o f 6 failing hearts at the time of LVAD implantation and was reduced in 4 of 5 hearts after chronic unloading by LVAD. Conclusion: Apoptosis is a rare or inconsistent finding in the failing huma n heart. Overexpression of such indicators of cellular stress and DNA repli cation and/or repair as Bcl-2 and PNCA in heart failure may be altered by o ptimizing left ventricular loading conditions by such mechanical devices as the LVAD.