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 undergoing LV assist device (LVAD) implantation remain poorly understood. We studied the cytokines tumor necrosis factor (TNF)-alpha and interleukin (IL)-1beta and IL-6 and the terminal stage of the apoptotic pathway in patients with decompensating heart failure who required LVAD support and compared them with patients with less severe heart failure undergoing elective heart transplantation.


RESULTS
Myocardial and serum samples from 23 patients undergoing LVAD implantation were compared with those from 36 patients undergoing elective 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) were elevated in the LVAD patients. Immunocytochemistry demonstrated TNF expression in the myocytes. Serum TNF-alpha was also elevated (12.5+/-1.9 versus 4.0+/-0.4 pg/mL; P<0.0001) in the LVAD patients. IL-6 mRNA (2.57-fold higher; P<0.005) and protein (27.83+/-9.35 versus 4.26+/-1.24 pg/mg protein; 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-1beta mRNA expression was 9.78-fold higher in the LVAD patients (P<0.001). iNOS mRNA expression was similar to that in advanced heart failure patients and was not further elevated in the LVAD patients. Levels of procaspase-9 (8.02+/-0.91 versus 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-1beta, and IL-6 and alterations in the apoptotic pathway were found in the myocardium and elevated TNF-alpha and IL-6 in serum of deteriorating patients who required LVAD support. These occurrences may have therapeutic implications and influence the timing of LVAD insertion.
Birks
E J
EJ
National Heart and Lung Institute at Imperial College School of Medicine, Royal Brompton and Harefield Hospital, Harefield, Middlesex.
Latif
N
N
Owen
V
V
Bowles
C
C
Felkin
L E
LE
Mullen
A J
AJ
Khaghani
A
A
Barton
P J
PJ
Polak
J M
JM
Pepper
J R
JR
Banner
N R
NR
Yacoub
M H
MH
D000293:Adolescent; D000328:Adult; D017209:Apoptosis; D002303:Cardiac Output, Low; D006348:Cardiac Surgical Procedures; D020169:Caspases / Q000378:metabolism; D016207:Cytokines / Q000096:biosynthesis* / Q000097:blood / Q000235:genetics; D018450:Disease Progression; D005260:Female; D006333:Heart Failure / Q000503:physiopathology*; D006353:Heart-Assist Devices; D006801:Humans; D007375:Interleukin-1 / Q000096:biosynthesis / Q000235:genetics; D015850:Interleukin-6 / Q000096:biosynthesis / Q000097:blood / Q000235:genetics; D008297:Male; D008875:Middle Aged; D009206:Myocardium / Q000737:chemistry / Q000378:metabolism*; D019001:Nitric Oxide Synthase / Q000096:biosynthesis / Q000235:genetics; D052247:Nitric Oxide Synthase Type II; D012333:RNA, Messenger / Q000032:analysis / Q000096:biosynthesis; D014409:Tumor Necrosis Factor-alpha / Q000096:biosynthesis / Q000235:genetics; D018487:Ventricular Dysfunction, Left / Q000503:physiopathology* / Q000628:therapy
D016207:Cytokines; D007375:Interleukin-1; D015850:Interleukin-6; D012333:RNA, Messenger; D014409:Tumor Necrosis Factor-alpha; C496319:NOS2 protein, human; D019001:Nitric Oxide Synthase; D052247:Nitric Oxide Synthase Type II; D020169:Caspases