Quantitative myocardial cytokine expression and activation of the apoptotic pathway in patients who require left ventricular assist devices

Background-Molecular mechanisms underlying the deterioration of patients un dergoing LV assist device (LVAD) implantation remain poorly understood. We studied the cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL )-1 beta and IL-6 and the terminal stage of the apoptotic pathway in patien ts with decompensating heart failure who required LVAD support and compared them with patients with less severe heart failure undergoing elective hear t transplantation. Methods and Results-Myocardial and serum samples from 23 patients undergoin g LVAD implantation were compared with those from 36 patients undergoing el ective heart transplantation. Myocardial TNF-alpha mRNA (1.71-fold; P <0.05 ) and protein (3.43 +/-0.19 versus 2.95 +/-0.10 pg/mg protein; P <0.05) wer e elevated in the LVAD patients. Immunocytochemistry demonstrated TNF expre ssion in the myocytes. Serum TNF-alpha was also elevated (12.5 +/-1.9 versu s 4.0 +/-0.4 pg/mL; P <0.0001) in the LVAD patients. IL-6 mRNA (2.57-fold h igher; P <0.005) and protein (27.83 +/-9.35 versus 4.26 +/-1.24 pg/mg prote in; P <0.001) were higher in the LVAD candidates, as was serum IL-6 (79.3 /- 23.6 versus 7.1 +/-1.6 pg/mL; P <0.0001). Interleukin-1 beta mRNA expres sion was 9.78-fold higher in the LVAD patients (P <0.001). NOS mRNA express ion was similar to that in advanced heart failure patients and was not furt her elevated in the LVAD patients. Levels of procaspase-9 (8.02 +/-0.91 ver sus 6.16 +/-0.43 oligodeoxynucleotide [OD] units; P <0.01), cleaved caspase -9 (10.02 +/-1.0 versus 7.34 +/-0.40 OD units; P <0.05), intact and spliced DFF-45 (4.58 +/-0.75 versus 2.84 +/-0.23 OD units; P <0.05) were raised in LVAD patients, but caspase-3 and human nuclease CPAN were not. Conclusions-Elevated TNF-alpha, IL-1 beta, and IL-6 and alterations in the apoptotic pathway were found in the myocardium and elevated TNF-alpha and I L-6 in serum of deteriorating patients who required LVAD support. These occ urrences may have therapeutic implications and influence the timing of LVAD insertion.