This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Citation Map Services Email this article to a friend Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Request Permissions Citing Articles Citing Articles via Google Scholar Google Scholar Articles by Birks, E. J. Articles by Yacoub, M. H. Search for Related Content PubMed PubMed Citation Articles by Birks, E. J. Articles by Yacoub, M. H. Pubmed/NCBI databases Compound via MeSH Substance via MeSH Medline Plus Health Information Heart Failure Related Collections Contractile function Other heart failure Congestive Apoptosis Gene expression Gene regulation Growth factors/cytokines Heart failure - basic studies Transplantation CV surgery: transplantation, ventricular assistance, cardiomyopathy

(Circulation. 2001;104:I-233.)
© 2001 American Heart Association, Inc.

Thoracic Transplantation and Ventricular Assist Devices

Quantitative Myocardial Cytokine Expression and Activation of the Apoptotic Pathway in Patients Who Require Left Ventricular Assist Devices

Emma J. Birks, MRCP; Najma Latif, PhD; Virginia Owen, PhD; Christopher Bowles, PhD; Leanne E. Felkin, BS; Anthony J. Mullen, BS; Asghar Khaghani, FRCS; Paul J.R. Barton, PhD; Julia M. Polak, DSc; John R. Pepper, FRCS; Nicholas R. Banner, FRCP; Magdi H. Yacoub, FRS, DSc

National Heart and Lung Institute at Imperial College School of Medicine (E.J.B., V.O., C.B., L.E.F., A.J.M., A.K., P.J.R.B., J.R.P., N.R.B., M.H.Y.), Royal Brompton and Harefield Hospital, Harefield, Middlesex; and Royal Postgraduate Medical School at Imperial College School of Medicine (J.M.P.), Hammersmith Hospital, London, UK.

Correspondence to Magdi Yacoub, FRS, Professor of Cardiothoracic Surgery, Heart Science Centre, Royal Brompton and Harefield Hospital, Harefield, Middlesex UB96JH, United Kingdom. E-mail emmabirks{at}hotmail.com

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)- and interleukin (IL)-1ß 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.

Methods and Results— Myocardial and serum samples from 23 patients undergoing LVAD implantation were compared with those from 36 patients undergoing elective heart transplantation. Myocardial TNF- 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- 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-1ß 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-, IL-1ß, and IL-6 and alterations in the apoptotic pathway were found in the myocardium and elevated TNF- 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.

Key Words: heart-assist device • interleukins • heart failure • nitric oxide synthase